ClinVar Miner

Submissions for variant Single allele

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Total submissions: 1772
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV001843396 SCV002102526 uncertain significance Monogenic diabetes 2022-02-17 reviewed by expert panel curation The c.-287G>A variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This region is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, the c.-287G>A variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low doses of sulfonylurea) (PP4_Moderate; PMID: 23348805). In summary, c.-287G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_supporting, PM2_Supporting, PP4_Moderate.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV002221974 SCV002499284 pathogenic Familial cancer of breast 2022-03-09 reviewed by expert panel curation The ATM EX27del variant is absent from gnomAD SVs v2.1 (PM2_supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant is absent from gnomAD SVs v2.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen RCV002221975 SCV002499295 likely pathogenic Familial cancer of breast 2022-03-09 reviewed by expert panel curation The ATM EX16_60dup variant is presumed to be a tandem duplication and results in the disruption of a critical domain (PVS1_Strong). The variant is absent in the GnomAD v2.1.1 cohort (PM2_Supporting). This variant has been observed in a compound heterozygous state (confirmed) in one individual with Ataxia-Telangiectasia (PM3, GTR Lab ID: 500031). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002222111 SCV002499532 uncertain significance Monogenic diabetes 2022-04-12 reviewed by expert panel curation The c.-286_-285del variant in the HNF1 homeobox A gene, HNF1A, is located in the promoter of NM_000545.8. This region is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50%); however, HNF4A was not tested (internal lab contributors), and therefore PP4 was not applied. In summary, c.-286_-285del meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1_supporting, PM2_Supporting.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel RCV003149088 SCV003836617 pathogenic Familial adenomatous polyposis 1 2023-02-26 reviewed by expert panel curation The NC_000005.10:g.(?_112707312)_(112707902_?)del variant in APC is a gross deletion in the 5' upstream region of APC impacting promoter 1B. This variant has been reported in many families with FAP, resulting in more than 16 phenotype points (PS4_VeryStrong; Ambry Genetics, Invitae, GeneDx, Bonn internal data, PMIDs 18982352, 26213617, 25941542, 24946964, 23725351, 27217144, 18433509, 28791770, 25243319). The variant has been reported to segregate with FAP in many members (more than 7) of multiple families (PP1_Strong; PMIDs 18982352, 25941542, 23725351, 18433509, 28791770, 25243319). This variant has also been identified as a de novo occurrence with unconfirmed parental relationships in one individual with FAP (PM6; PMID 27217144). RT-PCR, allele-specific PCR and quantitative RT-PCR assays show monoallelic expression of various SNPs and severely reduced RNA expression of APC transcripts supporting an allele silencing effect for this deletion (PS3_VeryStrong; PMIDs 18982352, 25941542, 24946964, 27217144, 18433509, 28791770 25243319). This variant is absent from gnomAD SVs v2.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3_VeryStrong, PS4_VeryStrong, PP1_Strong, PM6, and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel RCV003149089 SCV003836618 likely pathogenic Familial adenomatous polyposis 1 2023-02-26 reviewed by expert panel curation The NC_000005.10:g.(?_112775619)_(112801393_?)del variant in APC is a deletion predicted to result in an out-of-frame deletion of exons 5-8 in a gene in which loss-of-function is an established disease (PVS1). This variant is absent from gnomAD SVs v2.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as of Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003326070 SCV004032066 uncertain significance Monogenic diabetes 2023-08-18 reviewed by expert panel curation The c.-181G>T p.(?) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is located within the promoter region of HNF1A/HNF1B binding sites, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability could not be calculated due to missing information, and PP4 was not met. In addition, the c.-181G>A p.(?) variant at the same nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1_Supporting). In summary, c.-181G>T p.(?) meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PS1_Supporting.
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448645 SCV004176242 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation NC_000021.9:g.(?_34787801)_(35048958_?)del results in the complete absence of the coding sequence of the RUNX1 gene and therefore the absence of all functional domains. The deletion is not present in population databases. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM1 and PM2_supporting.
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448650 SCV004176271 pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation This variant is a frameshift variant resulting in exon deletion (PVS1). This variant is completely absent from population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting.
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003494034 SCV004242374 uncertain significance Monogenic diabetes 2024-01-28 reviewed by expert panel curation The c.-183T>C variant in the hepatic nuclear factor 4-alpha gene, HNF4A, is a single nucleotide variant in the promoter region of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.-183T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP4, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029934 SCV000052589 likely pathogenic Maturity-onset diabetes of the young type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171455 SCV000221654 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171473 SCV000221672 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171474 SCV000221673 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171479 SCV000221678 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171483 SCV000221682 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171488 SCV000221687 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171489 SCV000221688 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171500 SCV000221699 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171506 SCV000221705 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171508 SCV000221707 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171511 SCV000221710 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171535 SCV000221734 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171536 SCV000221735 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171540 SCV000221739 likely pathogenic not provided criteria provided, single submitter research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre RCV000171541 SCV000221740 likely pathogenic not provided criteria provided, single submitter research
Eurofins Ntd Llc (ga) RCV000178410 SCV000230484 uncertain significance not provided 2014-10-03 criteria provided, single submitter clinical testing
Dobyns Lab, Seattle Children's Research Institute RCV000191932 SCV000246158 pathogenic Ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome 2014-11-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210429 SCV000256763 pathogenic Immunodeficiency 104 2014-07-16 criteria provided, single submitter research segregates with the phenotype in an affected family
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust RCV000210049 SCV000257461 pathogenic Combined immunodeficiency due to DOCK8 deficiency 2015-08-25 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203452 SCV000258328 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203475 SCV000258329 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203458 SCV000258331 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203474 SCV000258332 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203463 SCV000258334 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203486 SCV000258335 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203462 SCV000258337 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203484 SCV000258338 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203447 SCV000258339 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203468 SCV000258340 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203483 SCV000258341 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203451 SCV000258342 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203466 SCV000258343 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203489 SCV000258344 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203456 SCV000258345 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203472 SCV000258346 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203499 SCV000258350 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203453 SCV000258351 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203481 SCV000258355 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203495 SCV000258356 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203464 SCV000258357 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203480 SCV000258358 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203449 SCV000258359 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203485 SCV000258361 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203448 SCV000258362 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203469 SCV000258363 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203491 SCV000258364 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203459 SCV000258365 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203467 SCV000258366 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203490 SCV000258367 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203473 SCV000258369 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203488 SCV000258370 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203492 SCV000258373 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203498 SCV000258376 pathogenic Hereditary spastic paraplegia 4 2014-08-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203289 SCV000258388 likely pathogenic Bosch-Boonstra-Schaaf optic atrophy syndrome 2014-02-06 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000203294 SCV000258389 likely pathogenic Bosch-Boonstra-Schaaf optic atrophy syndrome 2014-02-06 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210394 SCV000258457 pathogenic Chromosome 17p13.1 deletion syndrome 2015-11-06 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210404 SCV000258458 pathogenic Chromosome 17p13.1 deletion syndrome 2015-11-06 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210387 SCV000258459 pathogenic Chromosome 17p13.1 deletion syndrome 2015-11-06 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210397 SCV000258460 pathogenic Chromosome 17p13.1 deletion syndrome 2015-11-06 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000455872 SCV000264470 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000454803 SCV000264471 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000455222 SCV000264472 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000455812 SCV000264473 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000454759 SCV000264474 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000477897 SCV000264477 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000454618 SCV000264478 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000477751 SCV000264479 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Elsea Laboratory, Baylor College of Medicine RCV000455254 SCV000264480 pathogenic MBD5 associated neurodevelopmental disorder 2012-10-01 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000210384 SCV000266398 pathogenic Immunodeficiency 23 2014-07-03 criteria provided, single submitter research segregates with the phenotype in an affected family
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine RCV000210452 SCV000266536 pathogenic Loeys-Dietz syndrome 4 criteria provided, single submitter research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine RCV000210464 SCV000266537 pathogenic Loeys-Dietz syndrome 4 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000488894 SCV000267603 pathogenic not provided 2016-04-26 criteria provided, single submitter research compound heterozygous deletion identified in patient with congenital cataract, seizures, cerebellar and brainstem hypoplasia
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000488906 SCV000267604 pathogenic not provided 2016-04-26 criteria provided, single submitter research compound heterozygous deletion identified in patient with congenital cataract, seizures, cerebellar and brainstem hypoplasia
Geschwind lab, University of California Los Angeles RCV000225569 SCV000282087 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225670 SCV000282088 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225439 SCV000282089 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225548 SCV000282090 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225681 SCV000282091 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225457 SCV000282092 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225542 SCV000282093 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225679 SCV000282094 likely pathogenic Autism spectrum disorder criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225451 SCV000282095 likely pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225595 SCV000282096 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225368 SCV000282097 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225469 SCV000282098 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225572 SCV000282099 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225402 SCV000282100 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225508 SCV000282101 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225645 SCV000282102 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225379 SCV000282103 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225522 SCV000282104 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225625 SCV000282105 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research The CNV is pathogenic but didn’t cause the disorder in this individual due to incomplete penetrance.
Geschwind lab, University of California Los Angeles RCV000225436 SCV000282106 likely pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225546 SCV000282107 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225619 SCV000282108 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225434 SCV000282109 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225539 SCV000282110 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225676 SCV000282111 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225448 SCV000282112 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225559 SCV000282113 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225649 SCV000282114 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225471 SCV000282115 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225587 SCV000282116 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225404 SCV000282117 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225463 SCV000282118 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225607 SCV000282119 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225377 SCV000282120 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225525 SCV000282121 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225621 SCV000282122 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225398 SCV000282123 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225516 SCV000282124 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225620 SCV000282125 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225430 SCV000282126 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225540 SCV000282127 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225633 SCV000282128 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225410 SCV000282129 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225556 SCV000282130 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225671 SCV000282131 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225446 SCV000282132 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225549 SCV000282133 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225687 SCV000282134 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225459 SCV000282135 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225604 SCV000282136 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225659 SCV000282137 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research The CNV is pathogenic but didn’t cause the disorder in this individual due to incomplete penetrance.
Geschwind lab, University of California Los Angeles RCV000225479 SCV000282138 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225596 SCV000282139 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225373 SCV000282140 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225512 SCV000282141 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225576 SCV000282142 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225386 SCV000282143 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225492 SCV000282144 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225630 SCV000282145 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225408 SCV000282146 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research The CNV is pathogenic but didn’t cause the disorder in this individual due to incomplete penetrance.
Geschwind lab, University of California Los Angeles RCV000225528 SCV000282147 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research The CNV is pathogenic but didn’t cause the disorder in this individual due to incomplete penetrance.
Geschwind lab, University of California Los Angeles RCV000225629 SCV000282148 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225442 SCV000282149 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225550 SCV000282150 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225685 SCV000282151 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225421 SCV000282158 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225563 SCV000282159 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225663 SCV000282160 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225455 SCV000282161 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225599 SCV000282162 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225655 SCV000282163 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225476 SCV000282164 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225574 SCV000282165 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225391 SCV000282166 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225489 SCV000282167 likely pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225609 SCV000282168 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225382 SCV000282169 pathogenic Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225526 SCV000282170 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225626 SCV000282171 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225438 SCV000282172 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225497 SCV000282173 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225644 SCV000282174 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225420 SCV000282175 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225541 SCV000282176 association Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225635 SCV000282177 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225416 SCV000282178 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225562 SCV000282179 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225652 SCV000282180 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225468 SCV000282181 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225537 SCV000282182 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225674 SCV000282183 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225465 SCV000282184 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225606 SCV000282185 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225383 SCV000282186 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Geschwind lab, University of California Los Angeles RCV000225486 SCV000282187 uncertain significance Autism spectrum disorder 2015-10-12 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000234859 SCV000291989 pathogenic Syndromic X-linked intellectual disability Lubs type 2015-03-13 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000234878 SCV000291990 pathogenic Syndromic X-linked intellectual disability Lubs type 2015-03-13 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000234882 SCV000291993 pathogenic Blepharophimosis; Absent speech; Thick lower lip vermilion; Thin upper lip vermilion; Long eyelashes; Intellectual disability, moderate 2014-03-27 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235056 SCV000292303 pathogenic Spondylocostal dysostosis 5 2015-11-15 criteria provided, single submitter research This variant was observed in 17 individuals with vertebral malformations and rib abnormalities. In each case it was found to be in trans with a high-risk TBX6 haplotype, T-C-A (rs2289292, rs3809624, rs3809627).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235073 SCV000292310 likely pathogenic Epilepsy, progressive myoclonic, 1B 2015-09-17 criteria provided, single submitter research This deletion was identified in a patient with seizures and neuropathy. There was no evidence of the deletion in parental samples, indicating that the CNV likely arose de novo in the patient. There are reports in the literature of heterozygous mutations in PRICKLE1 in patients with seizures (PMID: 21276947). The patient also has a de novo heterozygous variant in MFN2.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235046 SCV000292314 uncertain significance Peripheral neuropathy 2015-09-17 criteria provided, single submitter research This deletion was identified in an individual with peripheral neuropathy. There is no association in the literature between KIF24 and neuropathy. This individual also has an MFN2 pathogenic variant.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235057 SCV000292315 likely pathogenic Charcot-Marie-Tooth disease type 1B 2015-09-17 criteria provided, single submitter research This deletion was identified in an individual with peripheral neuropathy.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235080 SCV000292316 pathogenic Smith-Magenis syndrome 2015-11-12 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235042 SCV000292317 pathogenic Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 2015-11-12 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235066 SCV000292340 pathogenic X-linked acrogigantism due to Xq26 microduplication 2015-11-12 criteria provided, single submitter research XLAG is a newly described condition, which is rare and the phenotype is incompletely characterized, particularly in terms of clinical responses to treatment. The aim of this study was to clinically characterize X-LAG in an expanded cohort of 18 affected patients.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000235052 SCV000292363 pathogenic PHARC syndrome 2015-08-18 criteria provided, single submitter research This copy number variation has been previously reported as disease-causing and was identified in a family with PHARC.
Eurofins Ntd Llc (ga) RCV000385479 SCV000330986 likely benign not specified 2015-09-29 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000299568 SCV000331783 uncertain significance not provided 2016-01-28 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000318149 SCV000334678 uncertain significance not provided 2015-08-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000273531 SCV000335444 uncertain significance not provided 2015-09-15 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000337319 SCV000336997 likely pathogenic not provided 2015-10-26 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000400412 SCV000340516 pathogenic not provided 2016-03-18 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000349357 SCV000340741 uncertain significance not provided 2016-04-15 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000309059 SCV000340769 likely benign not specified 2016-04-03 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000299738 SCV000341602 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000308584 SCV000341702 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000315072 SCV000341808 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000278127 SCV000341988 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000340414 SCV000343758 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000292125 SCV000344235 benign not specified 2016-08-08 criteria provided, single submitter clinical testing
Robarts Research Institute, Western University RCV000408813 SCV000484813 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000414385 SCV000490158 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000413848 SCV000490160 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000414056 SCV000490166 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000414007 SCV000490172 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000413482 SCV000490174 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000414360 SCV000490175 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000415472 SCV000493131 likely pathogenic X-linked acrogigantism due to Xq26 microduplication 2016-01-01 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000415468 SCV000493132 likely pathogenic X-linked acrogigantism due to Xq26 microduplication 2016-01-01 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000415470 SCV000493133 likely pathogenic X-linked acrogigantism due to Xq26 microduplication 2016-01-01 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000415471 SCV000493134 likely pathogenic X-linked acrogigantism due to Xq26 microduplication 2016-01-01 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000520873 SCV000494285 pathogenic Prader-Willi syndrome criteria provided, single submitter research This deletion of 15q11q13 is de novo and represents the typical recurrent type 2 deletion.
Neurogenetics Laboratory - MEYER, AOU Meyer RCV000416971 SCV000494569 pathogenic Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454279 SCV000538074 pathogenic Hypoparathyroidism-retardation-dysmorphism syndrome 2016-04-08 criteria provided, single submitter clinical testing The heterozygous deletion of exons 3 and 4 that was detected by a single copy loss of 16 oligonucleotide probes spanning approximately 7,842 bp in the TBCE gene, Hg19 chr1: g.(235575072_235577473)_(235582954_235583424)del (NM_ 003193) has not been previously reported in an affected individual. TBCE is the only gene implicated in HRD and suggests that this disorder has a single gene etiology. The out-of-frame deletion leads to premature protein truncation. Deletions and truncation variants are common mechanisms of disease; the c.155-166del12 in the TBCE gene is considered the most common pathogenic variant for this condition (Kerkeni E et al., 2015). Based on these criteria, this CNV is interpreted at pathogenic. We have confirmed the findings using a custom exon-centric microarray.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454326 SCV000538075 likely pathogenic Infantile nephronophthisis 2016-04-19 criteria provided, single submitter clinical testing A heterozygous deletion of the 5’-UTR and exons 1 and 2 was detected by a single copy loss of 117 oligonucleotide probes spanning approximately 139,883 bp in the INVS gene, Hg19 chr9: g.( 102814578_102860399)_(102967421_102968415)del (NM_ 001318381). This variant has not been previously reported in an affected individual. Exon 2, which is deleted in this CNV, contains the start codon, implying a loss of the initiation codon. Several frameshift and nonsense variants in this gene have been described in affected individuals (Tory K et al., 2009) suggesting that loss of functions is mechanism of disease. Based on these criteria, this CNV is interpreted at Likely Pathogenic. We have confirmed the findings using a custom exon-centric microarray.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454211 SCV000538076 likely pathogenic Fanconi anemia complementation group A 2016-04-01 criteria provided, single submitter clinical testing The c.1627-?_2778+?del deletion in the FANCA gene is novel, however, similar sized deletions in the same genomic vicinity have been previously reported as pathogenic (deletion of exons 18-25: Moghrabi et al. 2009) (deletion of exons 21-29: Castella et al., 2011). Mutations in the coding region of FANCA account for approximately 60-70% of Fanconi Anemia Complementation Group A (FA-A) patients, and approximately 10% of pathogenic mutations are large, multi-exonic deletions (Castella et al., 2011). This deletion encompasses amino acids 543-926 in the FANCA protein, and removes a portion of the BRCA-interacting region (amino acids 740-1083) as well as three important phosphoserines (amino acids 849, 850 and 858) (Folias et al., 2002). In addition, this deletion also disrupts a known nuclear export sequence (amino acids 860-880), which would effectively abolish protein transport from the nucleus to the cytoplasm (Ferrer et al., 2005). Therefore, this novel 11-exon deletion is expected to severely truncate the FANCA protein and compromise its function. The collective evidence supports the classification of the c.1627-?_2778+?del as a recessive likely pathogenic variant for Fanconi Anemia, Complementation Group A.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454303 SCV000538077 likely pathogenic Fanconi anemia complementation group A 2016-04-01 criteria provided, single submitter clinical testing The c.1627-?_2778+?del deletion in the FANCA gene is novel, however, similar sized deletions in the same genomic vicinity have been previously reported as pathogenic (deletion of exons 18-25: Moghrabi et al. 2009) (deletion of exons 21-29: Castella et al., 2011). Mutations in the coding region of FANCA account for approximately 60-70% of Fanconi Anemia Complementation Group A (FA-A) patients, and approximately 10% of pathogenic mutations are large, multi-exonic deletions (Castella et al., 2011). This deletion encompasses amino acids 543-926 in the FANCA protein, and removes a portion of the BRCA-interacting region (amino acids 740-1083) as well as three important phosphoserines (amino acids 849, 850 and 858) (Folias et al., 2002). In addition, this deletion also disrupts a known nuclear export sequence (amino acids 860-880), which would effectively abolish protein transport from the nucleus to the cytoplasm (Ferrer et al., 2005). Therefore, this novel 11-exon deletion is expected to severely truncate the FANCA protein and compromise its function. The collective evidence supports the classification of the c.1627-?_2778+?del as a recessive likely pathogenic variant for Fanconi Anemia, Complementation Group A.
Herman Laboratory, Nationwide Children's Hospital RCV000490618 SCV000579289 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Yang An-Suei Laboratory, Academia Sinica RCV000504607 SCV000583426 pathogenic Breast neoplasm criteria provided, single submitter clinical testing
Counsyl RCV000499484 SCV000590824 pathogenic alpha Thalassemia 2015-01-14 criteria provided, single submitter clinical testing -α3.7 is classified as an alpha+ mutation.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500763 SCV000590971 pathogenic Hereditary breast ovarian cancer syndrome 2012-07-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000502731 SCV000590975 uncertain significance not specified criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500209 SCV000590979 pathogenic Hereditary breast ovarian cancer syndrome 2016-10-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000504485 SCV000590987 pathogenic Lynch syndrome 2016-02-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000503082 SCV000590992 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000499720 SCV000590993 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000499564 SCV000590996 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000501388 SCV000590997 pathogenic Lynch syndrome 2015-05-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000503363 SCV000591001 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500604 SCV000591002 pathogenic Lynch syndrome 2014-01-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000502402 SCV000591003 pathogenic Lynch syndrome 2013-01-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000504163 SCV000591004 likely pathogenic Lynch syndrome 2016-08-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500987 SCV000591008 pathogenic Autosomal recessive polycystic kidney disease 2016-07-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000504539 SCV000591010 pathogenic Autosomal recessive polycystic kidney disease 2016-07-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000500855 SCV000591011 likely pathogenic Lynch syndrome 2014-12-11 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000500418 SCV000598154 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2016-08-04 criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505253 SCV000599309 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505214 SCV000599316 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505243 SCV000599317 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505182 SCV000599318 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505219 SCV000599319 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505246 SCV000599320 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000505401 SCV000599662 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2013-11-06 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000505435 SCV000599703 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2017-08-31 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000506461 SCV000605722 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-01-25 criteria provided, single submitter clinical testing Heterozygous deletion of exon 10 (also known as exon 11)
Fundacion Hipercolesterolemia Familiar RCV000509444 SCV000607397 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000509098 SCV000607398 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000509204 SCV000607427 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000509145 SCV000607447 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000509345 SCV000607700 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000509291 SCV000607711 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000548818 SCV000623513 uncertain significance Hypertrophic cardiomyopathy 2018-06-28 criteria provided, single submitter clinical testing A gross duplication of the genomic region encompassing the full coding sequence of the TNNI3 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals with a TNNI3-related disease. In summary, the exact genomic location of this variant is unknown and the effect of this whole TNNI3 gene duplication is unknown. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000531596 SCV000624563 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-04-11 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 1-4 of the MSH2 gene. If EPCAM has been tested and no copy number events are reported for it, then the 5' boundary of this event lies between the EPCAM and MSH2 genes. If EPCAM has not been tested, the 5' end of this event is unknown as it extends beyond the assayed region of this test. The 3' boundary is likely confined to intron 4 of the MSH2 gene. This duplication has not been reported in the literature in individuals with an MSH2-related disease. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on MSH2 protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000544514 SCV000624570 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-03-29 criteria provided, single submitter clinical testing This variant results in a copy number gain of the genomic region encompassing exons 5-7 of the MSH2 gene. While the exact position of this variant cannot be determined from this data, sub-genic copy number gains are generally in tandem (PMID: 25640679) and may result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for MSH2 duplications of exons 5-7 (Variation ID: 218047). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Invitae RCV000542078 SCV000624598 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-02-13 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 6-14 of the PMS2 gene. While the exact position of the duplicated exons cannot be determined from this data, the duplicated copy of this region is likely in tandem and in-frame, therefore preserving the integrity of the reading frame. This variant has not been reported in the literature in individuals with a PMS2-related disease. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on PMS2 protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000546533 SCV000626134 uncertain significance Fanconi anemia 2017-06-23 criteria provided, single submitter clinical testing A gross duplication of the genomic region encompassing the full coding sequence of the FANCG gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals with a FANCG-related disease. The exact genomic location of this variant is unknown. In summary, this variant has uncertain impact on FANCG function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000557921 SCV000629385 uncertain significance Spastic paraplegia 2017-03-21 criteria provided, single submitter clinical testing A gross duplication of the genomic region encompassing the full coding sequence of the HSPD1 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals with a HSPD1-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on HSPD1 protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000550770 SCV000630741 uncertain significance Hereditary pancreatitis 2017-07-07 criteria provided, single submitter clinical testing A gross duplication of the genomic region encompassing the full coding sequence of the SPINK1 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. This variant has not been reported in the literature in individuals with SPINK1-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000554640 SCV000631437 uncertain significance Ehlers-Danlos syndrome, classic type 2017-02-12 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 8-54 of the COL5A2 gene. The 5' boundary is likely confined to intron 7. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes . As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. Duplications of exons 8-54  sequence have not been reported in the literature in individuals with a COL5A2-related disease. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on COL5A2 protein function has not been established. Therefore, it has been classified as a Variant of Unknown Significance.
Invitae RCV000527946 SCV000632906 likely pathogenic Familial cancer of breast 2017-11-03 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 2-3 of the BARD1 gene. While the exact position of the duplicated exons cannot be determined from this data, sub-genic duplications are generally in tandem (PMID: 25640679) and may result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BARD1-related disease. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Invitae RCV000557636 SCV000635101 likely pathogenic Hereditary breast ovarian cancer syndrome 2017-03-21 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 12-13 of the BRCA2 gene. While the exact position of the duplicated exons cannot be determined from this data, the duplicated copy of this region is likely in tandem and may result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). In summary, sub-genic duplications are generally in tandem (PMID: 25640679), and result in an absent or disrupted protein. However, the exact location of this duplication has not been confirmed. Therefore, it has been classified as Likely Pathogenic.
Invitae RCV000545391 SCV000636113 benign Nephronophthisis 2017-02-10 criteria provided, single submitter clinical testing
Invitae RCV000534213 SCV000638448 uncertain significance Neuronopathy, distal hereditary motor, type 7A; Congenital myasthenic syndrome 20 2017-07-05 criteria provided, single submitter clinical testing A gross duplication of the genomic region encompassing the full coding sequence of the SLC5A7 gene has been identified. The boundaries of this event are unknown as the duplication extends beyond the assayed region for this gene and therefore may encompass additional genes. As the precise location of this duplication is unknown, it may be in tandem or it may be located elsewhere in the genome. This duplication has not been reported in the literature in individuals with SLC5A7-related disease. Experimental studies are not available for this duplication and the functional significance of an additional copy of this gene is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000528877 SCV000638530 uncertain significance Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9 2016-09-23 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 38 to 46 of the KIF1A gene. The 5' boundary is likely confined to intron 37. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals with a KIF1A-related disease, and its frequency in the general population is not known. In summary, because the exact 3' boundary of this variant has not been determined, and whether this duplication occurs in tandem is not known, the impact of this duplication on KIF1A protein function can not be established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000534639 SCV000638531 benign Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9 2018-01-03 criteria provided, single submitter clinical testing
Invitae RCV000543941 SCV000646080 uncertain significance Progressive familial heart block type IB 2018-01-04 criteria provided, single submitter clinical testing
Invitae RCV000534711 SCV000647150 likely pathogenic Familial adenomatous polyposis 1 2017-02-17 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 2-4 of the APC gene. The 5' end of this event is likely confined to intron 1 of the APC gene. The 3' boundary is likely confined to intron 4 of the APC gene. While the exact position of the duplicated exons cannot be determined from this data, the duplicated copy of this region is likely in tandem and may result in an absent or disrupted protein product. While this particular duplication has not been reported in the literature, loss-of-function variants including gross alterations in APC are known to be pathogenic (PMID: 23159591). In summary, sub-genic duplications are generally in tandem (PMID: 25640679), and result in an absent or disrupted protein. However, the exact location of this duplication has not been confirmed. Therefore, it has been classified as Likely Pathogenic.
Invitae RCV000548052 SCV000648588 uncertain significance Neuroblastoma, susceptibility to, 3 2017-04-10 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 5 to 29 of the ALK gene. The 5' boundary is likely confined to intron 4. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals with an ALK-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on ALK protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000547325 SCV000650689 uncertain significance Interstitial lung disease 2; Dyskeratosis congenita, autosomal dominant 2 2017-03-30 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 7-16 of the TERT gene. The 5' boundary is likely confined to intron 6. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. This gross duplication has not been reported in the literature in an individual with TERT-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on TERT protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance
Invitae RCV000527830 SCV000650882 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2017-01-24 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exon 47 of the FLNC gene. While the exact position of the duplicated exon cannot be determined from this data, the duplicated copy of this region is likely in tandem and in-frame, therefore preserving the integrity of the reading frame. This variant has not been reported in the literature in an individual with a FLNC-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the exact genomic location of this variant is unknown and the impact of this duplication on FLNC protein function has not been established. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000552282 SCV000652857 uncertain significance Joubert syndrome 20; Meckel syndrome, type 11 2017-06-07 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 4-6 of the TMEM231 gene. The 5' boundary is likely confined to intron 3. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. The exact genomic location of this variant is unknown. Gross duplications have not been reported in the literature in individuals with a TMEM231-related disease. In summary, this variant has uncertain impact on TMEM231 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV000558514 SCV000658808 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-01-19 criteria provided, single submitter clinical testing This variant is a gross duplication of the genomic region encompassing exons 6-9 of the SMAD3 gene. The 5' boundary is likely confined to intron 5. The 3' end of this event is unknown as it extends beyond the assayed region for this gene and therefore may encompass additional genes. This variant has not been reported in the literature in individuals with SMAD3-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000677251 SCV000681429 pathogenic Optic nerve hypoplasia criteria provided, single submitter research SOX5 previously described in Lamb-Schaffer syndrome that sometimes involves optic nerve hypoplasia. This individual also has intellectual disability and heart defects, also reported in Lamb-Schaffer syndrome. Similar deletions of SOX5 causing the same phenotype have been reported, PMID 22290657.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000585924 SCV000693907 pathogenic Glycogen storage disease, type II 2017-06-25 criteria provided, single submitter research PVS1: Identified truncating variant in compound heterozygote with common promoter pathogenic variant. Previously reported in 2 patients in the literature with adult onset GSDII. PM2: Absent from gnomAD (well covered) and PM3: 3 compound heterozygotes with GSDII, including 2 in literature (PMID: 17616415).
Eurofins Ntd Llc (ga) RCV000594755 SCV000703106 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000592422 SCV000703422 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000593500 SCV000704742 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000597577 SCV000706542 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000597921 SCV000707424 uncertain significance not provided 2017-03-30 criteria provided, single submitter clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000624863 SCV000740317 pathogenic Hereditary spherocytosis type 2 2018-03-29 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000627115 SCV000747919 likely pathogenic Autistic behavior; Severe global developmental delay 2012-12-17 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000627116 SCV000747920 likely pathogenic Autistic behavior; Severe global developmental delay 2017-04-30 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000627117 SCV000747921 likely pathogenic Autistic behavior; Moderate global developmental delay 2017-05-27 criteria provided, single submitter clinical testing
Department of Psychiatry, Nagoya University RCV000754118 SCV000777921 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754119 SCV000777922 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754124 SCV000777927 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754129 SCV000777932 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754131 SCV000777934 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754132 SCV000777935 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754147 SCV000777950 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754155 SCV000777958 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754156 SCV000777959 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754157 SCV000777960 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754158 SCV000777961 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754160 SCV000777963 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754162 SCV000777965 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754164 SCV000777967 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754166 SCV000777969 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754167 SCV000777970 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754168 SCV000777971 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754171 SCV000777974 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754172 SCV000777975 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754173 SCV000777976 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754174 SCV000777977 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754175 SCV000777978 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754177 SCV000777980 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754179 SCV000777982 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754180 SCV000777983 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754182 SCV000777985 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754184 SCV000777987 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754185 SCV000777988 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754186 SCV000777989 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754188 SCV000777991 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754189 SCV000777992 pathogenic Autism; Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754201 SCV000778004 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754205 SCV000778008 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754211 SCV000778014 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754212 SCV000778015 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754229 SCV000778032 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754248 SCV000778051 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754249 SCV000778052 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754250 SCV000778053 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754256 SCV000778059 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754258 SCV000778061 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754259 SCV000778062 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754267 SCV000778070 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754277 SCV000778080 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754283 SCV000778086 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754289 SCV000778092 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754292 SCV000778095 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754324 SCV000778127 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754329 SCV000778132 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754330 SCV000778133 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754331 SCV000778134 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754332 SCV000778135 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754333 SCV000778136 pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754334 SCV000778137 pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754346 SCV000778149 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754347 SCV000778150 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754348 SCV000778151 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754349 SCV000778152 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754350 SCV000778153 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754351 SCV000778154 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754352 SCV000778155 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754353 SCV000778156 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754362 SCV000778165 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754363 SCV000778166 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754364 SCV000778167 likely pathogenic Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754365 SCV000778168 pathogenic Autism; Schizophrenia 2018-03-20 criteria provided, single submitter research
Department of Psychiatry, Nagoya University RCV000754378 SCV000778181 likely pathogenic Autism 2018-03-20 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754926 SCV000787512 benign Global developmental delay 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754927 SCV000787513 pathogenic Global developmental delay 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754928 SCV000787514 likely benign Global developmental delay 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754929 SCV000787515 benign not specified 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754930 SCV000787516 benign not specified 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754931 SCV000787517 benign not specified 2018-05-08 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754932 SCV000787518 benign not specified 2018-05-08 criteria provided, single submitter clinical testing
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754403 SCV000787664 uncertain significance Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754413 SCV000787674 likely benign Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754448 SCV000787709 likely benign Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754469 SCV000787730 uncertain significance Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754473 SCV000787734 likely benign Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754474 SCV000787735 uncertain significance Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000754479 SCV000787740 uncertain significance Primary amenorrhea 2018-06-01 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754946 SCV000788371 pathogenic Jeune thoracic dystrophy 2018-05-01 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754969 SCV000788396 pathogenic 1q24q25 microdeletion syndrome 2018-05-01 criteria provided, single submitter research
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677147 SCV000803307 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This deletion was identified in an 8 year old female with intellectual disability, hyperkinesis, seizure disorder, and feeding disorder. She has a history of congenital hip dysplasia, chronic constipation, atrial septal defect, strabismus, and Raynaud's phenomenon. Brain MRI showed mild diffuse loss of the deep white matter in both cerebral hemispheres. This patient also has a pathogenic 43 Mb duplication at 4q. These copy number variants are a result of a derivative chromosome 4. The patient's sister, who is similarly affected, has the same derivative chromosome 4.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677148 SCV000803308 pathogenic not provided 2018-04-03 criteria provided, single submitter provider interpretation This duplication was identified in an 8 year old female with intellectual disability, hyperkinesis, seizure disorder, and feeding disorder. She has a history of congenital hip dysplasia, chronic constipation, atrial septal defect, strabismus, and Raynaud's phenomenon. Brain MRI showed mild diffuse loss of the deep white matter in both cerebral hemispheres. This patient also has a 770 kilobase deletion at 4pter, which is of uncertain significance. These copy number variants are a result of a derivative chromosome 4. The patient's sister, who is similarly affected, has the same derivative chromosome 4.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677149 SCV000803309 pathogenic not provided 2018-04-03 criteria provided, single submitter provider interpretation This duplication was identified in a 20 year old female with mild intellectual disability, superimposed expressive language disorder, and ADHD symptoms. X-inactivation analysis showed 84:16 ratio, consistent with moderate skewing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677150 SCV000803310 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This deletion was identified in an 8 year old female with developmental delays, severe superimposed expressive language disorder, uncertain overall intellectual abilities, ventricular septal defect, short stature, and hypertonia. Jaundice and sacral dimple were noted at birth. Notable facial features include: microcephaly, midface hypoplasia, triangular facies, fine hair, high forehead with broad and prominent brow, protruding low-set ears, epicanthus, deep-set eyes, sparse eyebrows, broad nasal root with low bridge, anteverted nares, small nasal tip, thin lips, small mouth, and small chin. She has proximally placed thumbs with small, abnormal nails. Renal ultrasound was normal. Additionally, a de novo, 23.7 Mb duplication on 9p was identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677151 SCV000803311 pathogenic not provided 2018-04-03 criteria provided, single submitter provider interpretation This duplication was identified in an 8 year old female with developmental delays, severe superimposed expressive language disorder, uncertain overall intellectual abilities, ventricular septal defect, short stature, and hypertonia. Jaundice and sacral dimple were noted at birth. Notable facial features include: microcephaly, midface hypoplasia, triangular facies, fine hair, high forehead with broad and prominent brow, protruding low-set ears, epicanthus, deep-set eyes, sparse eyebrows, broad nasal root with low bridge, anteverted nares, small nasal tip, thin lips, small mouth, and small chin. She has proximally placed thumbs with small, abnormal nails. Renal ultrasound was normal. Additionally, a de novo, 212 kilobase deletion on 9p was identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677152 SCV000803312 uncertain significance not provided 2018-04-05 criteria provided, single submitter provider interpretation This deletion was identified in a 14 year old male with intellectual disability, phonological disorder, ADHD, disruptive behavior, sleep disturbance, and constipation. Renal ultrasound revealed mild left-sided hydronephrosis, but kidneys were otherwise normal. The deletion was not found in his mother but the father was not available for testing. There is a paternal family history of behavior and developmental problems.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677153 SCV000803313 pathogenic Chromosome 1p32-p31 deletion syndrome 2018-03-01 criteria provided, single submitter provider interpretation This deletion was identified in an 18 year old female with autism spectrum disorder, learning disorder, macrocephaly, and ADHD. Brain MRI at age 2 months showed thinned and high riding corpus callosum. The same deletion was identified in her younger twin sisters, who are more severely impaired, as well as her mother, who has some learning disability but who lives independently.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677154 SCV000803314 uncertain significance Autism spectrum disorder due to AUTS2 deficiency 2018-04-03 criteria provided, single submitter provider interpretation This deletion was identified in a 12 year old female autism spectrum disorder, moderate intellectual disability, anxiety, history of seizures, short stature (less than 1st percentile), and low weight (1st percentile). The deletion was maternally inherited, and the mother has no history of neurodevelopmental disorders.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677155 SCV000803315 uncertain significance not provided 2017-03-27 criteria provided, single submitter provider interpretation This duplication was identified in an 11 year old male with mild to moderate intellectual disability, hyperkinesis, atypical stereotypic movement disorder, disruptive behavior, borderline microcephaly (51.40 cm), short stature (2%ile), and dysmorphic features. The duplication was paternally inherited, and the patient's father is unaffected. Of note, this patient also carries a maternally-inherited VUS in EFNB1 and VUS of unknown inheritance in TLK2.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677156 SCV000803316 pathogenic Generalized juvenile polyposis/juvenile polyposis coli 2017-05-01 criteria provided, single submitter provider interpretation This deletion was identified in an 8 year old male with autism spectrum disorder and intellectual disability. The patient has not yet had a colonoscopy or endoscopy but is scheduled to begin that surveillance at age 15. His cardiac evaluation was normal.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677157 SCV000803317 likely pathogenic not provided 2017-05-01 criteria provided, single submitter provider interpretation This duplication was identified in an 8 year old male with autism spectrum disorder and intellectual disability. Given the size of the duplication, the variant has been classified as likely pathogenic.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677158 SCV000803318 uncertain significance not provided 2018-04-16 criteria provided, single submitter provider interpretation This deletion was identified in a 12 year old female with a history of failure to thrive, infantile seizures, dysmorphic features, precocious puberty, and mild to moderate intellectual disability. Of note, Smith-Lemli-Opitz testing was negative.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677159 SCV000803319 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 123.5 kilobase deletion was detected in a patient with a history of choanal atresia, TE fistula, supraventricular tachycardia, renal reflux, craniosynostosis, congenital hydrocephalus, global developmental delay, bicuspid aortic valve, undesceneded testes, micropenis, and dysmorphic facial features. This deletion includes two OMIM genes CYP2E1 and SYCE1. This deletion was found to be maternally inherited. The patient's mother does not have a reported history of congenital anomalies or neurodevelopmental concerns. An additional variant identified in the patient was identified and felt to be consistent with CHARGE syndrome.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677160 SCV000803320 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This approximately 747 kilobase duplication was identified in a male with autism spectrum disorder. This region includes 5 OMIM genes, of which VSP37A and FGF20 have been associated with clinical conditions. Both are associated with autosomal recessive conditions - spastic paraplegia 53 and renal hypoplasia/aplasia 2 respectively. Parental testing has not been completed to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677161 SCV000803321 uncertain significance not provided 2018-04-04 criteria provided, single submitter provider interpretation This 2.6 Mb duplication was identified in a patient with a history of mild intellectual disability, superimposed severe expressive language disorder, congenital heart defect, seizure disorder, and rectal prolapse. The duplication includes approximately 25 known genes. Larger duplications have been reported in individuals with postnatal growth retardation, microcephaly, and characteristic facies (Grossman et al. 2009). This duplication was found to be paternally inherited. The patient's father has a history of speech delay and obesity.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677162 SCV000803322 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This approximately 395 kilobase duplication was identified in a male with a history of microcephaly, congenital lymphedema of the feet, superimposed expressive language disorder, popliteal cysts and intellectual disability. The duplication includes 7 OMIM genes. Two of these genes are associated with known conditions - TUBB2A and TUBB2B. Heterozygous missense variants in TUBB2B are associated with microcephaly, brain abnormalities, developmental delays, intellectual disability, and seizures. Heterozygous missense variants in TUBB2A have been associated with hypotonia, brain abnormlities, seizures, and intellectual disability. The effect of a duplication of these genes is unclear. This duplication was found to be paternally inherited. The patient's father has a reported history of a learning disability and speech delay.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677163 SCV000803323 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This approximately 3.3 Mb deletion was detected in an individual with a history of intellectual disability, dyspraxia, hypotonia, epicanthal folds, long facies with bitemporal narrowing, scoliosis, and increased joint laxity. A smaller, nested deletion was described in a patient with developmental delay, muscle hypotonia, dysmorphic features, and skeletal abnormalities (Shimojima et al. 2009). Several similar deletions have also been submitted to ClinVar (SCV000178752; SCV000175474; SCV000502982; SCV000502982). Parental testing has not been completed to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677164 SCV000803324 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This 127.2 kilobase deletion was identified in a 10 year old with a history of autism spectrum disorder, mild impairments of visual-motor/problem-solving skills, and hyperkinesis. Parental testing has not been completed to date. A 1q21.1 duplication (including TAR region) was also identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677165 SCV000803325 uncertain significance not provided 2017-12-01 criteria provided, single submitter provider interpretation This 582 kilobase duplication was identified in an individual with a history of developmental delay with borderline intellectual ability, developmental language impairment, umbilical hernia, and unilateral inguinal hernia. It includes 8 genes: CRLD2, CSF2RA, IL3RA, SLC25A6, ASMTL-AS1, ASMTL, P2RY8, AKAP17A, ASMT. The majority of these genes are not associated with known conditions. The CSF2RA gene is associated with hereditary pulmonary alveolar proteinosis, caused by loss of function of CSF2RA due to gene deletion or protein truncation. The ASMT gene has been implicated as potentially associated with autism spectrum disorders. Several association studies have published a possible increased risk for autism; however, additional studies failed to duplicate this association. Additionally, one publication (Cai et al. 2008) found an interstitial duplication of ASMT at a higher frequency in individuals with autism spectrum disorders compared to controls. This duplication included at least exons 2-8 of ASMT. The significance of entire gene duplications is unclear. Parental testing has not been completed to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677166 SCV000803326 likely pathogenic not provided 2018-03-22 criteria provided, single submitter provider interpretation This 720.71 kilobase deletion was identified in a male with a history of autism spectrum disorder, developmental delay, and short stature. The deletion includes the 5' end of the NRXN1 gene and deletes exons 1-5 of the alpha isoform. Variants in the NRXN1 gene, including intragenic copy number variants, have been associated with a variable neurodevelopmental diagnoses including autism spectrum disorders, intellectual disability, epilepsy, and schizophrenia. The features are variable from individual to individual. 2p16.3 deletions and variants in the NRXN1 gene have also been reported in healthy controls and unaffected parents of individuals with neuropsychiatric disorders indicating reduced penetrance or variable expressivity (Schaaf et al. 2012; Bena et al. 2013).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677167 SCV000803327 likely pathogenic not provided 2018-03-22 criteria provided, single submitter provider interpretation This 714.9 kilobase deletion was identified in a male with a history of developmental language disorder, patent foramen ovale, microcephaly, apraxia of speech, and scoliosis. This deletion includes the distal portion of the common 22q11.21 region, but does not include the TBX1 gene and is proximal to BCR. Similar deletions have been reported in individuals with a number of features including growth restriction, developmental delay, intellectual disability, language delay, and dysmorphic features (Burnside 2015; Rauch et al. 2005). The patient's mother reportedly has a history of kyphosis, spinal tumor, and had a normal microarray.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677168 SCV000803328 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This 1.93 Mb deletion was identified in a 9 year old female with microcephaly, mild intellectual disability, and ADHD. This deletion includes four genes, two of which are associated with known conditions. Single nucleotide variants in CHMP2B have been associated with familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis 17. Frontotemporal dementia due to variants in this gene are thought to result from a build-up of the abnormal protein. The impact of a whole gene deletion is unclear, however. Homozygous or compound heterozygous variants in POU1F1 have been associated with autosomal recessive combined pituitary hormone deficiency. Maternal inheritance of the variant was ruled out, but paternal testing has not been completed. Subsequent whole exome sequencing identified two VUSs in a gene associated with an autosomal recessive condition.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677169 SCV000803329 uncertain significance not provided 2018-03-28 criteria provided, single submitter provider interpretation This deletion was identified in a 10 year old male with mild hypotonia, autism spectrum disorder, learning disorder, OCD, ADHD, macrocephaly, borderline to mildly impaired verbal abilities with a large verbal/performance split, and was found to be paternally inherited. Proband's father has a history of depression and ADHD, along with a family history of autism. This deletion is within the RBFOX1 (also known as A2BP1) gene, which has not been clearly associated with human diseases. RBFOX1 has been implicated in a range of neurodevelopmental diseases including forms of epilepsy and autism spectrum disorders. It is not clear whether this deletion is related to the patient's neurodevelopmental history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677170 SCV000803330 uncertain significance not provided 2018-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 13 year old male with borderline intellectual functioning, superimposed expressive communication impairment/verbal apraxia, sleep disturbance, mood lability, irritability, and aggression. Parental testing for this duplication was not completed. Proband is a known carrier of a pathogenic 16p11.2 deletion, to which his symptoms are attributed. Within this duplication three OMIM genes are included; NF2, NEFH, and a portion of EWSR1. The clinical significance of a duplication of these genes is not currently known.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677171 SCV000803331 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2018-04-12 criteria provided, single submitter provider interpretation This deletion was identified in a 12 year old male with intellectual disability, autism spectrum disorder, anxiety, and obesity. Parental testing was not completed. This deletion includes three genes, including a portion of BRCA2. The patient's father has a strong family history of breast cancer in individuals under the age of 40 and so the deletion is likely paternally inherited. The father has a history of eye problems (ptosis, pain, diplopia), hypertension, and high cholesterol. Patient has a sister with autism who has not been tested for this deletion. The clinical significance of this deletion for the patient's current symptoms remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677172 SCV000803332 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 12 year old male with ADHD, oppositional defiant disorder, and a history of language disorder, and was found to be paternally inherited. The patient's father was born with bilateral polydactyly and a congenital heart anomaly. This duplication includes 4 genes, none of which are currently associated with a known clinical syndrome. DECIPHER reports one individual with a small duplication within this region in an individual with hypotonia, intellectual disability/developmental delay, microcephaly, proportionate short stature, and strabismus. The clinical significance of three copies of these genes remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677173 SCV000803333 pathogenic Charcot-Marie-Tooth disease type 1B; Variegate porphyria; Migraine, familial hemiplegic, 2; Paragangliomas 3 2018-04-13 criteria provided, single submitter provider interpretation This deletion was identified in a 21 year old female with developmental delays and intellectual disability. Parental testing was not completed. This deletion contains approximately 50 genes including MPZ, PPOX, ATP1A2, and SDHC. She is at risk for developing Charcot-Marie-Tooth syndrome (type 1B, 2I, 2J, and dominant intermediate D), porphyria variegata, Hereditary Paraganglioma and Pheochromocytoma syndrome, and has an increased risk for migraines based on this deletion. Notably, she currently has no muscular symptoms consistent with CMT, nor any skin findings consistent with porphyria. Similar overlapping deletions have been seen in individuals with symptoms included but not limited to: intellectual disability, proportionate short statue, dysmorphic features, bilateral cleft lip/palate, hemiatrophy, hypodysplasia of corpus callosum, IUGR, and complex heart defects. This individual also has 16p11.2 deletion syndrome, identified through chromosomal microarray, which is also likely contributing to her developmental phenotype.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754985 SCV000803395 uncertain significance Intestinal malrotation 2018-06-11 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754986 SCV000803396 likely pathogenic Intestinal malrotation 2018-06-11 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754987 SCV000803397 uncertain significance Intestinal malrotation 2018-06-11 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754988 SCV000803398 pathogenic Intestinal malrotation 2018-06-11 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754989 SCV000803399 pathogenic Intestinal malrotation 2018-06-11 criteria provided, single submitter research
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677908 SCV000804063 likely pathogenic Cystinuria 2016-06-16 criteria provided, single submitter provider interpretation This deletion was identified in a 6 year old female with developmental delays, microcephaly, craniosynostosis, hypertrophic cardiomyopathy, and history of acute lymphoid leukemia in remission. This deletion was inherited from a mother with a history of a kidney stone and the maternal grandfather is reported to have multiple kidney stones. Follow up testing for the proband showed elevated urine amino acids. This result indicates carrier status for cystinuria, at minimum. Additionally, 3 variants of uncertain significance were identified by exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677909 SCV000804064 uncertain significance not provided 2018-03-19 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old male with global developmental delay. Brain MRI at age 26 months showed a slightly delayed myelination pattern. Parental testing was not completed. There is a family history of learning and psychiatric illness on both the maternal and paternal side, and a paternal family history of seizures. No facial dysmorphisms were noted.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677910 SCV000804065 pathogenic not provided 2018-04-03 criteria provided, single submitter provider interpretation This deletion was identified in a 5 year old male with global developmental delays, velopharyngeal insufficiency, VSD, PFO, recurrent otitis media, mild astigmatism, bilateral single transverse palmar creases, narrow left palpebral fissure, full lips, bowed upper lip, and 5th finger clinodactyly. Brain MRI showed mega cisterna magna but was otherwise unremarkable. Parental testing was not completed.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677911 SCV000804066 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old male with global developmental delays, velopharyngeal insufficiency, VSD, PFO, recurrent otitis media, mild astigmatism, bilateral single transverse palmar creases, narrow left palpebral fissure, full lips, bowed upper lip, and 5th finger clinodactyly. Brain MRI showed mega cisterna magna but was otherwise unremarkable. Parental testing was not completed. Additionally, a 2.478 Mb pathogenic chromosomal deletion was identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677912 SCV000804067 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This duplication was identified in a 6 year old female with slightly upslanted palpebral fissures and autism spectrum disorder. She was born at term with significant issues in the neonatal period including meconium aspiration with respiratory distress, hypotension, metabolic acidosis, HIE, persistent fetal circulation, adrenal hypofunction, thrombocytopenia, and anemia. Parental testing was not available.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677913 SCV000804068 uncertain significance not provided 2018-02-05 criteria provided, single submitter provider interpretation This deletion was identified in a 5 year old female with autism spectrum disorder, global developmental delays, hyperkinesis, ADHD, feeding problems, sleep problems, and wide spaced teeth. The deletion was inherited from a father with ADHD and bipolar disorder. Follow up ophthalmological exam was normal and the father has normal vision. This history supports the putative PAX6 downstream regulatory region proposed by Balay et al, 2015 (PMID:26419218), which is not included in this patient's deletion region. It is not clear whether this deletion is related to the patient neurodevelopmental history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677914 SCV000804069 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This deletion was identified in a 20 year old male with autism spectrum disorder, sleep disturbance, mood disorder, anxiety, macrocephaly, a vocal tic, and obesity. He has astigmatism, eczema, and a history of frequent epistaxis. There is no paternal history of neurodevelopmental disorders.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677915 SCV000804070 likely benign not provided 2018-04-05 criteria provided, single submitter provider interpretation This deletion was identified in a 7 year old male with a history of global developmental delay (intellectual ability are uncertain) and superimposed expressive language delay. He has echolalia and will point in a protoimperative and protodeclarative manner. He is making progress with expressing emotions and will follow a familiar two-step command. He was found to have a pathogenic 8.2 Mb duplication of 18p11.32p11.22 by microarray.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677916 SCV000804071 pathogenic not provided 2018-04-05 criteria provided, single submitter provider interpretation This duplication was identified in a 7 year old male with a history of global developmental delay (intellectual ability are uncertain) and superimposed expressive language delay. He has echolalia and will point in a protoimperative and protodeclarative manner. He is making progress with expressing emotions and will follow a familiar two-step command. The duplication was also found in the patient's mother, who has a history of ADHD and learning disability.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677917 SCV000804072 uncertain significance not provided 2018-04-05 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old male with mild intellectual disability, expressive language delay, inattentiveness, and hyperkinesis. The duplication was inherited from a mother with no significant neurodevelopmental problems.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677918 SCV000804073 pathogenic not provided 2018-04-05 criteria provided, single submitter provider interpretation This deletion was identified in a 5 year old male with global developmental delays, mild neuromotor abnormalities, stereotypy, macrocephaly, and large stature. He is monitored for seizures due to spells. He has had normal cardiac echo and ECG, normal cranial ultrasound, normal renal ultrasound (except for a urachal cyst). The deletion was inherited from a father with a history of speech delay, learning disability, bipolar disorder, depression, anxiety, substance abuse, heart murmur, and congenital pancreatic divisum.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677919 SCV000804074 likely benign not provided 2018-02-26 criteria provided, single submitter provider interpretation This duplication was identified in a 10 year old male with autism spectrum disorder, large stature, anxiety, compulsive behavior, and uncertain intellectual abilities. The duplication was inherited from the patient's mother, who does not report learning or developmental problems. There is a maternal family history of psychiatric illness. Additionally, a de novo copy number gain at 19p13.2 was identified by CMA, and 2 variants of uncertain significance were identified by exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677920 SCV000804075 uncertain significance not provided 2018-02-26 criteria provided, single submitter provider interpretation This duplication was identified in a 10 year old male with autism spectrum disorder, large stature, anxiety, compulsive behavior, and uncertain intellectual abilities and was found to be de novo. Additionally, a maternally-inherited copy number gain at 6p22.3 was identified by CMA, and 2 variants of uncertain significance were identified by exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677921 SCV000804076 likely pathogenic not provided 2018-02-05 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old male with agenesis of the corpus callosum, macrocephaly secondary to enlarged third ventricle, ADHD, and a family history of psychiatric illness. His biological mother has agenesis of the corpus callosum, Tourette's syndrome, and depression. A maternal uncle has schizophrenia, agenesis of the corpus callosum, seizure disorder, and bipolar disorder. The maternal grandfather had schizophrenia and agenesis of the corpus callosum, and a maternal great uncle also had agenesis of the corpus callosum. Parental or other family member testing was not possible. This duplication includes the SHH gene and additional duplications in the literature suggest it is causative for this patient's clinical features (Heide, 2017; Wong, 2015).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677922 SCV000804077 likely pathogenic Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome 2018-02-05 criteria provided, single submitter provider interpretation This deletion was identified in a 4 year old female with global developmental delays, macrocephaly, telecanthus, and a wide based gait. It was found to be de novo and likely impacts expression of the GATAD2B gene due to loss of regulatory region. Clinical correlation with previously reported patients with GATAD2B-related disorder was thought to be very good. In addition, this patient has a paternally-inherited, likely benign duplication at 4q22.3.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677923 SCV000804078 likely benign not provided 2018-02-05 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with global developmental delays, macrocephaly, telecanthus, and a wide based gait. It was inherited from a clinically unaffected father. In addition, this patient carries a de novo, likely pathogenic deletion at 1q21.3.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677924 SCV000804079 uncertain significance not provided 2018-02-26 criteria provided, single submitter provider interpretation This duplication was identified in a 17 year old male with learning disorder and high functioning autism spectrum disorder. He has a recent diagnosis of sinus tachycardia. This duplication was inherited from the patient's mother, who has a history of anxiety disorder and obsessive-compulsive disorder. Her identical twin sister has a history of depression and severe obsessive-compulsive disorder. This patient's sister, who has mild autism and a phonological disorder, also carries this duplication.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677925 SCV000804080 uncertain significance not provided 2018-02-05 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with mild global developmental delays, receptive/expressive language disorder, hypotonia, microcephaly, and short stature. Brain MRI revealed pachygyria. Ophthalmology and endocrinology evaluations were normal. This patient's mother, who carries this variant, has learning disability. She has not had subsequent brain imaging. In addition, this patient and his mother were found to carry a novel missense variant in the TUBB2B gene.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677926 SCV000804081 pathogenic not provided 2018-04-05 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with global developmental delays, hearing impairment, sleep problems, short stature, esotropia, chronic constipation, anemia, and small PFO. Renal ultrasound was normal. Notable facial features include a long, narrow face, upslanting palpebral fissures, infraorbital creases, bulbous nasal tip, anteverted nares, and mild retrognathia. This patient also has a pathogenic 39 Mb terminal deletion of Xp22.3p11.2. These copy number variants are a result of a de novo rearrangement: 46,X,der(X)t(X;15)(p11.4;q11.2).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677928 SCV000804083 likely benign not provided 2018-02-26 criteria provided, single submitter provider interpretation This duplication was identified in a 6 year old male with a language disorder, delayed adaptive skills, hypotonia, and short stature. It was inherited from his clinically unaffected mother, who also has no vision abnormalities. Copy number gains of the GUCA1A and GUCA1B genes have been observed in the ExAC database.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677929 SCV000804084 uncertain significance not provided 2017-06-12 criteria provided, single submitter provider interpretation This duplication was identified in a 3 year old female with develomental delays. She is non-dysmorphic and has a strong maternal family history of psychiatric disorders, seizures, and intellectual disability. Paternal history is unknown. Parental samples were not available for testing. Additionally, a variant of uncertain significance was identified by whole exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677930 SCV000804085 uncertain significance not provided 2017-08-03 criteria provided, single submitter provider interpretation This deletion was identified in a 3 year old male with global developmental delay, expressive language disorder, mild hypotonia, short stature, dolichocephaly, laterally arched eyebrows, epicanthal folds, bulbous nasal tip, bowed upper lip, small toes, sleep disorder, and a history of prematurity. It was inherited from an unaffected mother. It is also a fairly gene-poor region. Additionally, whole exome sequencing identified a de novo, likely pathogenic sequence variant which most likely explains this patient's clinical history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677931 SCV000804086 pathogenic Becker muscular dystrophy 2017-05-16 criteria provided, single submitter provider interpretation This deletion was identified in a 10 year old male with mild intellectual disability, ADHD, oppositional-defiant disorder, and a history of gastroschisis. Muscle tone and strength appeared normal on exam and there were no gait abnormalities. CK levels, taken after identification of DMD deletion, were significantly elevated (2287).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677932 SCV000804087 pathogenic not provided 2017-10-31 criteria provided, single submitter provider interpretation This deletion was identified in a 4 year old female with autism spectrum disorder, global developmental delay, and mild hypotonia. She walked at age 2 but currently there are no motor concerns. She has significant language delay with no spoken words, does not point to request, and appears to understand only a few words (receptive age equivalent 10 months). She is slightly short (5th percentile). She has a long philtrum but is otherwise non-dysmorphic.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677933 SCV000804088 uncertain significance not provided 2018-03-29 criteria provided, single submitter provider interpretation This deletion was identified in a 6 year old male with autism spectrum disorder, disruptive behavior, hyperactivity, persistent insomnia, coordination disorder, and cyclic vomiting syndrome. Only a maternal sample was available for testing, and the patient's mother does not carry the deletion. Of note, this patient also carries a variant of uncertain significance in the ADCY5 gene.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677934 SCV000804089 pathogenic Chromosome 2p16.3 deletion syndrome 2017-07-29 criteria provided, single submitter provider interpretation This deletion was identified in a 5 year old male with mild intellectual disability, ADHD, mild phonological disorder, and disruptive behavior disorder. Parental testing was not completed. There is an extensive family history of substance abuse, psychiatric diagnoses, and learning disabilities. Two additional copy number variants were also identified in this patient, one likely pathogenic and one of uncertain significance.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677935 SCV000804090 likely pathogenic Spinocerebellar ataxia type 27 2017-07-29 criteria provided, single submitter provider interpretation This deletion was identified in a 5 year old male with mild intellectual disability, ADHD, mild phonological disorder, and disruptive behavior disorder. Parental testing was not completed. There is no family history of movement disorders. The patient does not currently show any signs of tremor, dyskinesia, or ataxia. He is described by his family as more uncoordinated than his peers. There are reports of individuals with FGF14-related cerebellar ataxia not presenting with motor abnormalities until later in childhood, so the patient will continue to be monitored. Two additional copy number variants were also identified in this patient, one that is pathogenic and one of uncertain significance.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677936 SCV000804091 uncertain significance not provided 2017-07-29 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old male with mild intellectual disability, ADHD, mild phonological disorder, and disruptive behavior disorder. Parental testing was not completed. The region is not known to vary in copy number in the normal population, but none of the genes in the region are currently associated with known clinical disorders. Two additional copy number variants were also identified in this patient, one that is pathogenic and one that is likely pathogenic.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677937 SCV000804092 uncertain significance not provided 2014-11-12 criteria provided, single submitter provider interpretation This deletion was identified in a 7 year old male with global developmental delays, phonological disorder, ADHD, and disruptive behavior. The deletion was inherited from his mother, who has a history of learning disabilities and ADHD. The deletion is also present in the patient's brother, who has a history of abnormal number of umbilical cord vessel, cardiac defect, and bilateral clubfoot deformity.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677938 SCV000804093 pathogenic Autosomal recessive nonsyndromic hearing loss 16 2018-03-29 criteria provided, single submitter provider interpretation This deletion was identified in a 3 year old female with bilateral sensorineural hearing loss, mixed receptive-expressive language disorder, mild visual-motor delay, mild hypotonia, and gross motor delay. While parental studies have not been done, both of the patient's sisters are homozygous for the same 15q15.3 deletion and both have hearing impairments, suggesting that the parents are each a carrier of the deletion.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677939 SCV000804094 pathogenic Becker muscular dystrophy; Duchenne muscular dystrophy; Dilated cardiomyopathy 3B 2017-02-06 criteria provided, single submitter provider interpretation This deletion was identified in an 8 year old female with autism spectrum disorder and intellectual disability. The deletion was maternally inherited, and the mother has a history of language delays in childhood, learning impairment, depression, anxiety, and bipolar disorder. She reported a family history of Duchenne muscular dystrophy. One of the patient's maternal uncles died at age 21, and another maternal uncle died at age 12 following anesthesia complications during surgery; they were both reported to have DMD. Neither the patient nor her mother have been evaluated by cardiology to assess for cardiomyopathy. Additionally, neither the patient nor her mother have a history of muscle weakness or gait abnormalities.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677940 SCV000804095 likely pathogenic Nemaline myopathy 6 2018-04-12 criteria provided, single submitter provider interpretation This deletion was identified in a 12 year old male with autism spectrum disorder, history of right talipes equinovarus, and leg length discrepancy. Parental studies (targeted microarray and FISH analysis) revealed that this deletion arose de novo.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677941 SCV000804096 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 12 year old male with intellectual disability and history of multiple non-traumatic fractures. While this duplication was de novo, the patient's father has a history of multiple fractures. Of note, this patient has had negative sequencing and deletion/duplication analaysis of the COL1A1 and COL1A2 genes.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677942 SCV000804097 pathogenic not provided 2018-04-15 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old female with global developmental delays, short stature, basiocciput hyperplasia and associated basilar invagination, and an arachnoid cyst. Parental studies were performed, and the duplication was found to be de novo.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677943 SCV000804098 pathogenic Axenfeld-Rieger syndrome type 3 2018-04-16 criteria provided, single submitter provider interpretation This deletion was identified in a 9 year old female with intellectual disability, microcephaly, craniosynostosis, left hemifacial microsomia, feeding disorder, congenital heart defects, congenital hypothyroidism, renal hypodysplasia/stage 3 chronic kidney disease, ptosis, alternating esotropia, recurrent otitis media, small teeth, and history of prematurity (born at 34 weeks). The deletion was inherited from the patient's father who carries a balanced chromosome translocation (46,XX,der(21),t(6;21)(p21.3q22.3)pat). Because of the patient's intolerance to opthalmological exams, it is not known whether or not she shows signs of glaucoma.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677944 SCV000804099 pathogenic not provided 2018-04-16 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old female with intellectual disability, microcephaly, craniosynostosis, left hemifacial microsomia, feeding disorder, congenital heart defects, congenital hypothyroidism, renal hypodysplasia/stage 3 chronic kidney disease, ptosis, alternating esotropia, recurrent otitis media, small teeth, and history of prematurity (born at 34 weeks). The duplication was inherited from the patient's father who carries a balanced chromosome translocation (46,XX,der(21),t(6;21)(p21.3q22.3)pat).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677945 SCV000804100 uncertain significance not provided 2017-10-09 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with global developmental delays. The duplication was paternally inherited, and the patient's father has a history of learning disabilities and bipolar disorder. The region is not known to vary in copy number in the normal population. The two genes in this region that are associated with human disease (SUMF1, ITPR1) are not known to cause disease when duplicated. Of note, this patient also carries the recurrent 22q11.2 duplication.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677946 SCV000804101 uncertain significance not provided 2018-04-15 criteria provided, single submitter provider interpretation This duplication was identified in an 18 year old male with mild intellectual disability, ADHD, disruptive behavior, and microcephaly (5th percentile). The patient's mother does not carry the duplication, and a paternal sample is unavailable.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677947 SCV000804102 uncertain significance not provided 2017-01-10 criteria provided, single submitter provider interpretation This deletion was identified in a 6 year old male with intellectual disability and motor stereotypies. The deletion was found to be maternailly-inherited; the patient's mother is unaffected. The deletion encompasses the non-coding exon 1 of RBFOX1. Haploinsuffiency of RBFOX1 has been implicated in several neurodevelopmental phenotypes, and some deletions have been inherited from a phenotypically normal parent. Of note, this patient also carries a paternally-inherited VUS in the SHANK2 gene.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677948 SCV000804103 uncertain significance Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15 2015-10-30 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with autism spectrum disorder, global developmental delays, and a feeding disorder. Parental testing has not been performed. Family history is significant for a cerebrovascular accident in the patient's mother at age 36, but there is no known history of cardiomyopathy. Of note, this patient's whole exome sequencing has thus far been negative.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677949 SCV000804104 uncertain significance Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis 2017-03-23 criteria provided, single submitter provider interpretation This duplication was identified in a 7 year old male with autism spectrum disorder. The duplication was maternally inherited, and his mother does not have a history of hearing impairment or learning disabilities. She does have a history of kidney stones; loss of function variants in AMMECR1, which is within this duplicated region, are associated with nephrocalcinosis. The patient does not have a history of any kidney concerns. Of note, the patient's whole exome sequencing has thus far been normal.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677950 SCV000804105 uncertain significance not provided 2017-06-13 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with autism spectrum disorder and global developmental delays. The duplication was maternally inherited, and this individual's mother does not have a history of neurodevelopmental disorders.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677951 SCV000804106 uncertain significance Autism spectrum disorder due to AUTS2 deficiency 2017-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with autism spectrum disorder, global developmental delays, and agenesis of the corpus callosum. The duplication was maternally-inherited, and the patient's mother has a history of depression and anxiety. The patient also carries a maternally inherited duplication of uncertain significance at 18q21.2. Of note, this patient's whole exome sequencing has thus far been normal.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677952 SCV000804107 uncertain significance Mirror movements 1 2017-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with autism spectrum disorder, global developmental delays, and agenesis of the corpus callosum. The duplcation was inherited from his mother, who has a history of anxiety and depression. The patient also carries a duplication of uncertain significance at 7q11.22. Of note, his whole exome sequencing has thus far been negative.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677953 SCV000804108 uncertain significance not provided 2017-03-26 criteria provided, single submitter provider interpretation This duplication was identified in a 7 year old male with autism spectrum disorder, history of developmental delays with uncertain intellectual abilities, and self-injurious behaviors. The duplication is maternally-inherited; the patient's mother has a history of anxiety and depression. Of note, the patient was found to carry a variant of uncertain significance in KIF4A through whole exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677954 SCV000804109 uncertain significance not provided 2014-01-24 criteria provided, single submitter provider interpretation This deletion was identified in a 15 year old male with autism spectrum disorder, intellecutal disability, disruptive behavior, sleep disturbances, and staring episodes. The deletion was found to be maternally inherited; his mother has a history of depression and phenomic disorder.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677955 SCV000804110 uncertain significance not provided 2017-05-01 criteria provided, single submitter provider interpretation This duplication was identified in a 16 year old female with autism spectrum disorder and intellectual disbaility. Parental studies were never performed, so inheritance is unknown.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677956 SCV000804111 uncertain significance not provided 2016-12-08 criteria provided, single submitter provider interpretation This duplication was identified in a 3 year old male with autism spectrum disorder and global developmental delays. The duplication was paternally inherited, and the patient's father has a history of learning disabilities, childhood speech delay, childhood seizures, and anxiety.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677957 SCV000804112 uncertain significance not provided 2017-06-08 criteria provided, single submitter provider interpretation This deletion was identified in a 16 year old male with intellectual disability and growth failure. Of note, this patient also carries a de novo likely pathogenic variant in the ZNF711 gene, which is felt to explain his intellectual disability. The patient's mother is unaffected.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677958 SCV000804113 pathogenic Hyperparathyroidism 1; Parathyroid carcinoma; Hyperparathyroidism 2 with jaw tumors 2017-04-25 criteria provided, single submitter provider interpretation This deletion was identified in a 13 year old female with borderline intellectual disability, motor coordination disorder, ADHD, skull anomalies, history of neonatal seizure, and amblyopia. The patient's biological parents are unavailable for parental studies. There is no known family history of parathyroid cancer or thyroid disease. Of note, the patient also carries a pathogenic deletion at 16p11.2.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677959 SCV000804114 uncertain significance not provided 2017-05-01 criteria provided, single submitter provider interpretation This duplication was identified in a 3 year old female with autism spectrum disorder and global developmental delays. The duplication is maternally-inherited, and the mother has no history of neurodevelopmental disorders.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677960 SCV000804115 uncertain significance not provided 2017-05-17 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with global developmental delays and autism spectrum disorder. The duplication was found to be paternally inherited. The patient's father required learning supports in school.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677961 SCV000804116 uncertain significance not provided 2017-05-19 criteria provided, single submitter provider interpretation This deletion was identified in an 11 year old male with left hemiplegia, mild intellectual disability, seizure disorder, and hypothyroidism. Parental samples are unavailable, so inheritance is unknown.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677962 SCV000804117 uncertain significance Hypogonadotropic hypogonadism 1 with or without anosmia 2017-08-10 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with global developmental delays. Parental samples are unavailable, so inheritance is unknown.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677963 SCV000804118 uncertain significance not provided 2018-01-31 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with autism spectrum disorder and speech delay. The duplication was found to be maternally inherited, and the patient's mother received learning supports in school.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677964 SCV000804119 pathogenic Exudative vitreoretinopathy 1 2017-10-18 criteria provided, single submitter provider interpretation This deletion was identified in an 11 year old male with autism spectrum disorder and intellectual disability. The patient does not tolerate thorough opthalmological evaluations, but he is not reported to show any signs of retinopathy at his current age.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677965 SCV000804120 uncertain significance Congenital plasminogen activator inhibitor type 1 deficiency 2017-10-18 criteria provided, single submitter provider interpretation This duplication was identified in an 11 year old male with autism spectrum disorder and intellectual disability. The duplication was maternally-inherited, and neither the patient nor his mother are reported to have abnormal bleeding after trauma or surgery.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677966 SCV000804121 uncertain significance not provided 2018-04-11 criteria provided, single submitter provider interpretation This duplication was identified in a 12 year old male with autism spectrum disorder, ADHD, history of global developmental delay (resolved, IQ currently in average range), and history of bilateral clubfoot deformity. The duplication was paternally inherited, and the patient's father has learning difficulties and a history of anxiety and depression.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677967 SCV000804122 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 6 year old male with autism spectrum disorder, global developmental delay, hypotonia, a heart murmur, feeding problems, GERD, and a history of a unilaterial inguinal hernia, and was found to be maternally inherited. The patient's mother does not have a history of any neurodevelopmental disorders. Notably, neither this patient nor his mother have any hand, foot, or bone defects.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677968 SCV000804123 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 6 year old male with autism spectrum disorder, global developmental delay, hypotonia, a heart murmur, feeding problems, GERD, and a history of a unilaterial inguinal hernia. The duplication was found to be maternally inherited. The patient's mother does not have a history of any neurodevelopmental disorders.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677969 SCV000804124 uncertain significance Macrocephaly, macrosomia, facial dysmorphism syndrome 2018-02-23 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with autism spectrum disorder, global developmental delay, and history of prematurity (born at 28 weeks). The duplication was maternally inherited, and the mother has a history of learning disability and depression.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677970 SCV000804125 uncertain significance not provided 2017-08-21 criteria provided, single submitter provider interpretation This 924 kilobase duplication includes portions of the NKAIN2 and TRDN genes. TRDN is associated with autosomal recessive catecholaminergic polymorphic ventricular tachycardia-5 with or without muscle weakness. NKAIN2 is not currently associated with any known disorders. Disruption of NKAIN2 due to de novo rearrangements have been reported in two patients previously (Yue et al. 2006; Bocciardi et al. 2005). One individual with disruption at exon 4 had a clinical history of a congenital heart defect, macrocephaly, undescended testes, recurrent infections, and developmental delays (Yue et al. 2006). The second individual's translocation disrupted the gene in intron 4 had a history of neurologic abnormalities including including epileptic encephalopathy with spastic tetraparesis and severe psychomotor retardation associated with cerebral atrophy with involvement of the periventricular white matter (Bocciardi et al. 2005). Similar, overlapping duplications have been reported in several individuals in DECIPHER including in an individual with cognitive impairment (Case: 300577) and an individual with short stature (Case:331671). Overlapping variants have also been submitted to dbVar/ClinVar previously (nssv582678; nsv2777188; nsv534388) and reported in developmental delay cohorts as well as in controls (nsv1022195; nsv1018599). A similar duplication has been reported in the literature in an individual with facial dysmorphism, severe developmental delay, complex neurological impairment and spasticity (Sheth et al. 2015). Both unaffected, consanguinous parents carried that duplication, however. Given that similar duplications have been reported in individuals with neurodevelopmental concerns as well as in control populations and unaffected parents, the clinical significance of this variant is unclear. This patient also had a maternally inherited, pathogenic 1q21.1q21.2 duplication identified on chromosomal microarray that provides an explanation for his autism spectrum disoder, speech delay, and other phenotypic features.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677971 SCV000804126 uncertain significance not provided 2017-10-31 criteria provided, single submitter provider interpretation This 259 kilobase duplication includes a portion of the PARK2 gene. The PARK2 gene is associated with autosomal recessive juvenile parkison disease type 2. Copy number variants (deletions and duplications) including PARK2 have been reported at a higher prevalence in individuals with ADHD compared to controls, suggesting deletions and duplications of PARK2 may be associated with increased susceptibility of ADHD (Jarick et al. 2014). Deletions and duplications including PARK2 have been suggested as a possible genetic suscpetibility of autism spectrum disorder (Glessner et al. 2009; Yin et al. 2016). A duplication also has been identified in an individual with cognitive impairments who is underweight and has short stature (Scheuerle & Wilson 2011). PARK2 partial gene duplications have been reported in DECIPHER in individuals with intellectual disability and behavioral abnormalities (279450; 279451). The copy number variants reported previously contain multiple exons, whereas, this patient's duplication only includes exon 2 of the gene. PARK2 copy number variants have also been identified in control populations (nsv605163; nsv605167; nsv1034495; nsv1021711; nsv1019976). Follow-up quantitative PCR confirmed overexpression of PARK2 in both the patient and his father suggesting this duplication was paternally inherited. The patient's father has a reported history of dyslexia and learning disability in early schooling. Based on the relatively low number of patients reported in the literature and the presence of duplications and deletions in healthy controls/unaffected parents, further evidence is needed to definitively classify this variant. Whole exome sequencing was also completed for this patient and a paternally inherited variant of uncertain significance was identified.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677973 SCV000804128 uncertain significance not provided 2017-10-30 criteria provided, single submitter provider interpretation The 211 kilobase duplication on chromosome 22 contains 4 genes (TXN2, FOXRED2, EIF3D, and a portion of CACNG2), none of which are known to be associated with a clinical disorder when duplicated. The TXN2 gene is associated with autosomal recessive oxidative phosphylation deficiency- 29 and CACNG2 has been reported to cause autosomal dominant intellectual disability due to loss of function variants. A smaller overlapping duplication was identified in a developmental delay cohort (nsv1064827). An overlapping duplication has also been reported in a control (nsv1060004). Parental testing for our patient showed that this variant was paternally inherited. The patient's father does not have a history of autism spectrum disorders or developmental differences making this variant less likely to be anexplanation for the patient's neurodevelopmental history. The patient also underwent whole exome sequencing that identified a de novo variant in a gene of uncertain significance.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677974 SCV000804129 uncertain significance not provided 2018-02-02 criteria provided, single submitter provider interpretation This 507 kilobase duplication was detected in an individual with developmental delay, autism spectrum disorder, dermititis, and sleep difficulties. This duplication includes a portion of the TWIST2 and HDAC4 genes. TWIST2 is associated with the autosomal recessive disorder focal facial dermal dysplasis 3, Setleis type. Haploinsufficiency of HDAC4 is associated with brachydactyly-mental retardation syndrome. Duplications of these genes have not been associated with any particular conditions, however. The genetic testing laboratory indicated that they have seen duplications in the area, and several other duplications have been reported in DECIPHER, including a smaller overlapping variant in an individual with an abnormal face shape and intellectual disability (Case: 282651). This area is not known to vary in the general population. Parental testing has not been completed to date to determine if this variant is de novo or inherited.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677975 SCV000804130 likely pathogenic not provided 2017-11-16 criteria provided, single submitter provider interpretation This approximately 9.1 Mb deletion was detected in a 10 year old male with a history of expressive language disorder, autism spectrum disorder, sleep difficulties, and ADHD. This deletion includes 25 genes, 4 of which have been associated with clinical disorders. Two genes, NEK1 and MSMO1, are associated with autosomal recessive conditions indicating the patient is a carrier for these conditions. Heterozygous missense variants in the TLL1 gene have been associated with atrial septal defects (Stanczak et al. 2009). A single missense variant in PALLD has been reported to increase susceptibility to pancreatic cancer. PALLD has conflicting literature regarding its link to pancreatic cancer risk, however. Some publications indicate a risk while other literature refutes this. Functionally, this variant has been shown to result in overexpression of the gene, and overexpression of the gene is not expected with a gene deletion (Pogue-Geile et al. 2006). Overlapping deletions have been reported in the literature in an individual with Robin sequence, mild developmental delays and ulnar anomalies and another individual with congenital heart defect, growth delay, and minor skeletal anomalies (Keeling et al. 2001; Xu et al. 2012). Overlapping deletions have been identified in several individuals in DECIPHER including an individual with a broad forehead, downslanted palpebral fissures, high anterior hairline, and intellectual disability (Case 257358). An overlapping variant was also submitted to ClinVar/dbVar in an individual with abnormal facial shape and learning disability (nsv532029). A follow-up echocardiogram for the patient was normal. Parental follow-up testing identified that this deletion is secondary to a maternal balanced rearrangement. Maternal family history includes a relative with multiple miscarriages, a pregnancy with congenital anomaly of the brain/skull, and a child with a congenital heart defect suggesting others in the family may also carry the balanced rearrangement.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677976 SCV000804131 uncertain significance not provided 2018-03-16 criteria provided, single submitter provider interpretation This 305 kilobase duplication was identified in an individual with autism spectrum disorder, delayed milestones, hyperopia, and asthma. This duplication includes portions of the SHOX and PPP2R3B genes. Nonsense variants and deletions of SHOX have been reported in individuals with idiopathic short stature and Leri-Weill dyschondrosteosis (Huber et al. 2001; Niesler et al. 2002; Rappold et al. 2002). Partial or complete duplications of SHOX and/or its enhancer regions have also been reported in patients with these conditions (Thomas et al. 2009; Benito-Sanz et al. 2011). Duplications of SHOX have also been reported in individuals with tall stature. Tropeano et al. 2016 identified an enrichment of SHOX microduplications in individuals with neurodevelopmental disorders including autism sprectrum disorders compared to controls. The patient's father also was found to carry this duplication although testing could not determine if the variant is on his father's X or Y chromosome since its location on the Y chromosome in the patient could be the result of recombination between the X and Y chromosomes in his father. The patient's father is also of typical height but does have a reported history of speech delay and learning disability. The patient was found to also carry a maternally inherited, distal 16p11.2 deletion.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677977 SCV000804132 uncertain significance not provided 2018-03-19 criteria provided, single submitter provider interpretation This 393 kilobase duplication was identified in an individual with autism spectrum disorder, intellectual disability, ADHD, constipation, hypotonia, and expressive language disorder. This duplication is within cytogenetic band 16p13.3. The duplication includes 15 entire genes and the portion of two additional genes. Four genes are associated with clinical conditions - TSC2, PKD1, ABCA3, and TBC1D24. A portion of TSC2 is included in this duplication. Heterozygous loss of function variants in TSC2 are associated with tuberous sclerosis-2 and heterozygous loss of function variants in PKD1 are associated with adult type 1 polycystic kidney disease. ABCA3 is associated with autsomal recessive pulmonary surfactant metabolism dysfunction, and TBC1D24 is associated with several autosomal recessive conditions including early infantile epileptic encephalopathy, familial infantile myoclonic epilepsy, autosomal recessive deaness, and DOOR syndrome. Slightly larger duplications have been reported in DECIPHER in an individual with a kidney abnormality and mild intellectual disability (Case 263885) and in the general population in a single individual (chr16:2124547-2679656). No smaller overlapping duplications have been reported.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677978 SCV000804133 pathogenic not provided 2018-03-19 criteria provided, single submitter provider interpretation This 13.9 Mb duplication from cytogenetic band 20p12.2 to 20q11.21 was determined to be present in the form of a supernumerary marker chromosome in an 8 year old male with a history of syndactyly of the toes, speech delay, developmental delay, nystagmus, and spontaneous pneumothorax. In particular, this result likely is indicative of a ring chromosome. This supernumerary chromosome was identifid in 88% of cells. Ring chromosomes of a similar size have been reported in databases in and in the literature (http://ssmc-tl.com/sSMC.html; Daber et al. 2012; Kitsiou-Tzeli et al. 2009; Guediche et al. 2010). Reported phenotypes of individuals with supernumerary marker chromosome are highly variable with unaffected individuals, growth retardation, atrial septal defect, facial dysmorphism, and developmental delay (Daber et al. 2012; Guediche et al. 2010; Kitsiou-Tzeli et al. 2009).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677979 SCV000804134 uncertain significance not provided 2018-03-19 criteria provided, single submitter provider interpretation This 82 kilobase duplication was identified in a patient with a history of autism spectrum disorder and global developmental delay. The duplication includes only the NDP gene. Loss of function of the NDP is associated with Norrie disease and exudative vitreoretinopathy, features of which include blindness in infancy, progressive hearing loss, developmental delays, intellectual disability, and psychosis. Females may rarely have some clinical manifestations. The impact of duplications of the NDP gene are unclear. This region is not known to vary in the general population. The patient's mother was found to carry this same duplication.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677980 SCV000804135 uncertain significance not provided 2018-03-27 criteria provided, single submitter provider interpretation This 960 kilobase duplication was identified in a patient with a history of macrocephaly, dysmorphic features, atrial septal defect, agenesis of the corpus callosum, seizures, feeding disorder and global developmental delays. Parental testing confirmed this duplication was maternally inherited. This patient's mother has a reported history of anxiety, depression, and a mild learning disability. The duplication includes a portion of the CTNND2 gene, a gene that has been suggested to play a role in severity of intellectual disability in cri-du-chat syndrome. The impact of a partial duplication of this gene is unclear. Partial duplications have been reported in association with schizophrenia and in an individual with cerebral palsy (Vrijenhock et al. 2008; McMichael et al. 2014).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677981 SCV000804136 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 1.1 Mb duplication within Xq12 was identified in a patient with a history of autism spectrum disorder and expressive speech delay. The duplication includes the EDA2R and AR genes. Smaller duplications within this region have been identified in individuals with intellectual disability (Madrigal et al. 2007; DECIPHER Case 249562). This duplication was identified in this patient's mother who has a reported history of a learning disability. A 15q11.2 deletion was also identified in this patient and his mother.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677982 SCV000804137 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 431 kilobase duplication was identified in a female patient with a history of developmental delay, eczema, and a receptive-expressive language disorder. This duplication was inherited from the patient's mother who reportedly has a history of learning difficulties and anxiety. This duplication includes 13 genes. Of those genes, only STK13 has been associated with a clinical condition. Specifically, STK13 is associated with autosomal recessive spermatogenic failure in males. The relevance of a duplication of this, or any of the other included genes, is unknown. Smaller, overlapping duplications in this region have been reported in DECHIPER in an individual with macrocephaly, hydrocephalus, and intellectual disability (Case 288189), an individual with inappropriate behavior and intellectual disability (Case 288524), and an individual with intellectual disability and psychosis (Case 290429). Smaller, overlapping duplications have also been reported in controls (Cooper et al. 2011).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677983 SCV000804138 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 804 kilobase deletion was identified in a patient with speech delay , hypotonia, disruptive behaviors, learning disorder and dysmorphic features. The deletion includes seven genes, none of which have been associated with clinical disorders. The deletion was not identified in the patient's mother. His father has not undergone testing to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677984 SCV000804139 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 184 kilobase duplication was identified in a male with global developmental delay, microcephaly, autism spectrum disorder, hearing impairment, idiopathic toe walking, and dysmorphic features. The duplication includes 6 genes, only one of which, NSDHL, has been associated with a clinical condition. The effect of a duplication of this gene, or the others included, is unclear. The patient's mother was found to also carry this duplication. His mother does not have a reported history of neurodevelopmental concerns. The patient also underwent whole exome sequencing and was found to carry two variants of uncertain significance.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677985 SCV000804140 likely pathogenic Dilated cardiomyopathy 1G 2017-12-04 criteria provided, single submitter provider interpretation This deletion was identified in a patient with a history of intellectual disability, autism spectrum disorder, and insomnia. A mitochondrial disorder has previously been suspected. The deletion includes a portion of the TTN and PLEKHA3 genes. PLEKHA3 has not been associated with a known condition at this time. TTN, however, is expressed in the skeletal and cardiac muscles and has been associated with several conditions including isolated cardiomyopathies, limb-girdle muscular dystrophy, proximal myopathy with early respiratory involvement, Salih myopathy, and Tibial muscular dystrophy. The deletion includes exons 229-313 of the TTN gene. This deletion includes the A and M bands of the protein and this particular deletion has not been reported previously. Deletions and loss of function variants in TTN that impact the A and M bands, such as the deletion found in this patient, are associated with isolated cardiomyopathies. 18-25% of dilated cardiomyopathies have been associated with such TTN variants. Deletions such as this have also been detected in healthy individuals (Herman et al. 2012). This could be due to reduced penetrance, however. The variant was also detected in the patient's mother who does not have a reported history of cardiomyopathy.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677987 SCV000804142 uncertain significance not provided 2018-02-01 criteria provided, single submitter provider interpretation This 468 kilobase deletion was identified in a male with a history of mild intellectual disability and autism spectrum disorder. The deletion includes four genes, two of which (FANF and ANO5) are associated with a clinical disorder via autosomal recessive or dominant negative mechanisms.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677988 SCV000804143 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This deletion was identified in a patient with a history of developmental delay, learning disorder, articulation disorder, stereotypic movements, and ADHD. The deletion overlaps with the Williams-Beuren critical region but does not include the ELN gene. The effect of this deletion is unclear. The patient also carries a 22q11.21 duplication and both copy number variants were found to be paternally inherited.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677989 SCV000804144 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 625 kilobase duplication was identified in an individual with a history autism and global developmental delay/intellectual disability. This duplication includes 15 genes, none of which are known to be triplosensitive at this time. This duplication was also identified in the patient's mother who reportedly has a history of speech and learning delays, asthma, and reflux.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677990 SCV000804145 uncertain significance not provided 2018-03-22 criteria provided, single submitter provider interpretation This 98 kilobase duplication was identified in a patient with a history of learning disability, large stature, and overgrowth. The duplication includes ANKRD11 and SPG7 genes. These genes are associated with autosomal dominant KBG syndrome and spastic paraplegia type 7, respectively, but the effect of a duplication involving these genes is unclear. Copy number variation in this region has been reported in the general population. The duplication was detected in the patient's mother who does not have a reported history of neurodevelopmental concerns and is of typical stature. Additional genetic testing, including whole exome sequencing, has been performed and has not yieled an explanation for the patient's phenotype.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677991 SCV000804146 uncertain significance not provided 2018-03-27 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old female with autism spectrum disorder and speech delay. The duplication was also found to be maternally inherited. Nonsense variants and deletions of SHOX have been reported in individuals with idiopathic short stature and Leri-Weill dyschondrosteosis (Huber et al. 2001; Niesler et al. 2002; Rappold et al. 2002). Partial or complete duplications of SHOX and/or its enhancer regions have also been reported in patients with these conditions (Thomas et al. 2009; Benito-Sanz et al. 2011). Tall stature has also been reported with duplications. This patient and her mother are of typical height. Whole exome sequencing also identified a variant of uncertain significance in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677992 SCV000804147 uncertain significance not provided 2018-03-27 criteria provided, single submitter provider interpretation This 421 kilobase duplication was identified in a female with a history of short stature, ADHD, developmental language disorder, and borderline delays in visual-motor/problem-solving adaptive skills. Similar duplications that involve the ARX gene have been reported in males in the literature. Two males had developmental delay and intellectual disability while two others had typical intelligence, causing the authors to postulate that another genetic varaint explained or contributed to the two patients' neurodevelopmental phenotype (Popoviel et al. 2014). A likely pathogenic 22q11.21 atypical deletion was also identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677993 SCV000804148 likely pathogenic not provided 2018-03-27 criteria provided, single submitter provider interpretation This 412 kilobase deletion was identified in an 11 year old patient with a history of intellectual disability, autism spectrum disorder, amblyopia, and congenital pes planus. Copy number variants of Xq28 have been associated with intellectual disability in males. Females in the literature have been reportedly asymptomatic due to skewed X-inactivation. X-inactivation studies for this patient demonstrated completely skewed X-inactivation (100:0). Similar deletions have been reported in the literature and are thought to be embryonic lethal in males (El-Hattab 2011; El-Hattab 2015). A likely benign 19p13.2 duplication was also identified, and parental testing indicated that the Xq28 deletion was maternally inherited. This patient's mother has a history of 3 miscarriages. Given the skewed X-inactivation in this patient, this deletion does not explain her neurodevelopmental phenotype. The deletion is likely associated with the mother's increased risk for miscarriage.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677994 SCV000804149 pathogenic not provided 2018-03-27 criteria provided, single submitter provider interpretation This 2.6 Mb deletion was identified in a 10 year old male with a history of autism spectrum disorder, intellectual disability, and ADHD. Overlapping deletions of 15q24.1q24.2 have been identified in individuals with developmental delay, intellectual disability, dysmorphic features, hypotonia, digital anomalies, joint laxity and genital anomalies (Mefford et al. 2012; El-Hattab et al 2009; Van Esch et al. 2009). In the literature, deletions were de novo in each case. Parental follow-up testing has not been completed for this family to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677995 SCV000804150 uncertain significance not provided 2018-03-27 criteria provided, single submitter provider interpretation This 1.6 Mb deletion was identified in a 16 year old male with a history of migraines, autism spectrum disoder, and anxiety. Maternal inheritance has been ruled out, but paternal testing has not been completed to date. A pathogenic 16p11.2 duplication was also identified in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677996 SCV000804151 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This 41 kilobase deletion was identified in a 15 year old with a history of mild intellectual disability, speech and language disorder, and ADHD. The deletion includes a portion of the TPRX1 gene and the entire CRX gene. Deletions and loss of function variants in CRX have been associated with Leber congenital amaurosis 7, cone-rod dystrophy 2, and late-onset retinitis pigmentosa. Aside from a history of strabismus, the patient does not have a history of vision concerns. This deletion was determined to be maternally inherited. The patient's mother does not have a reported history of vision concerns.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677997 SCV000804152 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This 156 kilobase duplication was identified in a 7 year old with a history of intellectual disability, autism spectrum disorder, pica, hyperkinesis, sleep disturbance, and polyuria. The duplication was found to be maternally inherited. The duplicated region includes a portion of the UPRT and ZDHHC15 genes. A loss of function variant in ZDHHC15 has been reported in an individual with intellectual disability (Manosouri et al. 2015), but the impact of a duplication of this variant is unclear.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677998 SCV000804153 pathogenic not provided 2018-04-03 criteria provided, single submitter provider interpretation This approximately 2.2 Mb deletion was identified in a 13 year old female with a history of autism spectrum disorder, intellectual disability, and disruptive behavior. The deleted region includes 4 genes, including FOXP2. Loss of function FOXP2 variants are associated with speech and language disorders (Watkins et al 2002; Laffin et al. 2012; Fedorenko et al. 2016). Parental testing has not been completed to date.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000677999 SCV000804154 uncertain significance not provided 2018-04-03 criteria provided, single submitter provider interpretation This 323 kilobase duplication was identified in a male with a history of obesity, acanthosis nigricans, mixed receptive-expressive language disorder, motor stereotypy. The duplication includes 15 genes, but none are known to be triplosensitive.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678000 SCV000804155 uncertain significance Mitochondrial complex I deficiency 2018-03-28 criteria provided, single submitter provider interpretation This deletion was identified in a 6 year old female with microcephaly, history of developmental delays, Duane's syndrome, and alopecia. Parental testing was not completed. This deletion includes 10 genes including, STRN3, CPR33, ARGHAP5, NUBPL, and APA4S1. NUBPL sequencing and del/dup was negative for any additional changes in this gene. Individuals with deletions of NUBPL are typically asymptomatic carriers for complex 1 defiencicy. The clinical significance of this deletion is unknown.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678001 SCV000804156 uncertain significance not provided 2018-03-28 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old female with global developmental delay, mild dysmorphic features, and esotropia. Parental testing was not completed. This deletion included a portion of the gene AUTS2. Additionally, a variant of uncertain significance in the LRRC7 gene was identified through whole exome sequencing. The clinical significance of this duplication remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678002 SCV000804157 uncertain significance not provided 2018-03-28 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old male with language disorder, mild intellectual disability, mild hypotonia, disruptive behavior, sleep problems, and a history of global developmental delay. Parental testing was not completed. This duplication includes ten genes, three of which are associated with known clinical disorders; LRRK2, CNTN1, and PRICKLE1. The clinical significance of this duplication remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678003 SCV000804158 uncertain significance not provided 2018-03-28 criteria provided, single submitter provider interpretation This duplication was identified in a 8 year old male with autism spectrum disorder, ADHD, and unspecified cognitive abilities. Parental testing was not completed. This duplication includes a portion of two genes, FSCN2 and RAAP100. The clinical consequences of a partial duplication of FSCN2 and FAAP100 remain unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678004 SCV000804159 uncertain significance Autism 2018-03-28 criteria provided, single submitter provider interpretation This deletion was identified in a 13 year old male with autism spectrum disorder, intellectual disability, bipolar disorder, conduct disorder, periventricular leukomalacia, and asthma. Parental testing was not completed. This deletion includes a portion of CNTN4. Disruptions of CNTN4 have been reported in individuals with autism spectrum disorders, individuals with 3p- syndrome, and unaffected parents. It is not clear whether this deletion is related to the patient's neurodevelopmental history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678005 SCV000804160 likely pathogenic Autosomal recessive juvenile Parkinson disease 2 2018-03-01 criteria provided, single submitter provider interpretation This deletion was identified in a 3 year old male with bilateral intra-abdominal testicle, hypertelorism, conductive hearing loss, exotropia, global developmental delay, echogenic kidneys, abnormality of gait, and hyperkinesis. Parental testing was not completed. This deletion includes a portion of PARK2. Individuals with deletions of PARK2 are typically asymptomatic carriers for juvenile onset Parkinson Disease. There is a maternal family history of Parkinson Disease that onset before 30 years of age. This deletion does not explain the findings in this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678006 SCV000804161 uncertain significance not provided 2018-03-28 criteria provided, single submitter provider interpretation This deletion was identified in a 18 year old female with autism spectrum disorder, ADHD, and epilepsy. Parental testing was not completed. This deletion includes a portion of TMEM132C and the entirity of TMEM132B, SLC15A4, and GLT1D1, none of which are associated with a known clinical disorder at present. The clinical significance of this deletion remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678007 SCV000804162 uncertain significance Landau-Kleffner syndrome 2018-03-28 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with macrocephaly, speech delay, autism spectrum disorder, large ears, and developmental delays, and was maternally inherited. Patient's mother has a history of anxiety, with a family history of depression, learning disabilities, and seizures. This duplication includes a portion of GRIN2A, which is associated with focal epilepsy and speech disorder with or without intellectual disability for heterozygous variants. However the clinical signifiance of this duplication is not known at this time. A maternally inherited variant of uncertain significance in the TB1X gene was also identified through whole exome sequencing.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678008 SCV000804163 uncertain significance not provided 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 10 year old female with nonintractable epilepsy with simple partial seizures, short stature, intellectual disability, and MRI brain abnormalities, and was maternally inherited. Patient's mother has a history of bipolar disorder and depression. This deletion contains 13 genes, including six OMIM genes: PTPN12, MAGI2, GNAI1, GNAT3, CD36, and SEMA3C. Individuals with varaints in CD36 are typically asymptomatic carriers for platelet glycoprotein IV deficiency. The clinical significance of this deletion beyond carrier status remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678009 SCV000804164 uncertain significance not provided 2018-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 3 year old male with global developmental delays and a mixed receptive-expressive language disorder, and was found to be paternally inherited. Proband's father is reportedly unaffected, with no history of developmental delays. This duplication includes a portion of CBX7 and RPL3 genes, and the entirety of PDGFB. The clinical significance of a duplication of these genes is not currently known.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678010 SCV000804165 uncertain significance Autism 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 7 year old male with developmental speech disorder, disruptive behavior disorder, hypermetropia, constipation, ADHD, dysmorphic features, and a history of failure to thrive. Parental testing was not completed. This deletion includes a portion of CNTN4 and is within the larger distal 3p deletion syndrome region. CNTN4 is a candidate gene for autism spectrum disorders. The clinical significance of this deletion remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678011 SCV000804166 uncertain significance Acrodysostosis 2 with or without hormone resistance 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 10 year old male with autism spectrum disorder, macrocephaly, some hyperpigmented patches, some joint hypermobility, and anxiety. This deletion was also identified in the proband's twin brother who is similarly affected, but parental testing was not completed. This deletion includes three genes, including PDE4D , and is within the region for the much larger 5q12.1 deletion syndrome. The clinical significance of a deletion of these genes is not currently known.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678012 SCV000804167 likely pathogenic not provided 2018-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 11 year old male with intellectual disability, autism spectrum disorder, ADHD, and a seizure disorder. Parental testing was not completed. This duplication includes 18 OMIM genes and 31 other genes. Identical duplications have not been reported, though overlapping duplications have been noted in DECIPHER in individuals with autism, intellectual disability, seizures, and dysmorphic features. Due to the size of this duplication, it is likely the explanation for this patient's presentation.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678013 SCV000804168 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 4 year old male with global developmental delays, macrocephaly, and craniosynostosis. Parental testing was not completed and there was a strong maternal family history of breast and ovarian cancer. This deletion includes BRCA2 and explains this family history, but is likely non-contributory to the proband's medical and developmental history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678015 SCV000804170 pathogenic Intellectual disability, autosomal recessive 7 2018-03-30 criteria provided, single submitter provider interpretation This homozygous deletion was identified in a 6 year old male with global developmental delays, short stature, chiari malformation type I, exotropia, and microcephaly. Microarray showed 5-6% homozygosity. Analysis of a maternal sample confirmed she is a heterozygous carrier for this deletion. This deletion includes at least exons 2-6 of TUSC3, which is associated with an autosomal recessive form of intellectual disability. This deletion explains the neurodevelopmental phenotype of this patient.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678016 SCV000804171 uncertain significance Pigmented nodular adrenocortical disease, primary, 2 2018-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old male with history of global developmental delay, unspecified intellectual disability, ADHD, and esotropia. This patient also has a 15q11.2 deletion that is a known recurrent deletion associated with neurodevelopmental phenotypes and is believed to be the cause of this patient's symptoms. Parental testing was not completed for either variant, though there is a maternal family history for the 15q11.2 deletion. This duplication involves a portion of PDE11A. The clinical significance of the duplication of a portion of this gene is unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678017 SCV000804172 uncertain significance not provided 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 19 year old female with mild intellectual disability, ADHD, anxiety, and hyperphagia, and was found to be de novo. This patient has had normal whole exome sequencing. This deletion includes no genes that are associated with a known clinical phenotype at present. It is unclear at this time if this deletion is related to the patient's neurodevelopmental history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678018 SCV000804173 uncertain significance SIN3A-related intellectual disability syndrome due to a point mutation 2018-03-30 criteria provided, single submitter provider interpretation This duplication was identified in a 12 year old male with autism spectrum disorder, dysmorphic features, ADHD, a patent foramen ovale, and intellectual disability. Parental testing was not completed. This duplication includes 10 genes, including SIN3A. This duplication is within the 15q24 region, and similar duplications have been reported in patients with a similar phenotype to the recurrent deletion. The clinical significance of this duplication remains unclear.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678019 SCV000804174 uncertain significance not provided 2018-03-30 criteria provided, single submitter provider interpretation This deletion was identified in a 8 year old male with autism spectrum disorder, ADHD, and obesity. Parental testing was not completed. This deletion contains the non-coding exon 1 of RBFOX1. Deletions within RBFOX1 have conflicting reports of clinical significance ranging from causing epilepsy and autism spectrum disorders to being normal variation. The clinical significance of the deletion of a portion of this gene is remains unclear.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678021 SCV000804176 pathogenic not provided 2018-04-02 criteria provided, single submitter provider interpretation This deletion was identified in a 16 year old male with intellectual disability, seizure disorder, irritability, submucosal cleft palate, microcephaly, short stature, sleep disturbances, and Emery-Driefuss muscular dystrophy. Parental testing was not completed. This region contains at least 36 genes and was also identified on a karyotype. A 16p13.11 intragenic deletion of ABCC6 was also identified through array and a FHL1 likely pathogenic variant identified through a HCM gene panel. Due to its size, this deletion is believed to explain this patient's neurodevelopmental history in combination with his FHL1 mutation.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678022 SCV000804177 uncertain significance not provided 2018-04-12 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old male with microcephaly, dysmorphic features (large ears, close set eyes, pointed chin), behavioral concerns, pica, myopia, astigmatism, and was found to be maternally inherited. This patient's mother has a history of learning problems and a bicornuate uterus, and a family history of ADHD, special education needs, schizophrenia, depression, deafness, and substance abuse. This duplication includes 18 genes, including MYO9B, CPAMD8, and GTPBP3. The clinical significance of the duplication of these genes remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678023 SCV000804178 pathogenic Pitt-Hopkins-like syndrome 2 2018-04-12 criteria provided, single submitter provider interpretation This deletion was identified in a 17 year old male with autism spectrum disorder, intellectual disability, ADHD, aggression, constipation, and weight loss. Parental testing was not completed. This deletion includes a portion of NRXN1, and similar other deletions are have been reported in individuals with autism, intellectual disability, ADHD, schizophrenia, and/or seizures. Biallelic mutations in NRXN1 are associated with Pitt-Hopkins-like syndrome 2. Of note this patient does not have hyperbreathing, developmental regression, or facial dysmorphism. This deletion appears to explain the patient's medical history.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678024 SCV000804179 uncertain significance Autosomal dominant nonsyndromic hearing loss 56 2018-04-12 criteria provided, single submitter provider interpretation This duplication was identified in a 13 year old male with learning disabilities, ADHD, articulation disorder, and mild dysmorphic features, and was maternally inherited. The patient's mother has a history of depression, anxiety, and five first trimester miscarriages. This duplication includes the entirity of TNC and DEC1, and a portion of PAPPA and TNFSF8. There is no family history of hearing loss. The clinical significance of carrying three copies of these genes is unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678025 SCV000804180 uncertain significance Hypertrophic cardiomyopathy 16 2018-04-12 criteria provided, single submitter provider interpretation This duplication was identified in a 10 year old male with intellectual disability, macrocephaly, autism spectrum disorder, hyperkinesis, sleep disturbances, and hypodontia. Parental testing was not completed. This duplication includes the gene MYOZ2, which is associated with hypertrophic cardiomyopathy. There is one overlapping duplication reported in the literature that includes two additional genes in a patient with Cantu syndrome. The clinical significance of this duplication remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678026 SCV000804181 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2018-04-12 criteria provided, single submitter provider interpretation This duplication was identified in a 9 year old male with autism spectrum disorder, and a history of ADHD and developmental delays. Parental testing was not completed. This duplication includes two genes, KCTD3 and USH2A. Of note this patient is negative for hearing loss or retinitis pigmentosa. The clinical significance of this duplication remain unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678027 SCV000804182 uncertain significance Charcot-Marie-Tooth disease axonal type 2K 2018-04-13 criteria provided, single submitter provider interpretation This deletion was identified in a 3 year old female with receptive-expressive language disorder, premature birth, hypotonia, poor feeding, posteriorly rotated ears, and up-slanting palpebral fissures, and is maternally inherited. This deletion includes six genes, including TMEM70, GDAP1, and JPH1. Individuals with single variants in TMEM70 are typically asymptomatic carriers for mitochondrial complex V deficiency. GADP1 and JPH1 have been described to cause an autosomal dominant Charcot-Marie-Tooth disease type 2K with muscle weakness and atrophy. Patient's mother reportedly has similar facial features and short stature, though no muscle concerns reported. The clinical significance of this deletion remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678029 SCV000804184 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 7 year old female with short stature, macrocephaly, intellectual disability, global developmental delays, midface hypoplasia, high forehead, periorbital fullness, thick eyebrows, broad nasal root, low nasal bridge, up-turned nasal tip, short philtrum, full lips, wide mouth, pointed chin, decreased motor strength, joint hyperflexibility, increased lordosis, hyperextensible joints, flat feet, and was found to be maternally inherited. This patient's mother has anxiety, asthma, required learning supports, and had a heart murmur. Mother and maternal grandmother reportedly had a history of infertility. This duplicated region contains six regions, including CDHR1, RGR, and a portion of CCSER2. The clinical significance of carrying three copies of these genes is unclear at this time. A second maternally inherited variant was identified through chromosomal microarray, a 1q32.3 deletion of uncertain significance.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678030 SCV000804185 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This duplication was identified in a 3 year old female with autism spectrum disorder, overgrowth, macrocephaly, fine motor delay and speech delay, and was maternally inherited. This patient's mother has average cognitive abilities and has anxiety, depression, and OCD. This duplication includes a portion of VCX3A and VCX2, and the entirety of HDHD1, STS, VCX, and PNPLA4. Identical duplications in this region have been reported with conflicting reported pathogenicity (benign-pathogenic) in individuals with features including developmental delay, seizures, autism spectrum disorder, and intellectual disability. The clinical significance of three copies of these genes remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678031 SCV000804186 uncertain significance not provided 2018-04-13 criteria provided, single submitter provider interpretation This deletion was identified in a 9 year old male with intellectual disability, gross motor delay, infantile benign external hydrocephaly, ADHD, overweight, and sleep difficulties, and was paternally inherited. This patient's father has bipolar and intellectual disability. This deletion includes ADARB2 and a portion of WDR37. Neither of these genes is associated with a known clinical disorder at present. Overlapping deletions have been seen in individuals with developmental delay or dysmorphic features, with some including the gene ZMYND11 that is known to cause intellectual disability. The clinical significance of this deletion remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678033 SCV000804188 uncertain significance not provided 2018-04-16 criteria provided, single submitter provider interpretation This duplication was identified in a 5 year old male with overgrowth, developmental regression, speech delay, autism spectrum disorder, with history of an EEG with paroxysmal discharges that were considered epileptiform, and a brain MRI that noted scattered foci of T2 hyperintensity in the cerebral white matter bilaterally. Parental testing was not completed. This duplication contains seven genes, including GCSH, and a portion of an eighth gene. The clinical significance of three copies of these genes remains unclear at this time.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678034 SCV000804189 pathogenic Spinocerebellar ataxia type 15/16 2018-04-16 criteria provided, single submitter provider interpretation This deletion was identified in a 4 year old male with global developmental delays, seizures, hypermetropia of both eyes, amblyopia of right eye, hemangioma, dysmorphic features (triangular facies, broad forehead, prominent crus, almond shaped eyes, thick eyebrows, hypoplastic alae, prominent nasal tip, thin lips, narrow palate, pointed chin, decreased motor strength), partial agenesis of the corpus callosum, and prenatal exposure to cigarettes. Parental testing was not completed for the patient's father and the patient's mother tested negative. This deletion contains two genes SUMF1 and SETMAR, and a portion of ITPR1. Heterozygous carriers of SUMF1 variants are most often asymptomatic carriers for multiple sulfatase deficiency. Deletions of ITPF1 have been shown to cause spinocerebellar ataxia type 15. Microarray also identified a likely pathogenic duplication at 13q13.3.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System RCV000678035 SCV000804190 likely pathogenic not provided 2018-04-16 criteria provided, single submitter provider interpretation This duplication was identified in a 4 year old male with global developmental delays, seizures, hypermetropia of both eyes, amblyopia of right eye, hemangioma, dysmorphic features (triangular facies, broad forehead, prominent crus, almond shaped eyes, thick eyebrows, hypoplastic alae, prominent nasal tip, thin lips, narrow palate, pointed chin, decreased motor strength), partial agenesis of the corpus callosum, and prenatal exposure to cigarettes. Parental testing was not completed for the patient's father and the patient's mother tested negative. This duplication contains two genes, MIR17HG and GPC5, and a portion of GPC6. Similar duplications including MIR17HG and a portion of GPC5 have been reported in two individuals: one with postaxial polydactyly, overgrowth, autistic features, and dysmorphic features and was inherited from a similarly affected mother, and in a patient with developmental delay, autism spectrum disorder, short stature, macrocephaly, brachydactyly, clinodactyly, and dysmorphic features that was also identified in a parent and sibling with similar features. This duplication likely contributes to the phenotype of this patient. Microarray in our patient also identified a pathogenic deletion at 3q26.1, which is associated with spinocerebellar ataxia type 15.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754994 SCV000804194 pathogenic Short-rib thoracic dysplasia 19 with or without polydactyly 2018-07-03 criteria provided, single submitter research
Daryl Scott Lab, Baylor College of Medicine RCV000681464 SCV000808912 pathogenic Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart 2017-09-12 criteria provided, single submitter clinical testing
Medical Genetics Lab, Policlinico S. Orsola.Malpighi RCV000681666 SCV000809058 uncertain significance Intellectual disability, mild 2018-09-27 criteria provided, single submitter clinical testing This is a homozygous deletion that involves only the BTBD9 gene, identified in a patient with mild intellectual disability, microcephaly, mild dismorphism. Parents are healthy, second-degree cousins of Italian origin, and are heterozygous carriers of the deletion. A healthy brother is also heterozygous. BTBD9 has not been currently associated to any monogenic disorder in humans, but it is expressed in brain and is a good candidate for neurodevelopmental disorders.
Undiagnosed Diseases Network, NIH RCV000708570 SCV000837689 pathogenic Cornelia de Lange syndrome 5 2018-03-16 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000708593 SCV000837720 likely pathogenic Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome 2018-01-04 criteria provided, single submitter clinical testing
Genetics - Synnovis, NHS South East Genomic Laboratory Hub RCV003232084 SCV000845782 pathogenic Ectrodactyly 2018-10-31 criteria provided, single submitter clinical testing Duplications of this region are associated with split hand/foot malformation 3.
Genetics - Synnovis, NHS South East Genomic Laboratory Hub RCV003232085 SCV000845790 pathogenic Ectrodactyly criteria provided, single submitter clinical testing Duplications of this region are associated with split hand/foot malformation 3.
Eurofins Ntd Llc (ga) RCV000734617 SCV000862771 other not provided 2018-08-06 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000735205 SCV000863411 uncertain significance Branched-chain keto acid dehydrogenase kinase deficiency 2018-03-16 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000735209 SCV000863416 likely pathogenic TAX1BP3-related arrhythmogenic right ventricular cardiomyopathy 2018-11-27 criteria provided, single submitter clinical testing A hemizygous c.233T>C (p.M78T) variant in the TAX1BP3 gene was detected in three brothers (14yo male, 20yo male, and male that died suddently at age 17) with similar symptoms. Exome sequencing showed that all three brothers are hemizygous, the mother is heterozygous, and the father is negative for this change. Concurrent array analysis revealed a heterozygous copy number loss of approximately 238 Kb in size (genomic position chr17:3394299- 3632836) in all three brothers. This large deletion encompasses the entire TAX1BP3 gene. SNP arrays detected this deletion as heterozygous in all three brothers and the father. The mother is negative for the deletion. Therefore, the 238 Kb deletion and the c.233T>C (p.M78T) variant are located on two chromosomes (in trans configuration). We believe the combination of the missense variant and deletion in trans is likely pathogenic.
Undiagnosed Diseases Network, NIH RCV000735211 SCV000863419 pathogenic Developmental and epileptic encephalopathy, 4 2017-10-23 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000735212 SCV000863420 pathogenic Deafness-infertility syndrome 2017-11-14 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000735214 SCV000863422 pathogenic Charcot-Marie-Tooth disease, type IA 2018-06-26 criteria provided, single submitter clinical testing 1.4Mb pathogenic copy number gain on chromosome 17 at 17p12. Detected by chromosomal microarray.
Undiagnosed Diseases Network, NIH RCV000735229 SCV000863438 pathogenic Wieacker-Wolff syndrome 2017-06-15 criteria provided, single submitter clinical testing 95 kb deletion includes coding exon 1 which explains X-linked pathogenicity. Carrier females may have mild features of Wieacker-Wolff syndrome compared to hemizygous males.
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano RCV000785663 SCV000863549 uncertain significance Silver Russell Syndrome-related disorder 2018-12-06 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735898 SCV000864010 uncertain significance Trichorhinophalangeal dysplasia type I 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735899 SCV000864011 uncertain significance Trichorhinophalangeal dysplasia type I 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735900 SCV000864012 pathogenic Trichorhinophalangeal dysplasia type I 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735901 SCV000864013 pathogenic Hypoparathyroidism, deafness, renal disease syndrome 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735904 SCV000864016 uncertain significance Cerebellar dysfunction with variable cognitive and behavioral abnormalities 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735905 SCV000864017 benign Cerebellar dysfunction with variable cognitive and behavioral abnormalities 2018-12-17 criteria provided, single submitter research
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000735906 SCV000864018 uncertain significance Cerebellar dysfunction with variable cognitive and behavioral abnormalities 2018-12-17 criteria provided, single submitter research
Raymond Lab, University of Cambridge RCV000850220 SCV000897737 pathogenic Intellectual disability 2019-02-13 criteria provided, single submitter research
Biochemistry Laboratory of CDMU, Chengde Medical University RCV000768460 SCV000899223 likely pathogenic not provided criteria provided, single submitter case-control
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852264 SCV000900011 likely pathogenic Hereditary factor IX deficiency disease 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852266 SCV000900014 likely pathogenic Hereditary factor X deficiency disease 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852267 SCV000900015 likely pathogenic Abnormal bleeding 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852258 SCV000900022 likely pathogenic 11q partial monosomy syndrome 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852269 SCV000900025 likely pathogenic Thrombocytopenia 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852261 SCV000900027 likely pathogenic Hereditary antithrombin deficiency 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852271 SCV000900030 likely pathogenic Deep venous thrombosis 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852272 SCV000900031 likely pathogenic Protein S deficiency disease 2019-02-01 criteria provided, single submitter research
Undiagnosed Diseases Network, NIH RCV000786772 SCV000924629 likely pathogenic 1p13.3 deletion syndrome 2019-06-06 criteria provided, single submitter clinical testing Both loss- and gain-of-function mutations in the KCNA2 gene cause early infantile epileptic encephalopathy-32 (EIEE-32; # 616366) (Allen, et al. Epilepsia. 2016 Jan;57(1):e12-7.). EIEE causes severe epilepsy with variable types of seizures, and neurological deficits, including intellectual disability, and delay of psychomotor and language development. Ataxia, tremor, and myoclonus have also been associated with EIEE. The onset of seizures has been reported to typically occur at less than five years of age and may remit later in childhood, however, one individual with a deletion involving all of the KCNA2 gene was reported to have onset of generalized tonic-clonic seizures at the age of 14 along with intellectual disability (Lal, et al. PLoS Genet. 2015 May 7;11(5):e1005226.) Within this deletion, two other genes, SLC25A24 and GNAI3 have been associated with autosomal dominant disorders. Mutations in SLC25A24 have been associated with Gorlin-Chaudhry-Moss syndrome and Fontaine progeroid syndrome (FPS, OMIM #612289), which have overlapping clinical features. Several studies suggest that the SLC25A24 mutations for these indiviudals induce a gain of function. Mutations of GNAI3 have been identified in patients with auriculocondylar syndrome-1 (ARCND1 or ACS, OMIM #602483), and it is thought that ACS is not caused by GNAI3 haploinsufficiency. For both of these disorders, whole gene deletions would not be expected to result in the same mechanism or clinical features of these disorders. Additionally, six genes are associated with autosomal recessive conditions, for which this deletion likely infers a carrier status. Chudley-McCullough syndrome (CMCS; #604213) is caused by homozygous or compound heterozygous mutation in the GPSM2 gene, while autosomal recessive mental retardation-60 (MRT60; # 617432) and autosomal recessive mental retardation-48 (MRT48; #616269) are caused by mutations in the TAF13 and SLC6A17 genes, respectively. Pontocerebellar hypoplasia type 9 (PCH9; #615809) is caused by mutations in both copies of the AMPD2 gene and frontonasal dysplasia-1 (FND1; OMIM #136760), are caused by mutations in both copies of the ALX3 gene.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787370 SCV000926332 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787371 SCV000926333 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787372 SCV000926334 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787374 SCV000926336 likely pathogenic Skeletal dysplasia 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787375 SCV000926337 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787376 SCV000926338 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787377 SCV000926339 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787378 SCV000926340 uncertain significance Tooth agenesis; Kidney disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787379 SCV000926341 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787381 SCV000926343 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787382 SCV000926344 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787383 SCV000926345 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787384 SCV000926346 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787385 SCV000926347 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787386 SCV000926348 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787387 SCV000926349 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787388 SCV000926350 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787389 SCV000926351 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787390 SCV000926352 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787391 SCV000926353 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787392 SCV000926354 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787395 SCV000926357 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787396 SCV000926358 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787397 SCV000926359 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787399 SCV000926361 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787400 SCV000926362 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787401 SCV000926363 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787402 SCV000926364 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787403 SCV000926365 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787404 SCV000926366 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787405 SCV000926367 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787406 SCV000926368 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787407 SCV000926369 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787409 SCV000926371 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787410 SCV000926372 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787411 SCV000926373 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787412 SCV000926374 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787413 SCV000926375 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787414 SCV000926376 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787415 SCV000926377 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787416 SCV000926378 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787417 SCV000926379 uncertain significance Encephalopathy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787418 SCV000926380 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787419 SCV000926381 uncertain significance Epilepsy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787420 SCV000926382 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787421 SCV000926383 uncertain significance Internal malformations 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787422 SCV000926384 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787425 SCV000926387 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787426 SCV000926388 pathogenic Epilepsy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787428 SCV000926390 pathogenic Epilepsy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787429 SCV000926391 uncertain significance Skeletal dysplasia 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787430 SCV000926392 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787435 SCV000926397 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787436 SCV000926398 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787437 SCV000926399 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787439 SCV000926401 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787440 SCV000926402 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787441 SCV000926403 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787442 SCV000926404 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787443 SCV000926405 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787444 SCV000926406 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787445 SCV000926407 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787447 SCV000926409 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787448 SCV000926410 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787449 SCV000926411 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787450 SCV000926412 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787451 SCV000926413 uncertain significance Arthrogryphosis 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787452 SCV000926414 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787453 SCV000926415 uncertain significance Premature ovarian failure 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787454 SCV000926416 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787455 SCV000926417 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787457 SCV000926419 likely pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787461 SCV000926423 uncertain significance Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787463 SCV000926425 uncertain significance Growth abnormality 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787464 SCV000926426 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787465 SCV000926427 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787466 SCV000926428 pathogenic Neurodevelopmental disorder 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787468 SCV000926430 likely pathogenic Muscle dystrophy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787469 SCV000926431 uncertain significance Internal malformations 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787470 SCV000926432 likely pathogenic Muscle dystrophy 2019-04-09 criteria provided, single submitter clinical testing
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000787472 SCV000926434 pathogenic Skeletal dysplasia 2019-04-09 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000754630 SCV000930559 pathogenic Kilquist syndrome 2019-01-01 criteria provided, single submitter clinical testing Homozygous deletion of SLC12A2 due to uniparental paternal isodisomy. Deletion from intron 1 to the beginning of exon 7 (chr5:127441491‐ 127471419) including an inversion of 34 base pairs (chr5:127441491‐127471419delins34). As a carrier, the father shows no symptoms of Kilquist syndrome. This family has been reported in PMID: 30740830.
Undiagnosed Diseases Network, NIH RCV000791288 SCV000930566 likely pathogenic Kleefstra syndrome 2 2017-12-15 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000824954 SCV000965989 pathogenic Intellectual disability, severe 2016-01-01 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000824957 SCV000965998 pathogenic Marfan syndrome 2016-01-01 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000825024 SCV000966219 pathogenic Obesity due to leptin receptor gene deficiency 2018-07-17 criteria provided, single submitter clinical testing Observed as a homozygote.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000825026 SCV000966221 pathogenic 15q11q13 microduplication syndrome 2018-10-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825598 SCV000966941 likely pathogenic Lynch syndrome 2018-04-27 criteria provided, single submitter clinical testing This MSH2 variant is a deletion encompassing exons 8 to 15, though it should be noted that its exact breakpoints cannot be determined due to limitations of the testing methodology. This multi-exon deletion has been reported in 1 individual with Lynch syndrome and 1 individual referred for hereditary cancel panel testi ng at a diagnostic laboratory (Liu 1994, Susswein 2015) and has also been report ed by another clinical laboratory in ClinVar (Variation ID# 417806). Deletions w ithin exons 8 to 15 as well as larger deletions spanning these exons have been r eported in multiple individuals with colorectal cancer in the Human Gene Mutatio n Database (HGMD: Stenson 2017). This deletion is predicted to result in a prema ture stop codon in the last exon on the MSH2 gene (exon 16), and while it is mor e likely to escape nonsense mediated decay, it is expected to result in a trunca ted protein where approximately half of the MSH2 coding sequence is removed. In summary, although additional studies are required to fully establish its clinica l significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PV S1_strong, PM2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825957 SCV000967442 uncertain significance not specified 2018-10-29 criteria provided, single submitter clinical testing This deletion encompasses MIR96; however, please note that the exact breakpoints of this deletion could not be determined by this assay. Several multi-gene dele tions encompassing MIR96 have been reported in individuals with developmental de lay and other features in the DECIPHER database, however hearing loss was not re ported for any of these individuals and the deletions reported impacted >200 gen es (https://decipher.sanger.ac.uk). Recurrent smaller deletions encompassing onl y the miR-183/182/96 cluster and the 3? end of an adjacent gene (NRF1) have been reported in dbVar in several control population studies with one study reportin g a MAF of 0.3% (12/4052 alleles) in healthy controls (Shaikh 2009), which sugge st that the loss of MIR96 is not likely to be disease causing. However, due to t he technical limitation of this assay in detecting the breakpoints and length of this deletion, the impact of this deletion on neighboring disease-relevant gene s cannot be determined. In summary, although loss of MIR96 is not expected to be related to hearing loss, due to uncertainty regarding the size and breakpoints of the deletion, the clinical significance of this deletion is uncertain. ACMG/A MP criteria applied: none.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826027 SCV000967517 uncertain significance not specified 2018-04-12 criteria provided, single submitter clinical testing The c.(?_-15)_(1947_?)dup variant in RAF1 is a duplication of the coding exons: exons 2-17. The exact breakpoints of this gain cannot be determined by this meth od, and exon 1 is not included in the test as it is non-coding. Gains of the RAF 1 gene, including large CNVs that include RAF1 and other genes, have been report ed in several individuals with variable phenotypes as well as in healthy control s. Large CNVs encompassing RAF1 and additional genes been reported in one indivi dual with TOF and two individuals with varying phenotypes and severity, one of w hich was inherited from an unaffected father (Silversides 2012, Luo 2012, Lissew ski 2015). Whole gene gains of RAF1 have also been reported in 3 individuals in Decipher (http://decipher.sanger.ac.uk/) with ID and other phenotypes, two of wh ich were inherited from an unaffected parent. Large CNVs encompassing RAF1 and a dditional genes has been reported as uncertain in ClinVar, in ten individuals in the Database of Genomic Variants (DGV, http://dgv.tcag.ca), and in 3/41234 tota l chromosomes in Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org). In summary, the clinical significance of this partial gain of the RAF1 gen e is uncertain.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826068 SCV000967562 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing The duplication of exons 192-244 in TTN has not been previously reported in indi viduals with cardiomyopathy. It is unknown if this duplication is in tandem, wit h the possibility of altering protein expression/function, or was inserted in a different locus, which may not impact the protein. A similar duplication, involv ing exons 193-244, was identified by our laboratory in one individual with DCM. A larger intragenic duplication involving this region was identified in one cont rol sample (Kidd 2008). In summary, the clinical significance of this duplicatio n is uncertain.
Academic Department of Medical Genetics, University of Cambridge RCV000850066 SCV000992232 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research
Academic Department of Medical Genetics, University of Cambridge RCV000850067 SCV000992233 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research
Academic Department of Medical Genetics, University of Cambridge RCV000850068 SCV000992234 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research
Academic Department of Medical Genetics, University of Cambridge RCV000850149 SCV000992322 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research
Academic Department of Medical Genetics, University of Cambridge RCV000850150 SCV000992323 pathogenic Hereditary leiomyomatosis and renal cell cancer; Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Observed in an individual with phenotype specific for variants in one of the deted genes
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000851176 SCV000993410 likely pathogenic Marfanoid habitus and intellectual disability criteria provided, single submitter research
GeneDx RCV000984805 SCV000998934 likely pathogenic not provided 2018-02-26 criteria provided, single submitter clinical testing The c.5419_5420insAlu variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is the result of an Alu mobile insertion element interrupting coding sequence in exon 30 and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 1999). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
GeneDx RCV001004047 SCV000998935 pathogenic not provided 2019-06-03 criteria provided, single submitter clinical testing The c.1276_1277insAlu variant in the EFTUD2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This individual harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 1999). Therefore, we interpret c.1276_1277insAlu as a pathogenic variant.
GeneDx RCV000984894 SCV000998936 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing The c.426_427insAlu variant in the ETFB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This fetus harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 2000). Therefore, we interpret c.426_427insAlu as a pathogenic variant.
GeneDx RCV000984895 SCV000998937 pathogenic not provided 2019-06-21 criteria provided, single submitter clinical testing Founder mutation in the Ashkenazi Jewish population which is observed in homozygous state in multiple unrelated patients in published literature (Tucker et al., 2011; Berzoykin et al., 2015), and not observed in homozygous state in controls. Mobile insertion element that consists of Alu sequence that is 353 base pairs in length, also described as c.1284_1285ins353 or c.428_429ins353 in the literature. Published functional studies demonstrate a damaging effect (loss of retina-specific isoform of MAK) (Tucker et al., 2011). Not observed in large population cohorts (Database of Genomic Variants). We interpret this as a Pathogenic Variant.
GeneDx RCV000984896 SCV000998938 pathogenic not provided 2018-02-01 criteria provided, single submitter clinical testing The c.1926_1927insAlu variant in the NSD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This individual harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 2000). Additionally, Alu-mediated recombination leading to microdeletions of the NSD1 gene has been previously described in individuals with Sotos syndrome (Mochizuki et al., 2008). Therefore, we interpret c.1926_1927insAlu as a pathogenic variant.
GeneDx RCV000985237 SCV000999045 pathogenic not provided 2018-06-12 criteria provided, single submitter clinical testing The c.431_432insAlu variant in the OFD1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This individual harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 1999). Therefore, we interpret c.431_432insAlu as a pathogenic variant.
GeneDx RCV000985238 SCV000999047 likely pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The c.131+2_c.131+3insAlu variant in the SLC26A3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This individual harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 2000). Therefore, we interpret c.131+2_c.131+3insAlu as a likely pathogenic variant.
GeneDx RCV000985239 SCV000999048 pathogenic not provided 2019-03-13 criteria provided, single submitter clinical testing The c.8932_8933insAlu variant in the USH2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This individual harbors a mobile insertion element that consists of Alu sequence that is approximately 300 base pairs in length and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian, 1999). Therefore, we interpret c.8932_8933insAlu as a pathogenic variant.
GeneDx RCV000985240 SCV000999049 pathogenic not provided 2018-11-15 criteria provided, single submitter clinical testing The c.1600_1601insAlu variant in the ZEB2 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is the result of an Alu mobile insertion element interrupting coding sequence in exon 8 and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 1999). Therefore, this variant is considered a pathogenic variant.
GeneDx RCV000985241 SCV000999050 pathogenic not provided 2019-08-22 criteria provided, single submitter clinical testing Has not been previously reported as pathogenic or benign to our knowledge. Not observed in large population cohorts (MacDonald et al., 2014). This variant is the result of an Alu mobile insertion element interrupting coding sequence in exon 30 and is predicted to cause loss of normal protein function. Mobile insertion elements, including retrotransposon-mediated events such as Alu inserts, are estimated to account for 1 in 600 disease causing variants (Kazazian et al., 1999). We interpret this as a Pathogenic Variant.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001171631 SCV000999934 pathogenic Intellectual disability 2019-11-18 criteria provided, single submitter research The variant is a deletion overlapping coding exons of CRHR1, SPPL2C, MAPT, STH genes, and exons 3-15 of the KANSL1 gene. Deletions overlapping KANSL1 gene have been shown to cause Koolen-de Vries syndrome, a clinically heterogeneous disorder characterized by hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism (PMID: 22544363, 26306646). This variant was identified in an adult undergoing exome sequencing due to a history of intellectual disability and developmental delay. For these reasons, this variant has been classified as Pathogenic.
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001031017 SCV001160792 pathogenic Proximal 16p11.2 microdeletion syndrome 2019-12-11 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001005017 SCV001164581 likely pathogenic Duchenne muscular dystrophy 2018-12-03 criteria provided, single submitter research The heteroygous deletion variant in DMD was identified by our study in one female with Duchenne Muscular Dystrophy. Manifesting female carriers of DMD have been previously reported (Mercieret al., 2013). This deletion variant in DMD has not been previously reported in individuals with Duchenne Muscular Dystrophy and was absent from large population studies. This variant is a deletion of Exon 1 and 2 and is predicted to impact the protein, including the start codon. Loss of function of the DMD gene is an established disease mechanism in autosomal recessive Duchenne Muscular Dystrophy. A splice site variant affecting Exon 2 has been reported pathogenic for Duchenne Muscular Dystrophy in ClinVar by Invitae and EGL Genetic Diagnostics, suggesting that Exon 2 is important for protein function (Variation ID: 283346). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001027727 SCV001190163 pathogenic Common variable immunodeficiency 2019-01-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV001027728 SCV001190164 pathogenic Common variable immunodeficiency 2019-01-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV001027643 SCV001190215 likely pathogenic Inherited Immunodeficiency Diseases 2019-01-01 criteria provided, single submitter research
Central Laboratory, The First Hospital of Lanzhou University RCV001200047 SCV001190325 pathogenic 22q13.3 interstitial deletion 2020-03-09 criteria provided, single submitter clinical testing
Invitae RCV001089808 SCV001245295 pathogenic Hereditary breast ovarian cancer syndrome 2019-02-04 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the BRCA2 gene (c.6003_6004insAlu), causing a frameshift at codon 2002 (p.Glu2002fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BRCA2-related disease. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089809 SCV001245296 pathogenic Hereditary breast ovarian cancer syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the BRCA2 gene (c.2844_2845insAlu), causing a frameshift at codon 948 (p.Val948fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BRCA2-related disease. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this allele has been classified as Pathogenic.
Invitae RCV001089810 SCV001245297 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2019-06-06 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 326 of the TTN mRNA (c.85261_85262insAlu), causing a frameshift at codon 28421 (p.Ile28421fs). The exact size and sequence of the insertion cannot be determined by the current assay. While this insertion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Invitae RCV001089811 SCV001245298 pathogenic not provided 2019-06-10 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 22 of the PHEX mRNA (c.2193_2194insAlu), causing a frameshift at codon 731 (p.Phe731fs). The exact size and sequence of the insertion cannot be determined by the current assay. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acids of the PHEX protein. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the C-terminus of the PHEX protein. Other variant(s) that disrupt this region (p.Arg747*) have been determined to be pathogenic (PMID: 9199930, 9768674). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089812 SCV001245299 pathogenic Neurofibromatosis, type 1 2019-04-07 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 2 of the NF1 mRNA (c.195_196insAlu), causing a frameshift at codon 65 (p.Val65fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538) and other Alu-mediated insertions in NF1 have been reported to be de novo in the literature (PMID: 1719426). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089813 SCV001245300 pathogenic Ataxia-telangiectasia syndrome 2019-07-05 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 5 of the ATM gene (c.364_365delinsAlu), causing a frameshift at codon 122 (p.Asnfs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089815 SCV001245302 uncertain significance Mitochondrial trifunctional protein deficiency; Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency 2019-09-05 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in intron 2 of the HADHA gene (c.110-25_110-24insAlu). It does not directly change the encoded amino acid sequence of the HADHA protein and it is unknown how it will affect the protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HADHA-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV001089816 SCV001245303 pathogenic Neurofibromatosis, type 1 2019-05-03 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 32 of the NF1 gene (c.4320_4321insAlu), causing a frameshift at codon p.Met1440 (p.Met1440fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089817 SCV001245304 pathogenic Familial cancer of breast 2019-06-07 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 13 of the CHEK2 gene (c.1406_1407insAlu), causing a frameshift at codon 469 (p.Val469fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with CHEK2-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089818 SCV001245305 pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2019-12-22 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 6 of the CRB1 gene (c.1454_1455insAlu), causing a frameshift at codon 486 (p.Leu486fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CRB1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in CRB1 are known to be pathogenic (PMID: 10508521, 22065545, 23379534, 25412400, 26957898, 28041643, 29391521). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089819 SCV001245306 pathogenic Ataxia-telangiectasia syndrome 2019-12-15 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 19 of the ATM mRNA (c.2852_2853insAlu), causing a frameshift at codon 951 (p.Leu951fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089820 SCV001245307 pathogenic Hereditary breast ovarian cancer syndrome 2019-02-16 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 16 of the BRCA2 mRNA (c.7665_7666insAlu), causing a frameshift at codon 2556 (p.Asn2556fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Although this variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584) and other Alu-mediated insertions in BRCA2 have been reported in the literature (PMID: 20232141). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089821 SCV001245308 pathogenic Ataxia-telangiectasia syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 20 of the ATM gene (c.3055_3056insAlu), causing a frameshift at codon 1019 (p.Leu1019fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with ATM-related disease. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089823 SCV001245310 pathogenic PTEN hamartoma tumor syndrome 2019-05-14 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 5 of the PTEN mRNA (c.432_433insAlu), causing a frameshift at codon 145 (p.Phe145fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Although this variant has not been reported in the literature, loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675) and similar Alu-mediated insertions in PTEN have been reported in individuals affected with Cowden syndrome (PMID: 28513612). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089824 SCV001245311 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2019-12-15 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 3 of the SDHB gene (c.250_251insAlu), causing a frameshift at codon 84 (p.Asp84fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with SDHB-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089825 SCV001245312 pathogenic Hereditary breast ovarian cancer syndrome 2019-05-28 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the BRCA2 gene (c.3083_3084insAlu), causing a frameshift at codon 1028 (p.Lys1028fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BRCA2-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089829 SCV001245316 uncertain significance Tumor predisposition syndrome 3 2019-01-17 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 10 of the POT1 gene (c.717_718insAlu), causing a frameshift at codon 240 (p.Arg240fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POT1-related conditions. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in POT1 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae RCV001089830 SCV001245317 pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 33 of the VPS13A mRNA (c.3525_3526insAlu), causing a frameshift at codon 1176 (p.Gln1176fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VPS13A-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Loss-of-function variants in VPS13A are known to be pathogenic (PMID: 12404112, 21598378). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089831 SCV001245318 pathogenic Fabry disease 2019-09-03 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 5 of the GLA mRNA (c.744_745insAlu), causing a frameshift at codon 249 (p.Asn249fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Although this variant has not been reported in the literature, loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089832 SCV001245319 pathogenic Cystic fibrosis 2019-07-28 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 24 of the CFTR gene (c.3955_3956insAlu), causing a frameshift at codon 1319 (p.Ala1319fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089833 SCV001245320 pathogenic Duchenne muscular dystrophy 2019-09-09 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 43 of the DMD mRNA (c.6220_6221insAlu), causing a premature translational stop signal (p.Leu2074_Met3685delinsArgSerIleAsnPheValAspMetGlnPro*). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DMD-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089834 SCV001245321 pathogenic Hereditary breast ovarian cancer syndrome 2019-09-24 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the BRCA2 gene (c.3082_3083insAlu), causing a frameshift at codon 1028 (p.Lys1028fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089835 SCV001245322 pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 4 of the RP1 gene (c.4052_4053insAlu), causing a frameshift at codon 1352 (p.Tyr1352Alafs*9). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). A similar variant has been observed in individual(s) with autosomal recessive retinal disease (PMID: 30913292, 31253780). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. That variant is also known as c.4052_4053ins328 (p.Tyr1352Alafs*9) in the literature. This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431). Therefore, variants that disrupt this region are expected to be disease-causing. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to disrupt protein function (PMID: 19763152, 20307669, 22406018). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089836 SCV001245323 pathogenic Ataxia-telangiectasia syndrome 2020-01-19 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 50 of the ATM gene (c.7388_7389insAlu), causing a frameshift at codon 2463 (p.Leu2463fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with ATM-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089839 SCV001245326 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-30 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the PMS2 gene (c.1848_1849insAlu), causing a frameshift at codon 617 (p.Pro617fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Although this variant has not been reported in the literature, loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089840 SCV001245327 pathogenic Li-Fraumeni syndrome 2019-06-30 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 9 of the TP53 gene (c.970_971insAlu), causing a frameshift at codon 324 (p.Asp324fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with TP53-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089842 SCV001245329 pathogenic Alstrom syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 20 of the ALMS1 gene (c.12184_12185insAlu), causing a frameshift at codon 4062 (p.Leu4062fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ALMS1-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089843 SCV001245330 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-04 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 12 of the MSH2 mRNA (c.1972_1973insAlu), causing a frameshift at codon 658 (p.Glu658fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Although this variant has not been reported in the literature, loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089844 SCV001245331 pathogenic Familial cancer of breast 2019-12-19 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 9 of the CHEK2 gene (c.985_986insAlu), causing a frameshift at codon 329 (p.Tyr329fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with CHEK2-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089845 SCV001245332 pathogenic not provided 2019-12-18 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 16 of the PHEX gene (c.1681_1682insAlu), causing a frameshift at codon 560 (p.Phe560fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PHEX-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089846 SCV001245333 pathogenic not provided 2020-01-03 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 9 of the MAK gene (c.1297_1298insAlu), causing a frameshift at codon 433 (p.Lys433fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. A similar Alu insertion has been observed in homozygosity in many individuals affected with autosomal recessive retinitis pigmentosa and may be a Jewish founder variant (PMID: 21825139, 25097241). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 21825139). Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in MAK are known to be pathogenic (PMID: 21148103, 21825139, 24938718, 29781741). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089847 SCV001245334 pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 4 of the RP1 gene (c.2321_2322insAlu), causing a frameshift at codon 774 (p.Leu774fs). The exact size and sequence of the insertion cannot be determined by the current assay. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1383 amino acids of the RP1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with autosomal dominant retinal disease (Invitae). This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431). Therefore, variants that disrupt this region are expected to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089848 SCV001245335 pathogenic Bardet-Biedl syndrome 2019-03-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala406Glnfs*65) in the BBS1 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with BBS1-related conditions. Loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089849 SCV001245336 pathogenic Hereditary breast ovarian cancer syndrome 2019-10-07 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 10 of the BRCA1 gene (c.3950_3951insAlu), causing a frameshift at codon 1317 (p.Leu1317fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089850 SCV001245337 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2019-02-08 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 273 of the TTN mRNA (c.52063_52064insAlu), causing a frameshift at codon 17355. This creates a premature translational stop signal (p.His17355Argfs*17) and is expected to result in a disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Invitae RCV001089851 SCV001245338 pathogenic Fanconi anemia 2019-04-23 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 14 of the FANCM gene (c.4143_4144insAlu), causing a frameshift at codon 1382 (p.Asp1382fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Similar retrotransposon insertions have not been reported in the literature in individuals with FANCM-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in FANCM are known to be pathogenic (PMID: 29895858, 30075111). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089852 SCV001245339 pathogenic Birt-Hogg-Dube syndrome 2019-11-06 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 14 of the FLCN gene (c.1557_1558insAlu), causing a frameshift at codon 520 (p.Lys520fs). The exact size and sequence of the insertion cannot be determined by the current assay. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acids of the FLCN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLCN-related conditions. This variant disrupts the C-terminus of the FLCN protein. Other variant(s) that disrupt this region (p.Arg527*) have been determined to be pathogenic (PMID: 15852235, 17028174, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089853 SCV001245340 pathogenic not provided 2019-10-30 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 4 of the RP1 gene (c.3352_3353insAlu), causing a frameshift at codon 1117 (p.Phe1117fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RP1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431). Therefore, variants that disrupt this region are expected to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089855 SCV001245342 pathogenic Ataxia-telangiectasia syndrome 2019-11-11 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 23 of the ATM gene (c.3292_3293insAlu), causing a frameshift at codon 1097 (p.Phe1097fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with ATM-related conditions. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089856 SCV001245343 pathogenic Hypertrophic cardiomyopathy 2019-08-09 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 33 of the MYBPC3 mRNA (c.3659_3660insAlu), causing a frameshift at codon 1220 (p.Asp1220fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with MYBPC3-related disease. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089857 SCV001245344 pathogenic Eichsfeld type congenital muscular dystrophy 2019-05-10 criteria provided, single submitter clinical testing This sequence change is an Alu-mediated insertion in exon 4 of the SELENON mRNA (c.487_488insAlu), causing a frameshift at codon 163 (p.Gln163fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018). While this particular variant has not been reported in the literature, loss of function variants in SELENON are known to be pathogenic (PMID: 21670436, 12192640). For these reasons, this variant has been classified as Pathogenic.
Invitae RCV001089858 SCV001245345 pathogenic Hereditary breast ovarian cancer syndrome 2019-07-07 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 11 of the BRCA2 gene (c.5007_5008insAlu), causing a frameshift at codon 1670 (p.Ala1670fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). A retrotransposon insertion at this location in BRCA2 has been reported in individuals undergoing testing for hereditary breast and ovarian cancer (PMID: 29025590) For these reasons, this variant has been classified as Pathogenic.
Genetics and Genomics, Alberta Children's Hospital RCV001095544 SCV001245472 likely pathogenic Hiatus hernia; Expressive language delay; Microcephaly; Delayed gross motor development; Mild short stature; Delayed fine motor development 2020-05-04 criteria provided, single submitter clinical testing This duplication was classified as likely pathogenic due to segregation studies and its absence from controls.
Undiagnosed Diseases Network, NIH RCV001090215 SCV001245610 pathogenic PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome 2019-09-20 criteria provided, single submitter clinical testing
Neurogenetics Research Program, University of Adelaide RCV001194626 SCV001338856 pathogenic Allan-Herndon-Dudley syndrome 2020-01-29 criteria provided, single submitter research
Blueprint Genetics RCV001250749 SCV001426168 pathogenic Angelman syndrome 2017-11-24 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250750 SCV001426169 pathogenic Angelman syndrome 2018-06-19 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250751 SCV001426170 pathogenic Angelman syndrome 2018-11-02 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250752 SCV001426171 risk factor Proximal 16p11.2 microdeletion syndrome 2017-12-08 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250753 SCV001426172 pathogenic Mowat-Wilson syndrome 2018-03-22 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001250754 SCV001426173 pathogenic Chromosome 1p36 deletion syndrome 2018-05-09 criteria provided, single submitter clinical testing
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research RCV001254217 SCV001430286 pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research RCV001254247 SCV001430287 pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research RCV001256004 SCV001430883 pathogenic Autosomal dominant polycystic kidney disease 2019-01-01 criteria provided, single submitter research
Laboratory of Medical Genetics, University of Torino RCV001257570 SCV001433614 likely pathogenic Intellectual disability, autosomal dominant 57 2020-09-24 criteria provided, single submitter research The deletion spans TLK2 and has been identified in a proband with intellectual disability and delayed motor development. The variant was de novo. The cells carrying the deletion show chromatin relaxation.
INGEBI, INGEBI / CONICET RCV001257507 SCV001434335 pathogenic Nonsyndromic genetic hearing loss 2020-08-31 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the deletion (g.20797177_21105945del) known as del(GJB6-D13S1830) eliminates a 309-kb fragment including the first five exons (and a portion of the sixth exon) of GJB6 and the whole CRYL1 genes. It was demonstrated that CX26 and Cx30 can form heteromeric connexons and heterotypic gap-junction channels (PMID: 14681039). The GJB2+/- GJB6+/tm1Kwi double heterozygous mice have moderate hearing loss and a significantly reduced of endocochlear potential (PMID: 12917317, 28823936). In addition to this, functional studies in mice demonstrated that the GJB6tm1Kwi mouse is not only a GJB6 knockout but also decreases the transcription of the contiguous GJB2 gene (PMID: 19047647, 22098503). Furthermore, an independent GJB6 knock-out strain that carries a complete deletion of the GJB6 coding sequence, without inserted material, diminish the effect on GJB2 decrease expression (PMID:23303923 ). Therefore, this evidence supports the existence of a regulatory element within some part of the deletion among with the digenic pattern mode of inheritance proposed (PS3). The filter allele frequency of this variant is 0.02% from Genome Aggregation Database and Database of Genomic Variants (last update 01-04-2020 and 17-05-2020 respectively) meeting PM2_Supporting criteria. This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 11807148). The del(GJB6-D13S1830) variant has been detected in trans with at least 4 GJB2 pathogenic variants applying to PM3_VeryStrong rule (PMID: 24158611, 11807148, 14571368). Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PS3, PS4, PM2_Supporting, PM3_VeryStrong).
INGEBI, INGEBI / CONICET RCV001257508 SCV001434336 pathogenic Nonsyndromic genetic hearing loss 2020-08-31 criteria provided, single submitter clinical testing The deletion: del(GJB6-D13S1854) (g.20802727_21034768del) eliminates a 232-kb fragment including the first five exons of GJB6 and the last 4 exons of CRYL1 gene. It was demonstrated that CX26 and Cx30 can form heteromeric connexons and heterotypic gap-junction channels (PMID: 14681039). Besides, Gjb2+/- Gjb6+/tm1Kwi double heterozygous mice have moderate hearing loss and a significantly reduced endocochlear potential (PMID: 12917317, 28823936) In addition to this, functional studies in mice demonstrated that the Gjb6tm1Kwi mouse is not only a Gjb6 knockout but also decreases the transcription of the contiguous Gjb2 gene (PMID:19047647, 22098503). Furthermore, an independent Gjb6 knock-out strain that carries a complete deletion of the Gjb6 coding sequence, without inserted material, diminish the effect on GJB2 decrease expression (PMID:23303923 ). Therefore, these evidence support the existence of the regulatory element within some part of the deletion among with the digenic pattern mode of inheritance proposed. (PS3). This deletion is absent from Genome Aggregation Database and Database meeting PM2 rule. This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 11807148). The del(GJB6-D13S1854) variant has been detected in trans with at least 4 pathogenic variants in GJB2 in hearing loss patients applying to PM3_VeryStrong rule (PMID: 15994881, 24158611). Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PS3, PS4, PM3_S, PM2).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001260502 SCV001437523 uncertain significance not provided 2019-11-05 criteria provided, single submitter clinical testing A deletion of approximately 1235.340 KB (chr14:22006109-23241448x1) located at 14q11.2 and encompassing 127 genes was detected in this individual. Deletions involving 14q11.2 have been previously reported in individuals with autism, developmental delay, intellectual disability, and seizures in DECIPHER. However, deletions involving 14q11.2 have also been observed in the Database of Genomic Variants and classified as benign in ClinVar. Based on the available evidence, this deletion is classified as a Variant of Uncertain Significance.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001260503 SCV001437524 pathogenic not provided 2020-05-13 criteria provided, single submitter clinical testing A deletion of approximately 7.5 Mb (chr10:81585301-89101700x1) located at 10q22.3q23.2 was detected in this individual. This deletion encompasses 31 protein encoding genes of which 7 have been reported in OMIM with a disease-association (PMID: 19344873). Pathogenic deletions involving this region are associated with Chromosome 10q22.3-q23.2 deletion syndrome (MIM: #612242), and have been previously reported in patients with dysmorphic features, developmental delay, behavioral concerns, limb anomalies, and congenital heart defects (PMID: 28588438, 21248748, 20345475). The reported congenital heart defects are of variable severity and include: patent ductus arteriosus, atrioventricular septal defect, tetralogy of Fallot, pulmonic regurgitation, tricuspid regurgitation, and ventricular septal defect (PMID: 28588438). This variant has not been observed at a significant frequency in the Database of Genomic Variants and thus is presumed to be rare. This result was confirmed by orthogonal testing. Analysis of the parental samples showed that the mother is negative and the father is negative for this variant, indicating that the 7.5 Mb deletion likely occurred as a de novo event in the proband. Based on the available evidence, this deletion is classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001260932 SCV001438021 pathogenic not provided 2019-09-16 criteria provided, single submitter clinical testing A 12.9 MB deletion on chromosome 13 (chr13:102175801-115169858del) encompassing the CARKD gene was identified in this patient, in trans with a missense variant in CARKD c.1112C>T (p.Ser371Leu) that was classified as Likely Pathogenic. On the basis of this evidence, the 12.9 MB deletion was classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001262041 SCV001439419 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
NIHR Bioresource Rare Diseases, University of Cambridge RCV001262047 SCV001439425 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2018-01-01 criteria provided, single submitter research PVS1+PM2+PP4
Center for Statistical Genetics, Columbia University RCV001261860 SCV001448212 pathogenic Intellectual disability 2020-10-16 criteria provided, single submitter research
Bertuch Lab, Baylor College of Medicine RCV001523792 SCV001450739 pathogenic Chromosome 16q22 deletion syndrome criteria provided, single submitter clinical testing This structural variant results in whole gene deletion of CARMIL2, ACD, PARD6A, ENKD1, C16orf86, and GFOD2, as well as partial deletion of CTCF and RANBP10. When heterozygous, this chromosomal deletion resulted in chr16q22.1 microdeletion syndrome, with phenotypes of developmental delay, poor growth, facial dysmorphism, and hypotonia. Telomere lengths were found to be between the 1st and 10th centiles for age in the five lymphocyte populations, although similar to the lengths of the proband's parents who did not have the chromosomal deletion. Multiple CBCs obtained between the ages of 16 months and 4 years were normal.
Institute of Medical Molecular Genetics, University of Zurich RCV001270921 SCV001451705 pathogenic Congenital miosis 2020-12-21 criteria provided, single submitter clinical testing
Center for Statistical Genetics, Columbia University RCV001271073 SCV001451899 uncertain significance Intellectual disability 2020-10-02 criteria provided, single submitter clinical testing
Hadassah Hebrew University Medical Center RCV001293248 SCV001468314 pathogenic Harel-Yoon syndrome criteria provided, single submitter clinical testing
Hadassah Hebrew University Medical Center RCV001293249 SCV001468315 pathogenic Harel-Yoon syndrome criteria provided, single submitter clinical testing
Hadassah Hebrew University Medical Center RCV001293250 SCV001468316 pathogenic Harel-Yoon syndrome criteria provided, single submitter clinical testing
Hadassah Hebrew University Medical Center RCV001293251 SCV001468317 pathogenic Harel-Yoon syndrome criteria provided, single submitter clinical testing
New York Genome Center RCV001281486 SCV001468794 uncertain significance Seizure 2019-09-04 criteria provided, single submitter clinical testing
New York Genome Center RCV001281541 SCV001468850 uncertain significance Heart, malformation of; Intellectual disability 2019-07-17 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV001578513 SCV001547742 uncertain significance Mucopolysaccharidosis, MPS-IV-A 2021-02-01 criteria provided, single submitter research Absent from gnomAD v2.1.1 (PM2_moderate)
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391666 SCV001593290 pathogenic Syndromic X-linked intellectual disability Lubs type 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391667 SCV001593291 pathogenic Deletion of short arm of chromosome 18 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391668 SCV001593292 pathogenic Developmental delay with variable intellectual impairment and behavioral abnormalities 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391669 SCV001593293 pathogenic not provided 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391670 SCV001593294 pathogenic Distal 10q deletion syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391671 SCV001593295 pathogenic Proximal 16p11.2 microdeletion syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391672 SCV001593296 pathogenic DiGeorge syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391673 SCV001593297 pathogenic Pelizaeus-Merzbacher disease; Hereditary spastic paraplegia 2 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391674 SCV001593298 likely pathogenic Chromosome 15q26-qter deletion syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391675 SCV001593299 pathogenic DiGeorge syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391676 SCV001593300 likely pathogenic Proximal 16p11.2 microdeletion syndrome 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391677 SCV001593301 pathogenic Distal monosomy 13q 2021-05-13 criteria provided, single submitter clinical testing
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University RCV001391678 SCV001593302 likely pathogenic not provided 2021-05-13 criteria provided, single submitter clinical testing
Genetic Disease Research Branch / Genetics Development and Disease Section, National Human Genome Research Institute RCV001420680 SCV001623011 pathogenic Tyrosinase-positive oculocutaneous albinism 2021-02-01 criteria provided, single submitter research This represents a loss of function allele in OCA2 in a well described reccessive disease. ACMG: PVS1. PM4, PM3
Genetic Disease Research Branch / Genetics Development and Disease Section, National Human Genome Research Institute RCV001420681 SCV001623012 pathogenic Tyrosinase-positive oculocutaneous albinism 2021-02-01 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV001449852 SCV001653249 pathogenic Hypercholesterolemia, familial, 1 2019-04-25 criteria provided, single submitter clinical testing An in-frame duplication involving exons 2-6 of the LDLR gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449853 SCV001653250 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing An in-frame deletion involving exons 3-4 of the LDLR gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449854 SCV001653251 pathogenic Hypercholesterolemia, familial, 1 2020-12-09 criteria provided, single submitter clinical testing An in-frame deletion involving exons 3-5 of the LDLR gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449855 SCV001653252 pathogenic Hypercholesterolemia, familial, 1 2019-09-18 criteria provided, single submitter clinical testing An in-frame deletion of exon 5 of the LDLR gene. Exon 5 of LDLR encodes LR6, one of the LDLR class A repeats/ligand binding domains. PS3, PS4, PM1, PM3, PM4
Mayo Clinic Laboratories, Mayo Clinic RCV001449856 SCV001653253 pathogenic Hypercholesterolemia, familial, 1 2019-08-30 criteria provided, single submitter clinical testing An out-of-frame deletion of exons 7-12 of the LDLR gene. PVS1, PM1, PM2
Mayo Clinic Laboratories, Mayo Clinic RCV001449857 SCV001653254 pathogenic Hypercholesterolemia, familial, 1 2019-11-21 criteria provided, single submitter clinical testing An in-frame deletion of exon 15 of the LDLR gene. PS4, PP1_Strong, PS3_Moderate, PM2, PM4
Mayo Clinic Laboratories, Mayo Clinic RCV001449858 SCV001653255 uncertain significance not provided 2019-06-14 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449859 SCV001653256 uncertain significance not provided 2021-03-24 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449860 SCV001653257 pathogenic Marfan syndrome 2020-04-23 criteria provided, single submitter clinical testing An in-frame deletion of exons 43-46 of the FBN1 gene. PVS1_Strong, PS3, PP4
Mayo Clinic Laboratories, Mayo Clinic RCV001449861 SCV001653258 pathogenic not provided 2020-10-07 criteria provided, single submitter clinical testing A deletion of exons 30-35 of the MYBPC3 gene. PVS1, PM1, PM2
Mayo Clinic Laboratories, Mayo Clinic RCV001449862 SCV001653259 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2019-05-09 criteria provided, single submitter clinical testing An out-of-frame duplication of exon 2 of the ENG gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449863 SCV001653260 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2021-03-11 criteria provided, single submitter clinical testing An out-of-frame deletion of exon 2 of the ENG gene. PVS1, PS4_moderate, PM2_supporting
Mayo Clinic Laboratories, Mayo Clinic RCV001449864 SCV001653261 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2019-06-25 criteria provided, single submitter clinical testing An in-frame deletion of exons 9-10 of the ENG gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449865 SCV001653262 pathogenic Telangiectasia, hereditary hemorrhagic, type 1 2020-05-15 criteria provided, single submitter clinical testing An in-frame deletion of exons 9-11 of the ENG gene. PVS1_Strong, PS4_moderate, PP5, PP4
Mayo Clinic Laboratories, Mayo Clinic RCV001449866 SCV001653263 pathogenic not provided 2020-07-30 criteria provided, single submitter clinical testing A whole gene deletion of the SLC2A1 gene. PVS1, PM2, PP4
Mayo Clinic Laboratories, Mayo Clinic RCV001449867 SCV001653264 uncertain significance not provided 2020-10-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449868 SCV001653265 likely pathogenic not provided 2020-10-20 criteria provided, single submitter clinical testing An out-of-frame deletion involving exon 2 of the NPRL3 gene. PVS1, PM2
Mayo Clinic Laboratories, Mayo Clinic RCV001449869 SCV001653266 uncertain significance not provided 2020-04-22 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449870 SCV001653267 uncertain significance not provided 2021-01-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449871 SCV001653268 uncertain significance not provided 2021-01-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449872 SCV001653269 uncertain significance not provided 2020-10-15 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449873 SCV001653270 pathogenic not provided 2021-02-14 criteria provided, single submitter clinical testing A whole gene deletion of the TSC2 gene. PVS1, PS4_moderate, PM2
Mayo Clinic Laboratories, Mayo Clinic RCV001449874 SCV001653271 pathogenic not provided 2019-06-18 criteria provided, single submitter clinical testing An out-of-frame deletion involving exons 8-9 of the CLN3 gene. PVS1, PS3, PS4, PM3
Mayo Clinic Laboratories, Mayo Clinic RCV001449875 SCV001653272 pathogenic not provided 2020-01-29 criteria provided, single submitter clinical testing A whole gene duplication of the PMP22 gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449876 SCV001653273 pathogenic not provided 2021-04-29 criteria provided, single submitter clinical testing A whole gene deletion of the PMP22 gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449877 SCV001653274 likely pathogenic not provided 2019-12-25 criteria provided, single submitter clinical testing A deletion involving exons 8-24 of the MAN2B1 gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449878 SCV001653275 uncertain significance not provided 2020-04-30 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001449879 SCV001653276 pathogenic not provided 2019-12-26 criteria provided, single submitter clinical testing An out-of-frame duplication involving exons 61-62 of the DMD gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449880 SCV001653277 pathogenic not provided 2019-07-23 criteria provided, single submitter clinical testing An in-frame deletion involving exons 45-57 of the DMD gene.
Mayo Clinic Laboratories, Mayo Clinic RCV001449881 SCV001653278 pathogenic not provided 2019-06-06 criteria provided, single submitter clinical testing An out-of-frame deletion involving exon 45 of the DMD gene.
Neurogenetics Research Program, University of Adelaide RCV001796573 SCV001737583 pathogenic Cerebral palsy 2021-06-10 criteria provided, single submitter research Clinical diagnosis neurofibromatosis type 1. Cardiovascular complications are a feature of NF1.
Neurogenetics Research Program, University of Adelaide RCV001796575 SCV001737585 pathogenic Cerebral palsy 2021-06-10 criteria provided, single submitter research
Kosik Lab, Neuroscience Research Institute, University of California Santa Barbara RCV001810749 SCV001751549 pathogenic Alzheimer disease 2021-07-01 criteria provided, single submitter case-control
Molecular Pathology Research Laboratory, SA Pathology RCV001541921 SCV001760553 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541922 SCV001760554 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541924 SCV001760556 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541925 SCV001760557 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541926 SCV001760558 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541927 SCV001760559 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
Molecular Pathology Research Laboratory, SA Pathology RCV001541928 SCV001760560 pathogenic Deafness-lymphedema-leukemia syndrome; GATA2 deficiency with susceptibility to MDS/AML 2021-07-06 criteria provided, single submitter curation PVS1, PS4_Supporting, PM2
New York Genome Center RCV001542285 SCV001760968 uncertain significance not provided 2020-07-10 criteria provided, single submitter clinical testing The inherited ~103 kb duplication identified overlaps with the well-known 1.4Mb recurrent 17q12 duplication [chr17:36,459,259-37,832,872, GRCh38, Reference 3]. The recurrent 1.4 Mb duplication contains 16 genes, four of which are located within the 103 kb duplication identified in this individual (ZNHIT3, MYO19, PIGW, and GGNBP2). Gene(s) responsible for clinical symptoms of the recurrent 1.4Mb 17q12 duplication are not identified yet [PMID: 26925472]. A 114 kb duplication involving full duplication of ZNHIT3, MYO19, and PIGW, as well as partial duplication of GGNBP2, TBC1D3G, and TBC1D3H is observed 117 times (55 homozygotes) in gnomAD SVs(v2.1). Given the uncertainty regarding the potential pathogenicity of ~103 kb duplication it is reported as a Variant of Uncertain Significance.
New York Genome Center RCV001542324 SCV001761010 uncertain significance Generalized epilepsy with febrile seizures plus, type 10 2020-07-03 criteria provided, single submitter clinical testing The inherited 5p12 duplication identified in this individual is a duplication on the short arm of chromosome 5, which contains the first 6 exons of the HCN1 gene. The distal breakpoint of this duplication is detected at Chr5:45270314, however due to the highly repetitive nature of centromeric regions, the proximal breakpoint cannot be determined by Whole Genome Sequencing, however microarray analysis suggests this duplication extends to the centromere of chromosome 5. The only gene contained in this region is HCN1, and the distal breakpoint confirms that exons 1-6 (NM_021072.4) of the HCN1 gene are contained within this duplication. This variant is absent from gnomAD(SV_v2.1) suggesting it is not a common benign variant in the populations represented in that database. This variant is absent from ClinVar, although a duplication containing exons 1-7 has been reported in ClinVar as a Variant of UncertainSignificance (VarID:646963). To our current knowledge neither this exact variant, nor similar intergenic duplications of HCN1, have been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity and uncertainty regarding its functional consequence, the inherited 5p12 duplication containing exons 1-6 of the HCN1 gene is reported as a Variant of Uncertain Significance.
New York Genome Center RCV001542388 SCV001761085 pathogenic not provided 2020-07-17 criteria provided, single submitter clinical testing To our current knowledge, the exact duplication observed in this individual has not been previously reported in the literature, however the exact breakpoints of many 16q duplications reported in historical literature were not characterized by molecular methods and the exact breakpoints are uncertain. However, individuals with duplications similar to the one identified here (dup(16q11.2q21)) have been described with developmental delay, dysmorphic facial features, speech delay, intellectual disability, and additional variable features including recurrent infections, behavioral abnormalities, hyper-or hypotonia, and MRI abnormalities [PMID:21674840; PMID:22921637]. Additional individuals have been reported with proximal (16q11-q13) duplications contained within the larger duplication identified here with clinical phenotypes including developmental delay, variable intellectual disability or learning difficulties, variable dysmorphic features, speech delay, and behavioral abnormalities [PMID:16954678; PMID:10999840]. Given its presence de novo in this individual, absence in population databases, observation of several individuals with similar duplications in the literature, and its genomic content, the de novo 14.8MB duplication 16q11.2-q21 identified here is reported here as Pathogenic.
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital RCV001729955 SCV001792241 pathogenic Waardenburg syndrome type 2A criteria provided, single submitter research de novo variant: proband with bilateral profound sensorineural hearing loss, hyperplasia of nasal root, One heterochromia iris and one hypoplastic blue iris, and hypochromic skin spots
GeneDx RCV001584572 SCV001812480 likely benign not provided 2019-10-21 criteria provided, single submitter clinical testing
New York Genome Center RCV001591740 SCV001815798 uncertain significance not provided 2020-09-19 criteria provided, single submitter clinical testing
GeneDx RCV001583839 SCV001820210 likely benign not provided 2018-10-27 criteria provided, single submitter clinical testing
GeneDx RCV001649721 SCV001865196 benign not provided 2019-08-21 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001663741 SCV001879354 pathogenic not provided 2022-04-27 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 46-55. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663743 SCV001879356 likely pathogenic not provided 2020-11-05 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. This deletion spans the last 8 exons of the CCM2 gene. Due to limitations of this analysis, the exact size of this deletion and how far it extends beyond the CCM2 gene is uncertain. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV001663744 SCV001879358 uncertain significance not provided 2021-06-11 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001663745 SCV001879359 pathogenic not provided 2021-04-05 criteria provided, single submitter clinical testing This variant is expected to severely disrupt protein function. In-frame deletions such as this one are typically associated with Becker muscular dystrophy (BMD). Yet, similar deletions of exons 56-60 have been identified in at least two individuals with Duchenne muscular dystrophy (DMD; PMID: 25972034, 26081009). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV001663746 SCV001879360 pathogenic not provided 2021-01-25 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Similar deletions of exon 45-55 have been reported primarily in patients with Becker muscular dystrophy (BMD), several cases with Duchenne muscular dystrophy (DMD; PMID: 28332368, 28181689, 25972034, 17854090), and at least two dilated cardiomyopathy cases (PMID: 18261911).
Athena Diagnostics RCV001663747 SCV001879361 pathogenic not provided 2023-06-30 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exon 52. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663748 SCV001879362 pathogenic not provided 2022-06-29 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated males with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 50-52. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663749 SCV001879363 pathogenic not provided 2022-04-08 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 49-52. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663750 SCV001879364 pathogenic not provided 2022-04-27 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 48-52. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663751 SCV001879365 pathogenic not provided 2022-03-23 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. A similar deletion of exons 46-51 has been identified in at least one individual with Duchenne muscular dystrophy (DMD). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663752 SCV001879366 pathogenic not provided 2020-10-30 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In-frame deletions such as this one are typically associated with Becker muscular dystrophy (BMD). Yet, deletions of exons 45-51 have been reported in patients with BMD and Duchenne muscular dystrophy (DMD).
Athena Diagnostics RCV001663753 SCV001879367 pathogenic not provided 2023-05-19 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 45-50 have been reported in multiple unrelated individuals with DMD. At least one BMD case has also been reported (PMID: 28116794). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663755 SCV001879369 likely pathogenic not provided 2021-02-26 criteria provided, single submitter clinical testing This variant is presumed to be inserted in tandem within the DMD gene and would maintain the transcript's reading frame, but is expected to disrupt protein function. Similar duplications of exons 45-49 have been identified in at least one male with Becker muscular dystrophy (BMD, PMID: 33101180), as well as multiple males with Duchenne muscular dystrophy (DMD, PMID: 28610567, 25751470, 17259292, 9800909). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV001663756 SCV001879370 pathogenic not provided 2022-10-20 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 46-48. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663757 SCV001879371 pathogenic not provided 2022-05-10 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 46-47 have been reported primarily in patients with Duchenne muscular dystrophy (DMD), and also in a few individuals with Becker muscular dystrophy (BMD). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663758 SCV001879372 pathogenic not provided 2020-10-22 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Similar deletions of exon 45 have been reported primarily in patients with Duchenne muscular dystrophy (DMD), and also in a few individuals with Becker muscular dystrophy (BMD; PMID: 19937601).
Athena Diagnostics RCV001663759 SCV001879373 pathogenic not provided 2022-10-04 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. A similar deletion of exon 44 has been identified in multiple unrelated individuals presenting with Duchenne muscular dystrophy (DMD). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV001663760 SCV001879374 likely pathogenic not provided 2021-05-11 criteria provided, single submitter clinical testing This variant is likely to be inserted in tandem within the DMD gene and would maintain the transcript's reading frame, but is expected to disrupt protein function. A similar duplication of exons 3-15 has been identified in at least one male with a dystrophinopathy. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV001663761 SCV001879375 likely pathogenic not provided 2020-11-16 criteria provided, single submitter clinical testing This variant is presumed to be inserted within the DMD gene, thus expected to result in the loss of a functional protein. A similar duplication of exons 5-7 has been identified in at least one individual with Duchenne muscular dystrophy (DMD). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV001663762 SCV001879376 pathogenic not provided 2020-10-27 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Out-of-frame deletions such as this one are typically associated with Duchenne muscular dystrophy (DMD). Yet, deletions of exons 3-7 have been reported in patients with DMD, Becker muscular dystrophy (BMD), and intermediate dystrophinopathies.
Athena Diagnostics RCV001663763 SCV001879377 pathogenic not provided 2021-01-12 criteria provided, single submitter clinical testing This deletion spans the entire coding sequence of the SPAST gene and is expected to result in the loss of a functional protein. Due to limitations of this analysis, the exact size of this deletion event is unknown. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). A similar variant has been identified in at least one individual with clinical features associated with this gene.
Athena Diagnostics RCV001663764 SCV001879378 pathogenic not provided 2022-07-26 criteria provided, single submitter clinical testing Similar deletions of exons 8-17 have been identified in multiple individuals with clinical features associated with this gene. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located in a region that is considered important for protein function and/or structure.
Athena Diagnostics RCV001663766 SCV001879381 pathogenic not provided 2021-02-09 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar deletion of exon 10 has been identified in at least one individual with clinical features associated with this gene.
GeneDx RCV001670531 SCV001891646 benign not provided 2021-06-19 criteria provided, single submitter clinical testing
New York Genome Center RCV001784115 SCV002025630 uncertain significance not provided 2020-06-11 criteria provided, single submitter clinical testing
New York Genome Center RCV001784120 SCV002025638 uncertain significance not provided 2020-04-25 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001801231 SCV002047443 pathogenic Developmental and epileptic encephalopathy, 9 criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807689 SCV002055985 pathogenic Thrombocytopenia 5 criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807691 SCV002055987 pathogenic Hereditary von Willebrand disease criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807693 SCV002055989 pathogenic Hereditary factor XI deficiency disease criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807694 SCV002055990 uncertain significance Hereditary factor XI deficiency disease criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807695 SCV002055991 likely pathogenic Factor X deficiency; Factor VII deficiency criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807696 SCV002055992 uncertain significance Hereditary factor IX deficiency disease criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807697 SCV002055993 pathogenic Bleeding disorder, platelet-type, 21 criteria provided, single submitter research
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV001807700 SCV002055996 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 criteria provided, single submitter research
New York Genome Center RCV001839062 SCV002098953 pathogenic Syndromic X-linked intellectual disability Lubs type 2021-02-19 criteria provided, single submitter clinical testing The Xq27.1-q28 duplication is an approximately 13.8MB gain on the long arm of the X chromosome. While the centromeric breakpoint was identified with whole genome sequencing, the telomeric breakpoint of this duplication is within a low copy repeat (LCR) region and is poorly mapped with genome sequencing technology. Microarray analysis suggests the telomeric breakpoint occurs between the L1 and L2 region at the Int22h1 border (see [PMID:29341460]) with the telomeric breakpoint between genes CTAG1B and FAM223B. Of note, this duplication does NOT contain the critical region associated with Int22h1/Int22h2 mediated Xq28 duplication syndrome [PMID:26962617]. While partial duplications of Xq28 are not common, a similar copy number gain to the one identified here, not including the distal end of the X chromosome has been reported in ClinVar as Pathogenic [VarID:58691]. The duplication observed here contains over 200 genes, approximately 111 of which are OMIM associated, and includes disease associated genes GDI1[MIM#300104], FLNA[MIM#300017], FMR1[MIM#309550], NSDHL[MIM#300275], FAM58A [MIM#300708], NAA10[MIM#300013], and MECP2[MIM#300005]. Of these, duplications of MECP2 are associated with a well-known MECP2/Xq28 duplication syndrome, characterized in males by developmental delay, intellectual disability, gastrointestinal disturbances, spasticity, seizures, and additional variable clinical manifestations [PMID:22679399]. It has been suggested that the size of the Xq28 duplication including MECP2 is correlated with the degree of severity, and that larger duplications including RAB39B, which is NOT contained within the duplication identified here, are more clinically severe than smaller duplications not extending to this region [PMID:30788845]. Females with MECP2/Xq28 duplication syndrome often have extreme or complete skewing of X-chromosome inactivation and have mild phenotypes or are asymptomatic [PMID: 22679399], however affected females as well as inter-and intra-familial variability have been observed [PMID:29141583, 28257338, 27761913, 27247049, others]. This variant was identified as a de novo variant in an individual submitted for clinical testing. The Xq27.1-q28 duplication identified in this individual is reported here as Pathogenic.
Rare Disease Group, University of Exeter RCV002281191 SCV002102567 likely pathogenic SLC4A10-related neurodevelopmental disorder 2022-01-22 criteria provided, single submitter research
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics RCV001843999 SCV002103299 likely pathogenic Mucopolysaccharidosis type 6 criteria provided, single submitter research The ARSB mRNA analysis demonstrated the premature transcription termination after the exon 4. Identified in-trans with the c.966G>A (p.Trp322Ter) pathogenic variant.
Laboratorio de Citogenómica y Microarreglos, Universidad Autonoma de Nuevo Leon RCV002273839 SCV002106412 likely pathogenic Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome 2022-03-22 criteria provided, single submitter research The present case involved breakpoint junctions and deletion between SH3 (that is, downstream DH1) and DH2 domains and DH2 and PH2 domains, that is, partially deleting GEF2D, a domain that activates RHOA. Although it does not affect DH1, this intragenic deletion included DH2 and could have resulted in aberrant shortened mRNAs and proteins, which, in turn, undergo rapid decay and consequently hypoactivation of RHOA. Because truncating variants (including those in DH2) resulting in a shortened protein and haploinsufficiency have an effect like those affecting GEF1D, the present disruption of TRIO most likely caused the patient’s MRD44-like phenotype, including mild ID, microcephaly, and facial features (Pengelly 2016, Ba 2016, Schultz-Rogers, 2020).
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics RCV001849900 SCV002107169 likely pathogenic Mucopolysaccharidosis, MPS-IV-B criteria provided, single submitter research The GLB1 mRNA analysis demonstrated the inclusion of the 18 b.p. fragment of the intron 5 (NC_000003.11:g.33100082_33100099) r.552_553insCATTTCTACCATGGGAAG. Detected in-trans with the pathogenic c.808T>G (p.Tyr270Asp) variant.
Provincial Medical Genetics Program of British Columbia, University of British Columbia RCV002067565 SCV002320830 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2022-01-01 criteria provided, single submitter clinical testing
New York Genome Center RCV002227583 SCV002506618 uncertain significance Becker muscular dystrophy; Duchenne muscular dystrophy 2021-05-14 criteria provided, single submitter clinical testing
New York Genome Center RCV002227585 SCV002506620 likely pathogenic Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome 2021-05-21 criteria provided, single submitter clinical testing The chr5:g.141572725_141615700del variant is a homozygous copy loss of coding exons 2-16 (total 28) as well as the 5’ and 3’ flanking intronic sequences and is present in one of the larger regions of homozygosity, as seen in the microarray data. The deleted exons (except one exon) are present in all the Refseq transcripts of DIAPH1. The variant is absent from gnomAD and DGV, suggesting it is not a common benign variant in the populations represented in these databases. This variant is not present in ClinVar, and to our current knowledge has not been identified in any affected individuals in the literature, however, other bi-allelic loss of function variants in DIAPH1 have been described in affected individuals with seizures, cortical blindness, microcephaly syndrome [MIM 616632; 2,3]. Given the predicted deleterious nature of this homozygous multi-exon deletion and its absence in population databases, the chr5:g.141572725_141615700del identified is reported as Likely Pathogenic.
New York Genome Center RCV002227597 SCV002506634 uncertain significance not provided 2021-06-30 criteria provided, single submitter clinical testing
New York Genome Center RCV002247703 SCV002506671 pathogenic Chromosome 3q29 microdeletion syndrome 2021-05-14 criteria provided, single submitter clinical testing The de novo deletion overlaps with 3q29 recurrent microdeletion region (includes DLG1), which has been curated by ClinGen to have “sufficient evidence to supportthe haploinsufficiency” [https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-37443]. Genes responsible for 3q29 deletion syndrome have not been definitively defined yet however,DLG1, FBXO45, PAK2, and RNF168 have been implicated [PMIID:27656750] and are located within the 1.5Mb region deleted here. Based on the available evidence, the de novo heterozygous ~1.5Mb interstitial deletion identified here is reported as Pathogenic.
New York Genome Center RCV002227664 SCV002506727 uncertain significance not provided 2021-06-22 criteria provided, single submitter clinical testing
New York Genome Center RCV002227667 SCV002506730 uncertain significance not provided 2021-05-21 criteria provided, single submitter clinical testing
New York Genome Center RCV002227670 SCV002506734 uncertain significance not provided 2021-07-09 criteria provided, single submitter clinical testing
New York Genome Center RCV002227708 SCV002506791 uncertain significance not provided 2021-05-21 criteria provided, single submitter clinical testing
New York Genome Center RCV002227715 SCV002506801 pathogenic Distal 16p11.2 microdeletion syndrome 2021-07-16 criteria provided, single submitter clinical testing The minimal deleted region in this de novo 16p11.2 deletion contains 12 genes, 9 of which are protein-coding and are OMIM-annotated (ATXN2L, TUFM, SH2B1, ATP2A1, RABEP2, CD19, NFATC2IP, SPNS1, and LAT). Of these, 4 genes are disease-associated; TUFM (autosomal recessive Combined oxidative phosphorylation deficiency 4; MIM#610678), ATP2A1 (autosomal recessive Brody Myopathy; MIM#617514), CD19 (autosomal recessive Immunodeficiency, common variable, 3, MIM# 613493), and LAT (autosomal recessive Immunodeficiency 52, MIM# 617514). Chromosome 16p contains several low copy repeat sequences, called BP1-BP5, and non- homologous recombination between these sequences leads to syndromes associated with recurrent copy number gains and losses. The ~220 Kb deletion observed here is between recurrent breakpoint regions BP2 and BP3 located in the distal region of 16p11.2. The minimal deleted region completely overlaps with 16p11.2 recurrent region (distal, BP2-BP3) (includes SH2B1), which has been curated by ClinGen to have “sufficient evidence for dosage pathogenicity” [https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-37486]. Based on the available evidence, the de novo heterozygous ~220 Kb interstitial 16p11.2 deletion is reported as Pathogenic.
New York Genome Center RCV002227717 SCV002506810 pathogenic Chromosome 1q21.1 duplication syndrome 2021-06-01 criteria provided, single submitter clinical testing The ~1.38Mb duplication on the long arm of chromosome 1 (1q21.1) is a recurrent microduplication that contains 42 genes, 9 of which are OMIM associated. Based on the available evidence, e.g., absence in population databases, observation of several individuals with similar duplications in the literature, and its genomic content, the inherited ~1.38Mb duplication in the 1q21.1 region is reported as Pathogenic.
New York Genome Center RCV002227746 SCV002506849 uncertain significance not provided 2021-06-25 criteria provided, single submitter clinical testing
New York Genome Center RCV002227747 SCV002506850 uncertain significance not provided 2021-06-25 criteria provided, single submitter clinical testing
New York Genome Center RCV002227754 SCV002506859 uncertain significance not provided 2021-06-25 criteria provided, single submitter clinical testing The exact duplication seen here is not reported before in the literature. However, a Microtriplication overlapping with this duplication has been reported in two unrelated patients whose clinical features include distinctive facial dysmorphisms, short stature with small extremities, keratoconus, overweight, and intellectual disability [PMID: 21617255]. Seizures were not reported in both patients [PMID: 21617255]. Based on the available evidence, the inherited ~1.26Mb duplication identified on 11q24.1 is reported as a variant of uncertain significance.
New York Genome Center RCV002227763 SCV002506868 uncertain significance Neurodevelopmental disorder 2021-07-02 criteria provided, single submitter clinical testing
New York Genome Center RCV002227783 SCV002506892 uncertain significance 7p22.1 microduplication syndrome 2021-07-08 criteria provided, single submitter clinical testing
New York Genome Center RCV002227787 SCV002506896 uncertain significance not provided 2021-05-07 criteria provided, single submitter clinical testing
New York Genome Center RCV002227822 SCV002506957 uncertain significance Wilson-Turner syndrome 2021-06-04 criteria provided, single submitter clinical testing This exact ~444Kb interstitial duplication identified on Xq11.2-q12 is not reported in the literature to the best of our knowledge. A similar sized duplication has 0.0003162 allele frequency in the gnomAD SVs v2.1 database (Total allele number = 15,814. Individuals with heterozygous duplication = 2, individuals with hemizygousduplication = 3, individuals with homozygous duplication = none). Based on the available evidence, the inherited ~444Kb interstitial duplication identified on Xq11.2-q12 is reported as a variant of uncertain significance.
New York Genome Center RCV002227826 SCV002506965 likely pathogenic not provided 2021-04-30 criteria provided, single submitter clinical testing The deleted region contains ~54 genes, 35 of which are protein-coding. Among these, 26 genes are OMIM-annotated, 8 of which are disease-associated (HTT, DOK7, LRPAP1, ADRA2C, MSX1, EVC, EVC2, WFS1). Heterozygous pathogenic variants in MSX1 have been associated with autosomal dominant Ectodermal dysplasia 3, Witkop type [MIM#189500; AD], Orofacial cleft 5 [MIM#608874; AD], and Tooth agenesis, selective, 1, with or without orofacial cleft [MIM#106600; AD]. Pathogenic variants in EVC and EVC2 have been associated with autosomal dominant Weyers acrofacial dysostosis [MIM#193530, AD] as well as autosomal recessive Ellis-van Creveld syndrome [MIM#225500, AR]. Heterozygous pathogenic variants in WFS1 have been associated with autosomal dominant Cataract 41 [MIM#116400; AD], {Diabetes mellitus, noninsulin-dependent, association with} [MIM#125853;AD], Wolfram-like syndrome, autosomal dominant [MIM#614296; AD], and Deafness, autosomal dominant 6/14/38 [MIM#600965; AD]. Further, multiple genes in the deleted region (HTT, KIAA0232, JAKMIP1, CRMP1, TBC1D14, GRPEL1) are constrained for loss of function variants (gnomADv2 pLi >= 0.9). The deleted region was not commonly seen in the online normal human genetic variation database. The exact deletion seen in this individual has not been reported before in the literature, to our knowledge. However, larger distal deletions at 4p16.3 which extend to this region have been seen in Wolf-Hirschhorn syndrome(WHS) [PMID: 24357569]. The deletion observed in this individual does not overlap with the WHS critical region. Based on the gene content and the size of this deletion, it is reported here as Likely Pathogenic.
GeneDx RCV002244366 SCV002512942 likely benign not provided 2021-11-02 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247710 SCV002515974 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2021-10-06 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247711 SCV002515975 likely pathogenic Microcornea-myopic chorioretinal atrophy 2021-07-06 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247713 SCV002515977 pathogenic Pulmonary valve stenosis; Short stature; Failure to thrive; Scoliosis; Nystagmus; Microcephaly; Intellectual disability; Gray matter heterotopia; Parietal foramina; Proportionate short stature; Intellectual disability, severe 2021-04-14 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247720 SCV002515982 pathogenic Chromosome 2q37 deletion syndrome 2022-02-22 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247722 SCV002515984 pathogenic ZTTK syndrome 2021-03-19 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247723 SCV002515985 pathogenic Chromosome 1p36 deletion syndrome 2021-03-19 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247726 SCV002515987 pathogenic Velocardiofacial syndrome 2021-10-04 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247731 SCV002515992 pathogenic Autoinflammatory syndrome, familial, Behcet-like 2021-10-14 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247737 SCV002515998 pathogenic Chromosome 9p deletion syndrome 2022-02-10 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247738 SCV002515999 likely pathogenic Chorea-acanthocytosis 2021-08-18 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247741 SCV002516002 pathogenic Suleiman-El-Hattab syndrome 2022-01-31 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247742 SCV002516003 pathogenic Immunodeficiency 33; Ectodermal dysplasia and immunodeficiency 1; Incontinentia pigmenti syndrome; Immunodeficiency 47 2022-02-24 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247743 SCV002516012 pathogenic Splenomegaly; Decreased circulating antibody level 2022-02-24 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002247751 SCV002516015 likely pathogenic Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies 2021-08-18 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV002253059 SCV002523165 uncertain significance ATAD3 gene cluster related condition 2020-07-02 criteria provided, single submitter clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV002254460 SCV002525642 pathogenic not provided 2021-01-29 criteria provided, single submitter clinical testing Exon-level microarray analysis identified an approximately 365 Kb deletion in 16q24.1 including the FOXF1 gene and its upstream regulatory region, including the non-coding RNA genes LINC01081 and LINC01082. Due to the nature of this array platform, with probes concentrated within exons, the actual deletion may extend into flanking intergenic regions, but it does not appear to include the neighboring FOXC2 gene.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002264893 SCV002546516 pathogenic Gollop-Wolfgang complex 2022-06-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002264898 SCV002546523 pathogenic Split hand-foot malformation 5 2022-06-07 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002264899 SCV002546524 pathogenic Chromosome 17P13.3, telomeric, duplication syndrome 2022-06-07 criteria provided, single submitter research
New York Genome Center RCV002266567 SCV002548571 uncertain significance not provided 2021-07-30 criteria provided, single submitter clinical testing Duplications and deletions involving CNTN6 gene have been implicated as possible susceptibility factors for neurodevelopmental disorders including developmentaldelays, intellectual disability, autism spectrum disorder, and seizures [PMID: 26257835, 30508811]. There are a considerable number of individuals with duplicationsand deletions spanning this CNTN6 region in both Database of Genome Variants (DGV) and gnomAD, which indicates a potential tolerance of genomic imbalance inthis region. Further, the ClinGen dosage sensitivity curation for CNTN6 duplications found no evidence for dosage pathogenicity (Triplosensitivity score: 0). Inheritance from an unaffected parent has been reported for CNTN6 duplications indicating incomplete penetrance and/or phenotypic heterogeneity [PMID:26257835]. The clinical significance of CNTN6 partial duplications is currently uncertain [PMID: 30836150]. Given the lack of compelling evidence for its pathogenicity, the inherited ~580 Kb duplication seen in this individual is reported as a Variant of Uncertain Significance.
New York Genome Center RCV002266588 SCV002548603 uncertain significance 7p22.1 microduplication syndrome 2021-08-06 criteria provided, single submitter clinical testing
New York Genome Center RCV002266602 SCV002548623 uncertain significance not provided 2021-05-21 criteria provided, single submitter clinical testing The inherited Chr20:62941782_63658260dup is an approximately 716.5KB duplication at 20q13.33. This duplication contains 32 genes, 18 of which are OMIM associated including the partial duplication of the RTEL1 gene. Of these OMIM associated genes, 4 are associated with disease phenotypes including SLC17A9 (Porokeratosis 8, disseminated superficial actinic type; AD, MIM#616063), CHRNA4(Epilepsy, nocturnal frontal lobe, 1; AD, MIM#600513), KCNQ2 (Developmental and epileptic encephalopathy 7; AD, MIM#613720, Myokymia; AD, MIM#121200,Seizures, benign neonatal, 1; AD, MIM#121200), and RTEL1 (Dyskeratosis congenita, autosomal dominant 4; AD,AR, MIM#615190, Dyskeratosis congenita, autosomalrecessive 5; AD, AR, MIM#615190; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3; AD, MIM#616373). This copy number variant is absent from population databases gnomAD(v2.1.1) and the Database of Genomic Variants (DGV). This variant is absent from ClinVar, and to our current knowledge this exact copy number gain has not been reported in affected individuals in the literature. While a similar reciprocal 20q13.33 deletion has been observed in individuals with developmental delays and seizures [PMID:25052858, 26030193, others], a duplication in this region similar to the one identified here has not been described to our current knowledge. Given the lack of compelling evidence for its pathogenicity, the inherited Chr20:62941782_63658260dup is reported as a Variant of Uncertain Significance.
New York Genome Center RCV002266628 SCV002548664 uncertain significance Luscan-Lumish syndrome 2021-07-16 criteria provided, single submitter clinical testing
New York Genome Center RCV002266707 SCV002548780 likely pathogenic Landau-Kleffner syndrome 2021-08-20 criteria provided, single submitter clinical testing This ~185Kb deletion contains the last 9 protein coding exons (6 through 14) as well as 3'Untranslated Region (3'UTR) of the GRIN2A gene. Approximately 75% of the GRIN2A protein is encoded by these exons (1,090 out of 1,464 amino acid resides; from p.Val375 through stop-codon). The variant is absent from the gnomAD SVs(v2.1) database suggesting it is not a common benign variant in the populations represented in that database. The exact same deletion has not been reported in affected individuals in the literature. However, several partial gene deletions affecting exons 6 to 14 of the GRIN2A gene have been reported in individuals affected with GRIN2A-related disorders [PMID: 30544257, 29655203]. Although the proband has inherited this deletion from his asymptomatic parent, given the wide spectrum of associated phenotypic severity, documented incomplete penetrance, and due to the expected loss-of-function effect of this variant, the inherited ~185Kb deletion is reported as Likely Pathogenic.
New York Genome Center RCV002266743 SCV002548831 uncertain significance not provided 2021-08-20 criteria provided, single submitter clinical testing The inherited Xp11.22 duplication observed here is absent from gnomAD SVs(v2.1.1) and the Database of Genomic Variants (DGV) suggesting it is not a common benign variant in the populations represented in that database. While this exact variant has not been reported in ClinVar, two copy number gains contained within the one identified here have been reported as both Likely Pathogenic (VarID:150778) and a Variant of Uncertain Significance (VarID:144464). Many larger duplications containing SHROOM4 have been reported in affected individuals in the literature, although these larger duplications contain many additional genes within the same copy number gain as SHROOM4 [PMID:26692240, 19716111, 25425167]. A small duplication containing the DGKK gene and exons 4-10 of the SHROOM4 gene was identified in a male with developmental delay, choanal atresia, ventricular septal defect, and camptodactyly [PMID:22659343]. However, full duplications of SHROOM4 have been identified in control individuals as well [PMID:26692240]. Given the uncertainty regarding the functional consequence of the inherited Xp11.22 duplication identified here, it is reported as a Variant of Uncertain Significance.
New York Genome Center RCV002266744 SCV002548832 uncertain significance not provided 2021-08-20 criteria provided, single submitter clinical testing The 21q21.1 mosaic deletion identified here is absent from gnomAD SVs(v2.1.1) and the Database of Genomic Variants (DGV) suggesting it is not a common benign variant in the populations represented in that database. While larger deletions and partially overlapping deletions have been reported in ClinVar, neither this exact deletion, nor a smaller deletion completely contained within it have been reported. This exact deletion has not been reported in the literature, although larger or partially overlapping deletions in this region were identified in individuals with variable phenotypes including developmental delay, intellectual disability, autism and seizures [PMID:25464110, 27625702]. Given the lack of compelling evidence for its pathogenicity, the 21q21.1 mosaic deletion identified here is reported as a Variant of Uncertain Significance.
New York Genome Center RCV002266756 SCV002548844 uncertain significance not provided 2021-07-23 criteria provided, single submitter clinical testing The approximately 918KB duplication observed at 9p24.1 is absent from gnomAD SVs (v2.1) and the database of genomic variants (DGV), suggesting it is not a common benign variant in the populations represented in those databases. The exact duplication observed here has not been reported in available databases, however duplications contained within or partially overlapping the one identified here have been reported in individuals with neurodevelopmental disorders [PMID:23731025, 21841781], however in at least one case the duplication was found to be inherited from a presumably unaffected parent [PMID:23731025]. Given the lack of compelling evidence for its pathogenicity the 9p24.1 duplication identified here is reported as a Variant of Uncertain Significance.
New York Genome Center RCV002266766 SCV002548861 pathogenic not provided 2021-09-17 criteria provided, single submitter clinical testing The 3.81MB 16q12.2q21 deletion identified here has not been observed in the Database of Genomic Variants (DVG) nor in gnomAD SVs(v2.1) suggesting it is not a common benign variant in the populations represented in this database. This variant is not reported in ClinVar, and while the exact deletion identified here has not been reported in affected individuals in the literature, deletions with similar genomic content or fully contained within this deletion have been reported in three individuals [PMID: 32045705, 20803649]. The 3.81MB, 16q12.2q21 copy number loss identified here is reported as Pathogenic.
New York Genome Center RCV002266770 SCV002548867 uncertain significance not provided 2021-07-16 criteria provided, single submitter clinical testing
New York Genome Center RCV002266809 SCV002548922 uncertain significance not provided 2021-10-07 criteria provided, single submitter clinical testing
New York Genome Center RCV002266854 SCV002548985 uncertain significance not provided 2021-06-04 criteria provided, single submitter clinical testing
New York Genome Center RCV002266887 SCV002549025 uncertain significance not provided 2021-06-04 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002271997 SCV002555543 uncertain significance Duchenne muscular dystrophy 2021-04-30 criteria provided, single submitter clinical testing A paternally-inherited heterozygous deletion of exons 27-29 in DMD was identified by prenatal genetic counseling testing in 1 female proband with normal clinical findings (hg38: chrX:32,438,012-32,452,548). The variant is found in another individual in the proband’s family not affected with the expected phenotype. This intragenic variant is not predicted to cause a frameshift, and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. The copy number loss in this gene has not been previously reported, but multi-exon deletions in DMD are usually associated with disease (ranging from mild Becker’s to severe Duchenne’s; and some female carriers can manifest with mild symptoms). A similar variant (in frame deletion of exons 28-29) was found in a male affected with Becker’s Muscular Dystrophy and two unaffected female siblings, from 1 family in the literature (PMID: 17259292). The location of the curated copy number loss is upstream of a known alternative splice site for the “B” isoform (Dp260) of DMD. This implies that the intronic ATG start site (in intron 29) is spared in this curated variant. In summary, while the clinical significance of the variant is uncertain, these data suggest that it is more likely to be benign. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2E PVS1_moderate: 0.3 points, 3A: 0 points, 5C: -0.15 points, 5E: -0.30 points; Total: 0 points; Riggs 2020 (PMID: 31690835).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002274294 SCV002558860 likely pathogenic See cases 2022-08-02 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002274295 SCV002558861 likely pathogenic See cases 2022-08-02 criteria provided, single submitter research
Center for Reproductive Medicine and Prenatal Diagnosis, The First Hospital of Jilin University RCV002274813 SCV002559239 pathogenic Alstrom syndrome 2022-06-18 criteria provided, single submitter clinical testing Exon 1 of ALMS1 is located in the deletion range
New York Genome Center RCV002276485 SCV002564247 uncertain significance not provided 2021-09-26 criteria provided, single submitter clinical testing
New York Genome Center RCV002275643 SCV002564305 uncertain significance not provided 2021-09-03 criteria provided, single submitter clinical testing
New York Genome Center RCV002275687 SCV002564377 pathogenic Xq25 microduplication syndrome 2021-08-20 criteria provided, single submitter clinical testing This de novo 1.7MB Xq25 duplication is absent from gnomAD SVs (v2.1) and the Database of Genomic Variants (DGV) suggesting it is not acommon benign variant in the populations represented in those databases. While this exact duplication has not been reported in the literature, other similar duplications containing the GRIA3, XIAP, and STAG2 genes have been reported in several individuals with variable clinical features including intellectual disability,developmental delay, behavioral abnormalities and seizures [PMID:23637084, 24733578, 31609727]. Smaller duplications minimally including STAG2 have also been reported independently in individuals with a neurodevelopmental phenotype including developmental delay, intellectual disability, as well as autism spectrum disorder and epilepsy in a subset of individuals [PMID:25450604, 26443594, 25677961], suggesting STAG2 is a critical gene for the Xp25 duplication phenotype. Additionally, partial duplications of GRIA3 including the 5’ region through intron 5 [PMID:17568425] and exon 1-12 [PMID:19449417] have been reported in males with intellectual disability. While this exact duplication has not been reported in the literature, the presence of many affected individuals in the literature with smaller duplications contained within the one identified here, including microduplications of the STAG2 gene, results in the classification of the de novo 1.7MB Xq25duplication identified here as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280352 SCV002568408 pathogenic 3p- syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous deletion ([GRCh38]13371737_20095506x1) in 3p25.1-p24.3 encompassing 82 genes was identified by whole exome sequencing of one individual with delayed speech and language development, global developmental delay, delayed gross motor development, delayed fine motor development, and delayed social development via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/).There is complete overlap with the KAT2B and SATB1 genes, which are not known to be haploinsufficient and have not been assessed by the ClinGen Dosage Sensitivity Working Group. Though dosage sensitivity has not been established, the Decipher database (https://www.deciphergenomics.org/) has predicted KAT2B and SATB1 genes to be haploinsufficient. Data from large population studies is insufficient to assess the frequency of this variant. A reported proband from the literature (PMID: 33513338) has a a copy-number loss in SATB1. This variant is confirmed de novo and the reported phenotype of the proband is nonspecific (intellectual disability, developmental delay, speech delay). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant chromosome 3pter-p25 deletion syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2H: 0.15 points, 3C: 0.90 points, 4: 0.15 points, 5A: 0.15 points; Total: 1.35 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280353 SCV002568409 pathogenic Interstitial 6q microdeletion syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous deletion of 6q22.1q23.2 ([GRCh38] 115941808_133892653x1) encompassing 184 genes was identified by whole exome sequencing of one individual with intellectual development disorders and seizures via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). There is complete overlap with the EYA4 gene, which is known to be haploinsufficient and has been assessed by the ClinGen Dosage Sensitivity Working Group. Additional genes, NUS1 and GJA1, also have evidence supporting haploinsufficiency, but have not yet been curated by the clingen dosage sensitivity group and do not meet the burden of evidence to support haploinsufficiency (PMID: 29100083; PMID: 11470490). Data from large population studies is insufficient to assess the frequency of this variant. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2A: 1.00 points, 3C: 0.90 points, 4: 0.0 points, 5A: 0.15 points; Total: 2.05 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280354 SCV002568410 pathogenic 15q11q13 microduplication syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous triplication in 15q11.2-13.1 ([GRCh38]22810652-29822566x4) encompassing 171 genes was identified by whole exome sequencing of one individual with intellectual development disorders and seizures via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). There is complete overlap with the 5q11.2q13 recurrent (PWS/AS) region (Class 2,BP2-BP3), which is known to be triplosenstive and has been assessed by the ClinGen Dosage Sensitivity Working Group. Data from large population studies is insufficient to assess the frequency of this variant. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Chromosome 15q11-q13 Duplication Syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2A: 1.0 points, 3C: 0.90 points, 4: 0.0 points, 5A: 0.15 points; Total: 2.05 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280355 SCV002568411 pathogenic Chromosome 15q13.3 microdeletion syndrome 2022-08-25 criteria provided, single submitter curation A confirmed paternally inherited deletion in chromosome 15q13.2-13.3 ([GRCh38]30626003_32111997x1) encompassing 19 genes was identified by whole exome sequencing in one individual with autism, delayed speech and language development, global developmental delay, delayed gross motor development, expressive language delay, and delayed fine motor development via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Data from large population studies is insufficient to assess the frequency of this variant. There is nearly complete overlap with the 15q13.3 recurrent region (BP4-BP5) (includes CHRNA7), which is known to be haploinsufficient and has been assessed by the ClinGen Dosage Sensitivity Working Group. However, this region does show incomplete penetrance and there are case/control studies demonstrating enrichment in affected individuals (PMID: 25217958; PMID: 21844811). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Chromosome 15q13.33 Deletion Syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2B: 1.0 points, 3A: 0. points, 4: 0. points, 5: 0. points; Total: points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280356 SCV002568412 pathogenic Chromosome 16p11.2 duplication syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous deletion of 16p11.2 ([GRCh38] 29663598_30188229x1) encompassing 30 genes was identified by whole exome sequencing of one individual with autism, delayed speech and language development, global developmental delay and abnormal social behavior via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). There is complete overlap with the PRRT2 gene which is known to be haploinsufficient and has been assessed by the ClinGen Dosage Sensitivity Working Group. The additional gene, TAOK2, also has evidence supporting haploinsufficiency, but has not yet been curated by the clingen dosage sensitivity group (PMID: 29467497). Data from large population studies is insufficient to assess the frequency of this variant. In summary, this variant meets criteria to be classified as pathogenic for Chromosome 16p11.2 Deletion Syndrome, 593-KB. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2A: 1.00 points, 3C: 0.45 points, 4: 0.0 points, 5A: 0.15 points; Total: 1.60 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280357 SCV002568413 pathogenic Deletion of long arm of chromosome 18 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous deletion of 18q21.33-q23 ([GRCh38]61,490,305_80,247,612x1) encompassing 129 genes was identified by whole exome sequencing of one individual with global developmental delay, delayed speech and language development, dystonia, delayed gross and fine motor development, steppage gait, and abnormal social behavior via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Data from large population studies is insufficient to assess the frequency of this variant. At least three probands from the literature (Yu et al. 2022, PMID: 21977138, PMID: 34616427) have a copy-number loss in 18q22.2q23 similar in genomic content to the variant in our study. Of these probands, two have deletions that are confirmed de novo, and the reported phenotypes are nonspecific (mild intellectual disability, developmental delay, motor delay, lack of expressive and receptive language). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Chromosome 18 Deletion Syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2B: 0 points, 3C: 0.90 points, 4C: 0.40 points, 5A: 0.15 points; Total: 1.45 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003232577 SCV002568414 pathogenic Chromosome 22q11.2 deletion syndrome, distal 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous deletion in chromosome 22q11.21 ([GRCh38]18985739_21081116x1) encompassing 88 genes was identified by whole exome sequencing in two unrelated individuals with intellectual disability, with one also presenting with delayed speech and language development and the other presenting with seizures and delayed ability to walk, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). There is complete overlap with the DGCR8 gene, which is not known to be haploinsufficient and has not been assessed by the ClinGen Dosage Sensitivity Working Group. Though dosage sensitivity has not been established, the Decipher database (https://www.deciphergenomics.org/) has predicted the DGCR8 gene to be haploinsufficient. Data from large population studies is insufficient to assess the frequency of this variant. More than 10 reported probands from the literature (PMID: 24311469, PMID: 33482818) have a copy-number loss in chromosome 22q11.21 similar in genomic content to the variant in our study. All of these probands have deletions that are confirmed de novo and the reported phenotypes of the probands are nonspecific (mild developmental delay, epilepsy, language delay). In summary, this variant meets criteria to be classified as pathogenic for Chromosome 22q11.21 deletion syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2H: 0.15 points, 3C: 0.90 points, 4C: 0.90 points, 5A: 0.30 points; Total: 2.10 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003232578 SCV002568415 pathogenic Chromosome 22q11.2 microduplication syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous duplication ([GRCh38]18985739_21081116x3) in chromosome 22q11.21 encompassing 88 genes was identified by whole exome sequencing in one individual with global developmental delay, delayed speech and language development, and delayed social development via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Data from large population studies is insufficient to assess the frequency of this variant. Two reported probands from the literature (PMID: 17250668; PMID: 26719767) have copy-number gains in chromosome 22q11.21 similar in genomic content to the variant in our study. Of these probands, one has a duplication that is confirmed de novo and in both probands the reported phenotypes are nonspecific (delay in social and language development, autism, neuromotor delay). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Chromosome 22q11.21 duplication Syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2B: 0 points, 3C: 0.90 points, 4C: 0.25 points, 5A: 0.15 points; Total: 1.30 points; Riggs 2020 (PMID: 31690835).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002280361 SCV002568416 pathogenic Chromosome 22q13 duplication syndrome 2022-08-25 criteria provided, single submitter curation A confirmed de novo heterozygous duplication in chromosome 22q13.33 ([GRCh38]49883237_50740457x3) encompassing 39 genes was identified by whole exome sequencing in one individual with delayed speech and language development, intellectual disability, expressive language delay, and delayed ability to walk via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Data from large population studies is insufficient to assess the frequency of this variant. At least three reported probands from the literature (PMID: 2784604; PMID: 24153177) and one proband from the DECIPHER database (Decipher ID: 396055) have a copy-number gain in chromosome 22q13.33 similar in genomic content to the variant in our study. Of these probands, one has a duplication that is confirmed de novo, and the reported phenotypes of all probands are nonspecific (autism, ADHD, seizures, bipolar disorder). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Chromosome 22q13 duplication Syndrome. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1A: 0 points, 2H: 0 points, 3C: 0.45 points, 4C: 0.45 points, 5A: 0.15 points; Total: 1.05 points; Riggs 2020 (PMID: 31690835).
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology RCV002280381 SCV002568449 likely pathogenic Hereditary factor XI deficiency disease criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286364 SCV002576315 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286365 SCV002576316 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286366 SCV002576317 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286367 SCV002576318 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286369 SCV002576320 pathogenic not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286370 SCV002576321 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286371 SCV002576322 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286372 SCV002576323 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286373 SCV002576324 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286374 SCV002576325 likely pathogenic not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286375 SCV002576326 pathogenic 5q35 microduplication syndrome 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286376 SCV002576327 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286377 SCV002576328 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286378 SCV002576329 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286379 SCV002576330 uncertain significance not specified 2022-09-28 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286380 SCV002576331 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286381 SCV002576332 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286382 SCV002576333 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286383 SCV002576334 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286384 SCV002576335 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV002286385 SCV002576336 uncertain significance not specified 2021-05-25 criteria provided, single submitter research
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV002287860 SCV002578132 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2022-09-27 criteria provided, single submitter clinical testing
Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital RCV003223355 SCV002584967 pathogenic Pearson syndrome criteria provided, single submitter research
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV002294568 SCV002587056 pathogenic Muscular dystrophy, limb-girdle, autosomal recessive 23 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV002294569 SCV002587057 pathogenic Muscular dystrophy, limb-girdle, autosomal recessive 23 criteria provided, single submitter clinical testing
Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center RCV002308493 SCV002600098 pathogenic Lynch syndrome 1 2022-11-08 criteria provided, single submitter clinical testing This sequence change causes a complete deletion of the PMS2 gene. This variant has been detected in patients under 20 years of age with PMS2-deficient glioblastoma and colorectal adenocarcinoma in IHC, along with another variant, PMS2 (NM_000535.7): c.241G>T (p.Glu81*, located in trans). The patient is considered constitutional mismatch repair deficiency (CMMRD).
Ambry Genetics RCV002379639 SCV002672400 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing The c.7388_7389insALU likely pathogenic variant results from an Alu element insertion located in coding exon 49 of the ATM gene. Alu element insertions contribute to pathogenicity by either disrupting the coding sequence or inducing aberrant splicing (Belancio VP et al. Semin. Cancer Biol. 2010 Aug;20:200-10; Deininger P et al. Genome Biol. 2011 Dec;12:236). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
New York Genome Center RCV002468504 SCV002764450 uncertain significance Brugada syndrome 3; Long qt syndrome 8 2021-12-01 criteria provided, single submitter clinical testing
New York Genome Center RCV002468505 SCV002764451 uncertain significance Maturity-onset diabetes of the young type 8 2021-11-15 criteria provided, single submitter clinical testing
New York Genome Center RCV002468511 SCV002764465 uncertain significance Maturity-onset diabetes of the young type 8 2020-12-09 criteria provided, single submitter clinical testing
New York Genome Center RCV002468550 SCV002764594 uncertain significance Maturity-onset diabetes of the young type 8 2021-04-28 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002475193 SCV002771489 pathogenic not provided 2020-07-21 criteria provided, single submitter clinical testing Duplication of the APP locus has been reported in multiple unrelated families and/or individuals with clinical features of Alzheimer's disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475194 SCV002771490 uncertain significance not provided 2022-03-07 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002475195 SCV002771491 pathogenic not provided 2021-06-18 criteria provided, single submitter clinical testing A similar deletion involving all of CAPN3 and a portion of a neighboring gene has been identified in two families with limb-girdle muscular dystrophy type 2A (LGMD2A; PMID: 24715573). The frequency of similar variants in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475196 SCV002771492 uncertain significance not provided 2021-10-20 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002475197 SCV002771493 pathogenic not provided 2022-06-07 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual tested at Athena Diagnostics with clinical features associated with this gene.
Athena Diagnostics RCV002475198 SCV002771494 pathogenic not provided 2022-04-18 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have been identified in multiple unrelated individuals with Duchenne muscular dystrophy (DMD). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475199 SCV002771495 pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 49-50 have been reported primarily in patients with Duchenne muscular dystrophy (DMD), and also in a few individuals with Becker muscular dystrophy (BMD; PMID: 19937601, 28610567). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475200 SCV002771496 pathogenic not provided 2022-03-01 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 46-50 are reported primarily in patients with Duchenne muscular dystrophy (DMD), and also in a few rare cases with Becker muscular dystrophy (BMD; PMID: 16936400, 17253928). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475201 SCV002771497 pathogenic not provided 2022-06-28 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 48-50. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475202 SCV002771498 likely pathogenic not provided 2021-07-26 criteria provided, single submitter clinical testing This variant is likely to be inserted in tandem within the DMD gene and is expected to disrupt protein function. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar duplication of exon 20 has been identified in at least one individual with Duchenne muscular dystrophy (DMD).
Athena Diagnostics RCV002475203 SCV002771499 pathogenic not provided 2023-08-24 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exon 50 have been reported in multiple patients with DMD, and also a few cases with BMD (PMID: 28610567, 16834926). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475204 SCV002771500 pathogenic not provided 2022-04-20 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated males with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 8-11. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475205 SCV002771501 pathogenic not provided 2021-07-30 criteria provided, single submitter clinical testing This variant is likely to be inserted in tandem within the DMD gene and would maintain the transcript's reading frame, but is expected to disrupt protein function. Similar duplications of exons 3-4 have been reported in multiple unrelated patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and intermediate dystrophinopathies. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475206 SCV002771502 pathogenic not provided 2021-06-11 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Similar deletions of exons 42-43 have been reported in patients with Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), and an intermediate dystrophinopathy (IMD).
Athena Diagnostics RCV002475207 SCV002771503 pathogenic not provided 2021-09-08 criteria provided, single submitter clinical testing Similar deletions of exons 3-4 have been reported in multiple individuals described as having BMD, and also in several with Duchenne muscular dystrophy (DMD; PMID: 1864612, 9048922, 12324874, 16049303), as well as in individuals where the type of dystrophinopathy was not specified. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475208 SCV002771504 pathogenic not provided 2021-06-15 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Similar deletions of exon 63 have been identified in individuals with Duchenne muscular dystrophy (DMD).
Athena Diagnostics RCV002475209 SCV002771505 pathogenic not provided 2022-06-10 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 46-53. Similar deletions have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475210 SCV002771506 likely pathogenic not provided 2021-08-25 criteria provided, single submitter clinical testing This variant is likely to be inserted in tandem within the DMD gene and would maintain the transcript's reading frame, but is expected to disrupt protein function. Similar duplication of exons 45-55 has been identified in at least one male with dystrophinopathy. Similar deletions have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475211 SCV002771507 pathogenic not provided 2021-06-14 criteria provided, single submitter clinical testing This variant is likely to be inserted in tandem within the DMD gene and is expected to disrupt protein function. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Similar duplications of exons 45-51 have been identified in multiple unrelated males with dystrophinopathies, including at least three with Duchenne muscular dystrophy (DMD; PMID: 15643612, 25482253, 28332368).
Athena Diagnostics RCV002475212 SCV002771508 pathogenic not provided 2022-08-18 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Multiple unrelated individuals with DMD have been reported with similar deletions of exon 18-44. Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475213 SCV002771509 pathogenic not provided 2021-12-17 criteria provided, single submitter clinical testing Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Multiple unrelated individuals with Duchenne muscular dystrophy (DMD) have been reported with similar deletions of exons 8-13.
Athena Diagnostics RCV002475214 SCV002771510 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002475215 SCV002771511 pathogenic not provided 2022-04-07 criteria provided, single submitter clinical testing This deletion variant is predicted to maintain the open reading frame. However, due to the altered protein length, it is expected to severely disrupt protein function. Similar deletions of exons 49-51 have been reported in the literature to be associated with both Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and dilated cardiomyopathy (DCM). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475216 SCV002771512 uncertain significance not provided 2021-08-05 criteria provided, single submitter clinical testing
Athena Diagnostics RCV002475217 SCV002771513 pathogenic not provided 2022-06-29 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 46-49 have been reported primarily in patients with Duchenne muscular dystrophy (DMD), and also in a few individuals with Becker muscular dystrophy (BMD; PMID: 17259292, 34602496). Similar variants have not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)).
Athena Diagnostics RCV002475218 SCV002771514 pathogenic not provided 2021-06-15 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar deletion of exon 67 has been reported in at least one individual with Duchenne muscular dystrophy (DMD).
Athena Diagnostics RCV002475219 SCV002771515 pathogenic not provided 2022-03-15 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 51-52 have been reported in multiple individuals described as having Duchenne muscular dystrophy (DMD), or in individuals where the type of dystrophinopathy was not specified. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475220 SCV002771516 likely pathogenic not provided 2021-08-20 criteria provided, single submitter clinical testing This variant is expected to severely disrupt protein function. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475221 SCV002771517 likely pathogenic not provided 2021-09-24 criteria provided, single submitter clinical testing This deletion variant is predicted to maintain the open reading frame. However, due to the altered protein length, this is predicted to result in abnormal protein function. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Deletion of exons 49-55 has not been reported in the literature. Other in-frame deletions in this region (e.g. exons 49-53) have been reported in multiple patients with dystrophinopathy-related diseases.
Athena Diagnostics RCV002475222 SCV002771518 likely pathogenic not provided 2022-03-08 criteria provided, single submitter clinical testing This variant is likely inserted in tandem within the DMD gene (PMID: 25640679) and, if so, would severely disrupt protein function. A similar duplication of exons 53-60 has been reported in at least one male with Duchenne muscular dystrophy (DMD). Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475223 SCV002771519 pathogenic not provided 2022-02-28 criteria provided, single submitter clinical testing Similar deletions of exons 10-29 have been reported in multiple males described as having Becker muscular dystrophy (BMD), or in males where the type of dystrophinopathy was not specified. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475224 SCV002771520 pathogenic not provided 2022-08-03 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar deletions of exons 35-50 have been reported in at least two individuals with DMD, and at least one with BMD. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475225 SCV002771521 pathogenic not provided 2022-09-13 criteria provided, single submitter clinical testing This deletion is predicted to maintain the transcript reading frame, however, it also disrupts an important binding domain of the protein and is thus expected to severely disrupt function. Similar deletions of exon 3-44 have been reported in patients with DMD and those with BMD.
Athena Diagnostics RCV002475226 SCV002771522 pathogenic not provided 2022-02-15 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar variant has been identified in at least one individual with clinical features associated with this gene.
Athena Diagnostics RCV002475227 SCV002771523 pathogenic not provided 2022-05-03 criteria provided, single submitter clinical testing This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. Similar variants have been identified in multiple unrelated individuals with clinical features associated with this gene. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475228 SCV002771524 likely pathogenic not provided 2021-08-25 criteria provided, single submitter clinical testing This deletion variant maintains the transcript's reading frame, but is expected to disrupt protein function. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar deletion of exons 14-16 has been identified in at least one individual with clinical features associated with this gene.
Athena Diagnostics RCV002475229 SCV002771525 pathogenic not provided 2021-08-26 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). A similar variant has been identified in at least one individual with clinical features associated with this gene.
Athena Diagnostics RCV002475230 SCV002771526 pathogenic not provided 2021-11-09 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. A similar variant has been identified in at least one individual with clinical features associated with this gene. Similar variants have not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Athena Diagnostics RCV002475231 SCV002771527 likely pathogenic not provided 2022-01-05 criteria provided, single submitter clinical testing This deletion variant maintains the transcript's reading frame, but is likely to disrupt protein structure or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual tested at Athena Diagnostics with clinical features associated with this gene.
Laboratory of Medical Genetics, University of Torino RCV002481168 SCV002774884 likely pathogenic Developmental and epileptic encephalopathy, 54 2022-12-23 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, University of Torino RCV002481171 SCV002774889 likely pathogenic Developmental and epileptic encephalopathy, 54 2022-12-23 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, University of Torino RCV002481172 SCV002774890 likely pathogenic Developmental and epileptic encephalopathy, 54 2022-12-23 criteria provided, single submitter clinical testing
Genomic Medicine, Universita Cattolica del Sacro Cuore RCV002510483 SCV002817425 pathogenic See cases 2022-12-21 criteria provided, single submitter clinical testing The variant is de novo.
Optical Genome Mapping Laboratory, Clinical Institute of Genomic Medicine, University Medical Center Ljubljana RCV002510242 SCV002818293 uncertain significance Pelizaeus-Merzbacher disease 2023-01-06 criteria provided, single submitter clinical testing This duplication initially identified by arrayCGH, containing the PLP 1 gene, and found in a male child was initially interpreted as pathogenic 1A, 2A. Optical genome mapping identified the part of the duplication containing the complete PLP1 gene to be inverted and the exact location of the invdup to be between two lamina-associated domains (LADs). Additionally, segregation of the extended family identified additional carriers, including an adult male without clinical manifestation of PLP1. On the basis of this evidence the variant was reclassified as a variant of uncertain significance (1A, 2A, 4J, total points: 0.70).
Ambry Genetics RCV004078068 SCV003544153 uncertain significance not specified 2022-04-07 criteria provided, single submitter clinical testing The c.14773C>T (p.P4925S) alteration is located in exon 98 (coding exon 98) of the SSPO gene. This alteration results from a C to T substitution at nucleotide position 14773, causing the proline (P) at amino acid position 4925 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Ambry Genetics RCV004218794 SCV003723034 uncertain significance not specified 2023-12-21 criteria provided, single submitter clinical testing The c.14095C>T (p.P4699S) alteration is located in exon 92 (coding exon 92) of the SSPO gene. This alteration results from a C to T substitution at nucleotide position 14095, causing the proline (P) at amino acid position 4699 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154619 SCV003843209 likely pathogenic See cases 2021-03-08 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154620 SCV003843213 likely pathogenic Rubinstein-Taybi syndrome due to CREBBP mutations 2021-03-09 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154621 SCV003843214 pathogenic See cases 2020-01-29 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154622 SCV003843215 pathogenic See cases 2020-01-06 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154623 SCV003843216 likely pathogenic See cases 2021-02-12 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154628 SCV003843234 pathogenic See cases 2019-09-23 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154629 SCV003843235 uncertain significance See cases 2021-11-17 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154631 SCV003843239 likely benign See cases 2021-10-20 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV003154634 SCV003843243 pathogenic See cases 2021-12-13 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV003156207 SCV003845199 pathogenic Peeling skin syndrome 1 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV003156208 SCV003845201 pathogenic Bartter disease type 3 criteria provided, single submitter clinical testing
Ambry Genetics RCV004249286 SCV003874123 uncertain significance not specified 2023-02-22 criteria provided, single submitter clinical testing The c.368C>T (p.P123L) alteration is located in exon 4 (coding exon 4) of the FAM86C1 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
New York Genome Center RCV003221320 SCV003915654 likely pathogenic 16p13.11 recurrent microdeletion syndrome 2021-10-06 criteria provided, single submitter clinical testing The inherited ~1.5Mb interstitial 16p13.11 BP2-BP3 deletion contains 14 OMIM associated genes, and 4 of those are disease associated (MYH11, ABCC6, NDE1, and ABCC1). This region harbors a cluster of low copy repeats that lead to recurrent copy number changes, mainly three single copy intervals between segmental duplications (PMID: 21150890, 19786961). Interval I includes the genes RRN3 and PDXDC1; Interval II includes MYH11, NDE1, and ABCC6, and Interval III includes XYLT1. Deletions and duplications most commonly include the genes in interval II but may extend to include intervals I and III (PMID:21150890, 19786961). The presence of these repeats makes mapping the exact breakpoints with short-read sequencing and/or microarray difficult. Deletions in this region are associated with 16p13.11 BP2-BP3 recurrent deletion syndrome, which has a high degree of phenotypic variability and confers susceptibility to a variety of developmental disorders including developmental delay, microcephaly, epilepsy, short stature, facial dysmorphism, and behavioral problems (PMID: 18550696, 19843651, 24246141). Microdeletions appear de novo or are inherited from mildly affected or completely normal parents in an autosomal dominant manner, suggesting that the microdeletion has incomplete penetrance and variable expressivity (PMID: 17480035, 18550696, 19843651). ClinGen haploinsufficiency score is 3 for this region meaning sufficient evidence for dosage pathogenicity. Based on the available evidence the 16p13.11 BP2-BP3 deletion identified here is classified as likely pathogenic.
New York Genome Center RCV003221321 SCV003915655 pathogenic 22q11.2 deletion syndrome 2021-10-01 criteria provided, single submitter clinical testing The ~3Mb proximal 22q11.21 recurrent (DGS/VCFS) region (proximal, A-D) deletion identified here contains 44 OMIM associated genes, and 14 of those are diseases associated (includes TBX1). ClinGen Haploinsufficiency score is 3 for this region meaning sufficient evidence for dosage pathogenicity. Based on the available evidence the 22q11.2 proximal (A-D) deletion identified here is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV003222762 SCV003917194 likely benign not provided 2023-06-01 criteria provided, single submitter clinical testing DDX11: BS2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003226030 SCV003922110 uncertain significance Dihydropteridine reductase deficiency 2023-05-02 criteria provided, single submitter curation The homozygous c.*119+12119G>A variant in QDPR was identified by our study in one individual with hyperphenylalaninemia, global developmental delay, hypertonia, macrocephaly, seizures, constipation, drooling, dysphagia, and absent DHPR activity (PMID: 32022462). The phenotype of this individual homozygous for this variant is highly specific for dihydropteridine reductase deficiency based on the absent DHPR activity observed (PMID: 33903016). The c.*119+12119G>A variant in QDPR has not been previously reported in individuals with dihydropteridine reductase deficiency, but has been identified in 0.06% (3/5190) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs898384584). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The affected individual with this variant had an alternate molecular basis for the disease (dihydropteridine reductase deficiency) (PMID: 32022462, ClinVar Variation ID: 626310), suggesting that this variant may not be pathogenic. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.*119+12119G>A variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PP4, BP4, BP5 (Richards 2015).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003226031 SCV003922111 uncertain significance Dihydropteridine reductase deficiency 2023-05-02 criteria provided, single submitter curation The homozygous c.*119+4759T>C variant in QDPR was identified by our study in one individual with hyperphenylalaninemia, global developmental delay, hypertonia, macrocephaly, seizures, constipation, drooling, dysphagia, and absent DHPR activity (PMID: 32022462). The phenotype of this individual homozygous for this variant is highly specific for dihydropteridine reductase deficiency based on the absent DHPR activity observed (PMID: 33903016). The c.*119+4759T>C variant in QDPR has not been previously reported in individuals with dihydropteridine reductase deficiency, but has been identified in 0.02% (13/68032) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1167539604). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The affected individual with this variant had an alternate molecular basis for the disease (dihydropteridine reductase deficiency) (PMID: 32022462, ClinVar Variation ID: 626310), suggesting that this variant may not be pathogenic. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.*119+4759T>C variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PP4, BP4, BP5 (Richards 2015).
New York Genome Center RCV003228624 SCV003925276 uncertain significance Dilated cardiomyopathy 1I 2022-08-12 criteria provided, single submitter clinical testing The ~42kb duplication on the long arm of chromosome 2 encompasses exons 3 to 9 of DES and exons 1 to 8 (out of 41) of SPEG. Biallelic pathogenic variants in SPEG are associated with Centronuclear myopathy 5 [AR; MIM#615959]. Partial gene duplication in DES has not been reported previously in the literature, ClinVar, or DECIPHER. This gene has not been evaluated by ClinGen Dosage Sensitivity Working Group. Many disease-associated desmin variants cause an accumulation of disorganized intracytoplasmic aggregates containing desmin and other cytoskeletal proteins. Most ofthe known DES pathogenic variants are missense or small in-frame deletions; truncating variants have been more rarely reported in the literature (heterozygous orbiallelic) [PMID: 29926427]. Based on the available evidence, this ~42kb duplication is reported as a Variant ofUncertain Significance.
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia RCV003388953 SCV003927989 pathogenic KBG syndrome 2022-07-27 criteria provided, single submitter clinical testing
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia RCV003388954 SCV003927990 pathogenic KBG syndrome 2022-07-27 criteria provided, single submitter clinical testing
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia RCV003388955 SCV003927991 pathogenic KBG syndrome 2022-07-27 criteria provided, single submitter clinical testing
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia RCV003388956 SCV003927992 likely pathogenic KBG syndrome 2022-07-27 criteria provided, single submitter clinical testing
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia RCV003388957 SCV003927993 likely pathogenic KBG syndrome 2022-07-27 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV003234736 SCV003932629 pathogenic Williams syndrome 2023-06-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV004295500 SCV003946009 likely benign not specified 2023-05-17 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Ambry Genetics RCV004299430 SCV003963907 uncertain significance not specified 2023-03-29 criteria provided, single submitter clinical testing The c.368C>A (p.P123Q) alteration is located in exon 4 (coding exon 4) of the FAM86C1 gene. This alteration results from a C to A substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV003328726 SCV004035142 pathogenic X-linked ichthyosis with steryl-sulfatase deficiency criteria provided, single submitter clinical testing
Center for Molecular Medicine, Children’s Hospital of Fudan University RCV003328531 SCV004035252 likely pathogenic Fructose-biphosphatase deficiency 2022-12-21 criteria provided, single submitter clinical testing
New York Genome Center RCV003336017 SCV004046513 likely pathogenic Aortic aneurysm, familial thoracic 12 2023-04-13 criteria provided, single submitter clinical testing The chr15:((71456875_71457375)_71687553) loss is an approximately 230kb deletion on the long arm of chromosome 15. This deletion removes exon 8/18 and flanking intronic sequences of the THSD4 gene (MANE Select transcript NM_024817.3), and is predicted to lead to an out of frame consequence and loss of function via nonsense mediated decay. This variant is absent from population databases (gnomAD SVs v2.1, Database of GenomicVariation) suggesting it is not a common benign variant in the populations represented in those databases. A similar deletion of exon 8 has been reported in ClinVar as a Variant of Uncertain Significance (VarID: 1808966), and to our current knowledge this exact deletion nor similar deletions have been reported in affected individuals in the literature. However, nonsense and frameshift variants upstream and downstream of exon 8 have been reported in individuals in the literature withTAAD, and have been found to segregate with disease in affected families [PMID:32855533]. Given its deleterious nature and absence in population databases, the chr15:((71456875_71457375)_71687553) deletion identified in the THSD4 gene is reported as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV003406791 SCV004124534 likely benign not provided 2022-09-01 criteria provided, single submitter clinical testing NBPF11: PM2:Supporting, BP4, BP7; NBPF8: PM2:Supporting, BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003406792 SCV004124535 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing RP4-565E6.1: BS2
CeGaT Center for Human Genetics Tuebingen RCV003406793 SCV004124536 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing NBPF12: PM2:Supporting, BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003406794 SCV004124537 likely benign not provided 2024-02-01 criteria provided, single submitter clinical testing NBPF12: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003406795 SCV004124538 likely benign not provided 2022-06-01 criteria provided, single submitter clinical testing NBPF12: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003408827 SCV004124561 likely benign not provided 2022-03-01 criteria provided, single submitter clinical testing NBPF14: BS1
CeGaT Center for Human Genetics Tuebingen RCV003408828 SCV004124562 likely benign not provided 2023-03-01 criteria provided, single submitter clinical testing NBPF14: BP4, BS2
CeGaT Center for Human Genetics Tuebingen RCV003408829 SCV004124563 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing NBPF14: BP4, BS2
CeGaT Center for Human Genetics Tuebingen RCV003408830 SCV004124564 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing NBPF14: BP4, BS2
CeGaT Center for Human Genetics Tuebingen RCV003408837 SCV004124571 likely benign not provided 2023-05-01 criteria provided, single submitter clinical testing NBPF16: BP4, BS2
CeGaT Center for Human Genetics Tuebingen RCV003417250 SCV004126513 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing MRC1L1: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003417349 SCV004127625 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing FAM21B: PM2:Supporting, BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003426462 SCV004129329 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing GOLGA8IP: BP4, BP7, BS2
CeGaT Center for Human Genetics Tuebingen RCV003426463 SCV004129330 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing GOLGA8IP: BP4, BP7, BS2
CeGaT Center for Human Genetics Tuebingen RCV003424838 SCV004129455 likely benign not provided 2022-05-01 criteria provided, single submitter clinical testing HYOU1: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003390474 SCV004131568 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing GOLGA8Q: BS2
CeGaT Center for Human Genetics Tuebingen RCV003389974 SCV004134946 benign not provided 2023-06-01 criteria provided, single submitter clinical testing SYCE1: BS1, BS2
CeGaT Center for Human Genetics Tuebingen RCV003394651 SCV004134947 likely benign not provided 2023-03-01 criteria provided, single submitter clinical testing SYCE1: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003411191 SCV004137449 benign not provided 2022-11-01 criteria provided, single submitter clinical testing CSPG4P13: BS1, BS2
CeGaT Center for Human Genetics Tuebingen RCV003419695 SCV004142526 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing RNF135: BS2
CeGaT Center for Human Genetics Tuebingen RCV003437700 SCV004149223 likely benign not provided 2022-10-01 criteria provided, single submitter clinical testing TPRXL: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003437522 SCV004152295 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing GSTT2B: BS2
CeGaT Center for Human Genetics Tuebingen RCV003437523 SCV004152296 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing GSTT2B: BS2
CeGaT Center for Human Genetics Tuebingen RCV003427098 SCV004155158 likely benign not provided 2023-01-01 criteria provided, single submitter clinical testing ENSG00000284879: BS2
CeGaT Center for Human Genetics Tuebingen RCV003425669 SCV004157763 likely benign not provided 2023-03-01 criteria provided, single submitter clinical testing SPATA31A2: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003435799 SCV004157777 likely benign not provided 2022-04-01 criteria provided, single submitter clinical testing CNTNAP3B: PM2:Supporting, BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003430034 SCV004158127 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing ENSG00000249109: BS2
CeGaT Center for Human Genetics Tuebingen RCV003436714 SCV004163907 benign not provided 2022-12-01 criteria provided, single submitter clinical testing TARP: BS1, BS2
CeGaT Center for Human Genetics Tuebingen RCV003438310 SCV004166339 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing GAGE2D: BP4, BP7
CeGaT Center for Human Genetics Tuebingen RCV003432466 SCV004167554 likely benign not provided 2023-02-01 criteria provided, single submitter clinical testing PGRMC1: BS2
CeGaT Center for Human Genetics Tuebingen RCV003432467 SCV004167555 likely benign not provided 2022-12-01 criteria provided, single submitter clinical testing PGRMC1: BS2
New York Genome Center RCV003448557 SCV004176033 likely pathogenic KBG syndrome 2022-10-03 criteria provided, single submitter clinical testing The de novo copy number loss identified here is a ~37.3Kb deletion on the long arm of chromosome 16. This deletion contains ZNF778 and exon 13 of OMIM annotated ANKRD11, which is associated with KBG syndrome (MIM #148050). While the exact deletion identified here has not been previously reported in an affected individual in the literature, similar partial or completely overlapped 16q24.3 microdeletions have been reported in affected KBG syndrome individuals with features of developmental delay, intellectual disability, behavioral issues, speech delay, facial anomalies including macrodontia [PMID: 19920853, 23885231, 22307766, 21654729, 34440431]. The shortest common overlapping region among these reported individuals have been narrowed to ~28.3 kb encompassing the exon 13 of ANKRD11 [PMID: 23463723], suggesting it to be a critical gene for the KBG phenotype. The ~37.3Kb, 16q24.3 de novo deletion identified here has not been observed in the Database of Genomic Variants(DVG) nor in gnomAD SVs(v2.1), suggesting it is not a common benign variant in the populations represented in this database. Based on the available evidence, this ~37.3Kb, de novo copy number loss Chr16:g(89232406_89233606)_(89269724_89268645)del is reported as Likely Pathogenic.
Illumina Laboratory Services, Illumina RCV003448664 SCV004176306 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing This CNV is a 547 kb duplication of 16p11.2 on chromosome 16, (seq[GRCh37]dup(16)(p11.2);NC_000016.9:g.29651786_30199024dup), which is inherited. This CNV affects 27 protein-coding genes and is consistent with the proximal 16p11.2 recurrent region, which is subject to recurrent copy number changes due to the presence of a cluster of low copy repeats (PMID: 20301775). These recurrent breakpoints are sometimes referred to as BP4 and BP5. A few similar duplications have been observed in controls, consistent with the incomplete penetrance and variable phenotypes associated with 16p11.2 duplication (PMID: 21841781). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448665 SCV004176307 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing This CNV is a 1.4 Mb deletion of 17q12 on chromosome 17 (seq[GRCh37]del(17)(q12),;NC_000017.10:g.34814816_36249107del). The CNV encompasses the following protein coding genes: AATF, ACACA, C17orf78, DDX52, DHRS11, DUSP14, GGNBP2, HNF1B, LHX1, MRM1, MYO19, PIGW, SYNRG, TADA2A, and ZNHIT3. The region of the CNV is flanked by segmental duplications that mediate recurrent breakpoints, and overlaps the well described 17q12 recurrent deletion syndrome (PMID: 27929632). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448666 SCV004176308 pathogenic not provided 2023-06-05 criteria provided, single submitter clinical testing This CNV is a 3.9 Mb deletion of 3q22.3-q23 on chromosome 3, (seq[GRCh37]del(3)(q22.3q23);NC_000003.11:g.137912620_141811656del) that occurred de novo. This CNV encompasses 28 protein coding genes, including the FOXL2 gene, which is associated with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). Additionally, interstitial deletions specifically involving bands 3q22 and 3q23 have been reported in multiple individuals with BPES (PMID: 8291545; 19344873; 20232352; 21934608). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448667 SCV004176309 pathogenic not provided 2023-05-24 criteria provided, single submitter clinical testing This CNV is a 9.9 Mb deletion of 4q34.3-q35.2 on chromosome 4, (seq[GRCh37]del(4)(q34.3q35.2); NC_000004.11:g.180937545_190915069del). This CNV constitutes a loss of 38 protein coding genes and has not been reported in controls. Deletions of 4q of varying size and position have been associated with 4q deletion syndrome. Deletions of a similar size and location to this event, including at least three that occurred de novo, have been reported in individuals with developmental delay, craniofacial and skeletal anomalies, congenital malformations, and additional features (PMID: 19344873; 19921640; 22847869). Of note, this event fully encompasses the F11 gene. Individuals with 4q deletions which disrupt the F11 gene may display coagulation defects (PMID: 22159456; 34481514). The CNV also fully encompasses CYP4V2, KLKB1, TRAPPC11, TENM3 and SLC25A4, genes in which loss of function variants are associated with autosomal recessive disorders (PMID: 30013777; PMID: 34648194). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448668 SCV004176310 pathogenic not provided 2023-04-13 criteria provided, single submitter clinical testing This CNV is a 2 Mb duplication of 17p11.2 on chromosome17, (seq[GRCh37]dup(17)(p11.2); NC_000017.10:g. 16757513_18772328dup). This CNV encompasses 31 protein coding genes, including the RAI1 gene, and overlaps the well-described Potocki-Lupski syndrome (PMID: 17357070; 20188345). The 17p11.2 duplication has not been reported in published controls and is not found in the Genome Aggregation Database (gnomAD SVs version 2.1.). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448669 SCV004176311 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing This CNV is a 1.87 Mb deletion of 5q35.2q35.3 on chromosome 5, (seq[GRCh37]del(5)(q35.2q35.3);NC_000005.9:g.175559209_ 177430432del), that occurred de novo. This event is located near the q terminus of chromosome 5 but does not extend to the telomere. This CNV encompasses 38 protein coding genes, including NSD1, DDX41, and SLC34A1. Haploinsufficiency of NSD1 is a known cause of Sotos syndrome (PMID: 11896389; 17565729; 20301652; 23190751). Microdeletions of 5q35.2q35.3 involving NSD1 have been especially frequently observed in Japanese patients with Sotos syndrome (PMID: 14517949; 20301652). Similar CNVs have not been reported in controls (PMID: 21841781; 24174537). This CNV also encompasses the DDX41 gene, haploinsufficiency of which is associated with DDX41-related hematologic malignancy predisposition syndrome. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448670 SCV004176312 likely pathogenic not provided 2023-04-21 criteria provided, single submitter clinical testing This CNV is a 94 kb deletion of 15q21.3 on chromosome 15 (seq[GRCh37]del(15)(q21.3); NC_000015.9:g.55525602_ 55619376del). This CNV affects the PIGB, PIGBOS1, and RAB27A protein coding genes. Similar deletions have been reported in ClinVar (VID: 1459351, 1808194) and have been identified in control populations, though not at a frequency that precludes involvement in a disorder with an autosomal recessive inheritance pattern (PMID: 21841781; 24174537). This deletion results in the loss of exons 1-3 of the PIGB gene, which is associated with glycosylphosphatidylinositol deficiency. Loss of function is a known mechanism of this disease (PMID: 31256876), and this CNV is expected to result in an absent or non-functional PIGB gene product. This CNV was identified in trans with a missense variant in the PIGB gene that was classified as a variant of uncertain significance. Based on the available evidence, this CNV is classified as likely pathogenic.
Illumina Laboratory Services, Illumina RCV003448671 SCV004176313 uncertain significance not provided 2023-09-01 criteria provided, single submitter clinical testing This CNV is a 589 kb duplication of 17p13.1 on chromosome 17 (seq[GRCh37]dup(17)(p13.1);NC_000017.10:g.7709286_8297901dup) that occurred de novo. This CNV encompasses 29 protein-coding genes including CHD3, and has breakpoints in DNAH2 and RNF222. This CNV has not been reported in association with a specific phenotype, nor has it been reported in control cohorts. Small variants in CHD3 have been described in association with Snijders Blok-Campeau syndrome which is characterized by developmental delay, intellectual disability, and characteristic facial features; however, there is limited information on larger duplications encompassing this gene. A duplication which partially overlaps but is larger than this CNV has been reported two siblings with features consistent with Snijders Blok-Campeau syndrome (PMID: 32483341). Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448672 SCV004176314 pathogenic not provided 2023-05-24 criteria provided, single submitter clinical testing This CNV is a 13.0 Mb duplication of 2q36.3-q37.3 on chromosome 2, (seq[GRCh37]dup(2)(q36.3q37.3); NC_000002.11:g.230077026_243049549dup). This CNV constitutes a gain of 124 protein coding genes and has not been reported in controls. Duplications of a similar size and location to this event, including at least six that occurred de novo, have been reported in individuals with intellectual disability, craniofacial and skeletal anomalies, and additional features (PMID: 19344873; 36357380). 2q duplications arise primarily from a parental chromosomal rearrangement associated with the deletion of a partner chromosomal segment (PMID: 19344873; 25851921). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448673 SCV004176315 pathogenic not provided 2023-07-25 criteria provided, single submitter clinical testing This CNV is a 287 kb deletion of Xp21.1 on chromosome X, (seq[GRCh37]del(X)(Xp21.1); NC_000023.10:g.32448462_32735062del), that is inherited. The breakpoints for this CNV lie within introns 7 and 29 of the DMD gene, resulting in disruption of exons 8-29. These exons code for the actin binding and central rod domains. Smaller deletions in this region have been reported in at least 10 individuals with dystrophinopathies (PMID: 18752307). This CNV has not been reported in controls (PMID: 19344873). Based on the available evidence, this CNV is classified as a pathogenic.
Illumina Laboratory Services, Illumina RCV003448674 SCV004176316 pathogenic not provided 2023-08-29 criteria provided, single submitter clinical testing This CNV is a 679 kb deletion of 9q34.3, on chromosome 9, (seq[GRCh37]del(9)(q34.3);NC_000009.11:g.140395736_141075109del) that occurred de novo. The CNV encompasses the following protein coding genes: ARRDC1, CACNA1B, DPH7, EHMT1, MRPL41, PNPLA7 and ZMYND19, with a proximal break point disrupting the PNPLA7 gene. Heterozygous deletions of chromosome 9 at 9q34.3 that include at least part, or all of the EHMT1 gene are associated with Kleefstra syndrome (PMID: 20945554). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448675 SCV004176317 likely pathogenic not provided 2023-02-14 criteria provided, single submitter clinical testing This CNV is a 71 kb deletion of 2p16.3 on chromosome 2, (seq[GRCh37]del(2)(2p16.3);NC_000002.11:g.51149000_51220337del), which is inherited. This CNV constitutes an in-frame loss of exons 4-6 of the NRXN1 gene. Across a selection of the available literature, similar in-frame deletions of the same exons have been reported in at least 15 individuals with autistic behavior, developmental delays, intellectual disability, dysmorphism, congenital malformations, and other features (PMID: 23495017; PMID: 20468056; PMID: 21827697; PMID: 22617343; PMID: 31932357; PMID: 29165669; PMID: 25408897). In some cases, the deletion was inherited from an unaffected parent. A similar deletion also occurred de novo in at least two cases, although in one individual additional variants were identified that were thought to contribute to the phenotype. Similar deletions have also been reported in several controls (PMID: 21841781; PMID: 24174537; PMID: 23495017), consistent with the reduced penetrance and variable expressivity associated with intragenic deletions of NRXN1. Based on the available evidence, this CNV is classified as likely pathogenic.
Illumina Laboratory Services, Illumina RCV003448676 SCV004176318 pathogenic not provided 2023-03-16 criteria provided, single submitter clinical testing This CNV is a 16.7 Mb deletion on chromosome 9, (seq[GRCh37]del(9)(q22.2q31.2); chr9:NC_000009.11:92679543_109378847del), of unknown inheritance. This CNV constitutes a deletion encompassing 102 protein coding genes, including the PTCH1 gene and the minimal critical region of the 9q22.3 microdeletion (PMID: 21850767; PMID: 22190277; PMID: 32028043). The TGFBR1 gene is also fully encompassed within the region deleted in this individual, with emerging evidence suggesting that haploinsufficiency of this gene may be associated with multiple self-healing squamous epithelioma, an autosomal dominant predisposition to skin cancer (PMID: 21358634). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448677 SCV004176319 pathogenic not provided 2023-03-21 criteria provided, single submitter clinical testing This CNV is a 2.3 Mb deletion of 20p13, on chromosome 20, (seq[GRCh37]del(20)(p13);NC_000020.10:g.61001_2316914del) which occurred de novo. This CNV constitutes a loss encompassing 37 protein coding genes. A total of 11 cases with deletions of 20p13, ranging from 900 kb-2.1 Mb in size and occurring in a de novo state have been reported in the literature (PMID: 19344873; PMID: 20358616; PMID: 22274139). The phenotypic features among these individuals are variable due to the different size of the deletions and include global developmental delay, intellectual disability, short stature, amblyopia, attention deficit hyperactivity disorder, delayed speech and language development, growth abnormality, motor delay, specific learning disability, visual impairment, 2-3 toe syndactyly, abnormality of the skin, adducted thumb, intrauterine growth retardation, postnatal growth retardation, delayed tooth eruption and non-specific dysmorphic features. Of note, this CNV, as well as other reported 20p13 deletions, involve the complete deletion of the CSNK2A1 gene in which intragenic loss of function variants (both missense and truncating variants) are associated with autosomal dominant Okur-Chung neurodevelopmental syndrome characterized by developmental delay, intellectual disability, dysmorphic facial features, behavior issues, hypotonia, seizures, non-specific abnormal brain MRI findings, musculoskeletal defects, short stature, and failure to thrive (PMID: 35679446). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448678 SCV004176320 uncertain significance not provided 2023-05-23 criteria provided, single submitter clinical testing This CNV is a 1.2 Mb deletion of 2q11.1-q11.2, on chromosome 2, (seq[GRCh37]del(2)(q11.1q11.2); NC_000002.11:g.96555654_97769352del). This CNV encompasses 35 genes, including 23 protein coding genes, and overlaps the recurrent 2q11.2 deletion region. Patients with similar losses in this region are noted to display highly variable and nonspecific clinical features including developmental delay, intellectual disability, autism spectrum disorder, ADHD, speech delay, craniofacial features, pectus excavatum, and inversion of the foot. Additional features may include hypotonia, encephalopathy, recurrent ear infections, hip joint hypermobility, café au lait spots, aortic coarcation, scoliosis, and other skeletal anomalies (PMID: 19344873; PMID: 19443486; PMID: 26227573). Although segregation was noted in one family with two affected siblings, inheritance from unaffected parents has also been reported (PMID: 19344873; PMID: 26227573). Case-control studies suggest a nominal increase of this deletion in the clinical population (PMID: 25217958). Two similar losses in this region have been reported in controls (PMID: 24174537). Based on the available evidence, this variant is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448679 SCV004176321 pathogenic not provided 2023-05-22 criteria provided, single submitter clinical testing This CNV is an approximately 9.7 Mb gain of 15q11.2-q13.3 on chromosome 15, (seq[GRCh37]dup(15)(q11.2q13.3);NC_000015.9:g.22750407_32516333dup) that occurred de novo. The CNV consists of a ~7.6 Mb triplication and a ~1.6 Mb duplication. This region encompasses the Prader Willi/Angelman critical region; duplication or triplication of this imprinted region is associated with the well described maternal 15q duplication syndrome when maternally derived (PMID: 27308687). This chromosomal region is known to be susceptible to rearrangements due to a cluster of five low copy repeats (BP1-BP5); however the exact breakpoints cannot be clearly identified. Together, the triplication and duplication suggest an asymmetric recombination event between BP4 and BP5 resulting in the formation of an isodicentric 15q11.2-q13.2 supernumerary chromosome, idic(15) which includes a region of tetrasomy from the centromere to BP4 and a region of trisomy from BP4 to BP5 (PMIDs: 22585586; 15197683). The CNV has not been reported in published controls and is not present in the Database of Genomic Variants (PMID: 24174537). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448680 SCV004176322 pathogenic not provided 2023-04-24 criteria provided, single submitter clinical testing This CNV is a 57.7 Mb duplication of 3q23-q29 on chromosome 3, (seq[GRCh37]dup(3)(3q23q29); NC_000003.11:g.140154329_197847235dup) that occurred de novo. This CNV encompasses 284 protein-coding genes and overlaps previously described 3q duplications, occurring as de novo duplications, inversions, or part of an unbalanced translocation. These have been identified in individuals with facial dysmorphism, hirsutism, intellectual disability, developmental delays, poor growth, genitourinary, hand, and foot anomalies, and renal and cardiac defects, among other features (PMID: 27549440; 19344873). Similar duplications have not been described in controls (PMID: 24174537; 21841781). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448681 SCV004176323 uncertain significance not provided 2023-08-11 criteria provided, single submitter clinical testing This CNV is a 2.2 Mb duplication of 15q26.2-q26.3 on chromosome 15, (seq[GRCh37]dup(15)(q26.2-26.3);NC_000015.9:g.96345673_98563904dup) that occurred de novo. This CNV encompasses two protein coding genes, ARRDC4 and NR2F2. Duplication of a similar region is not common in controls and has not, to our knowledge, been described in the peer-reviewed literature. However, a larger, 3.6 Mb duplication affecting the same protein coding genes has been classified as likely pathogenic in ClinVar (VID 395722). In addition, a patient in the DECIPHER database, 266158, whose phenotype includes triangular face, brachydactyly, 5th finger clinodactyly, lower limb hypertrophy, abnormal repetitive mannerisms, and intellectual disability, is reported to have inherited a 1.85 Mb duplication of 15q26.3 including the NR2F2 gene from an unaffected parent. This individual also carried additional inherited CNVs, including a 5.0 Mb terminal deletion of 15q26.3 distal to the duplication. Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448682 SCV004176324 pathogenic not provided 2023-09-15 criteria provided, single submitter clinical testing This CNV is a 4.6 Mb deletion of 17p13.3-p13.2 on chromosome 17, (seq[GRCh37]del(17)(p13.3-p13.2);NC_000017.10:g.2_4611147del) that occurred de novo. The CNV encompasses 82 protein coding genes and overlaps the well-described Miller-Dieker syndrome (MDS). This CNV results in the deletion of the MDS telomeric critical region including the PAFAH1B1 gene (previously known as LIS1), YWHAE (previously known as 14-3-3-epsilon), and many other contiguous genes (PMID: 12621583). This CNV has not been reported in controls (PMID: 24174537). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448683 SCV004176325 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing This CNV is a 3.8 Mb deletion of 15q26.3 on chromosome 15, seq[GRCh37]del(15)(q26.3), NC_000015.9:g.98565904_102400021del, which is found in a de novo state. This CNV encompasses 21 protein coding genes, including the IGF1R, ALDH1A3, LRRK1, CHSY1, SELENOS, SNRPA1, and PCSK6 genes. Deletions of 15q26.3, both including and distal to IGF1R, have been reported in more than 30 individuals with phenotypes that include poor pre- or postnatal growth, developmental delay or intellectual disability, facial dysmorphism, congenital heart defects, skeletal anomalies, and microcephaly (PMID: 19344873; 27826649; 29165669; 37434556). In some cases, the deletions were shown to occur de novo. A microdeletion of 15q26.3 affecting the IGF1R gene has also been shown to segregate with short stature in one three-generation family (PMID: 19955558). Similar deletions are not common in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448684 SCV004176326 likely pathogenic not provided 2023-05-04 criteria provided, single submitter clinical testing This CNV is a 121 kb deletion of 2q32.2 on chromosome 2 (seq[GRCh37]del(2)(q32.2), NC_000002.11:g.191078575_191199676del). The CNV encompasses exons 1-11 of the HIBCH gene and is predicted to result in loss of protein function. To our knowledge, this CNV has not been reported in individuals with primary mitochondrial disorder. The 2q32.2 has not been reported in healthy controls. Based on the available evidence, this CNV is classified as likely pathogenic.
Illumina Laboratory Services, Illumina RCV003448685 SCV004176327 likely pathogenic not provided 2023-03-22 criteria provided, single submitter clinical testing This CNV is a 10 kb duplication of 15q21.1 on chromosome 15, (seq[GRCh37]dup(15)(q21.1), chr15:g.48724466_48734658dup). The breakpoints of this CNV lie within the FBN1 gene, in introns 49 and 55, resulting in duplication of exons 50-55. These exons encode for the calcium binding EGF domains, which is a critical domain for protein function and harbors clinically significant variants (PMID: 27138491). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as likely pathogenic.
Illumina Laboratory Services, Illumina RCV003448686 SCV004176328 pathogenic not provided 2023-07-25 criteria provided, single submitter clinical testing This CNV is a 33 kb deletion of 22q11.21 on chromosome 22 (seq[GRCh37]dup(22)(q11.21);NC_000022.10:g.20028654_20061617del). This CNV encompasses exons 3-9 of the TANGO2 gene. An ~34 kb deletion encompassing exons 3-9 is the most common variant reported in association with TANGO2 deficiency (PMID: 29369572). It is most common in the non-Finnish/European population, where it has an estimated allele frequency of 0.14% (PMID: 29369572; 26805782). Across a selection of the available literature, homozygous deletion of TANGO2 exons 3-9 has been reported in at least 12 unrelated patients (PMID: 26805781; 26805782; 31276219; 30245509; 19344873). The deletion has also been identified in trans with at least five other TANGO2 variants in individuals with a phenotype consistent withTANGO2 deficiency and to segregate with the phenotype in multiple families in the literature. This variant was found in a homozygous state. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448687 SCV004176329 uncertain significance not provided 2023-09-15 criteria provided, single submitter clinical testing This CNV is a 1.2 Mb duplication of 17q25.3, on chromosome 17, seq[GRCh37]dup(17)(q25.3), NC_000017.10:g.79928042_8115212dup, which is found in a de novo state. This CNV encompasses 29 protein coding genes. Individuals with 17q25.3 duplication of varying sizes presented with abnormal brain imaging, eye and muscular/skeletal abnormalities, ADHD, and psychiatric disorders (PMID: 26070612). A partially overlapping duplication in this region was inherited from an unaffected parent in a proband with developmental delay, intellectual disability, low muscle tone, posterior cerebellar artery syndrome, and dysmorphic features (PMID: 37430334). At least one slightly smaller CNV gain encompassing most of this region has been reported in controls (PMID: 24174537). Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448688 SCV004176330 uncertain significance not provided 2023-09-12 criteria provided, single submitter clinical testing This CNV is a 19.5 kb deletion of 15q11.2 on chromosome 15, seq[GRCh37]del(15)(q11.2), NC_000015.9:g.25064951_25084452del. This CNV encompasses an upstream region, exon one and part of the first intron of the longest (canonical) transcript of the SNRPN gene, NM_022806.3. This region does not overlap with the Prader-Willi syndrome (PWS) imprinting center (IC) (PMID: 9973278; 20301505; 22237428; 28554868; 29437285). A similar deletion, which was paternally inherited, has been described in an individual with features consistent with PWS (PMID: 27659333). Similar deletions have been reported in controls but not demonstrated to be paternally derived (PMID: 21841781; 24174537). A similar deletion has been observed at a frequency of 0.00965 in the African/African American population of the Genome Aggregation Database (gnomAD SVs version 2.1). Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448689 SCV004176331 pathogenic not provided 2023-05-05 criteria provided, single submitter clinical testing This CNV is a 980 kb deletion of 20p13 on chromosome 20, seq[GRCh37]del(20)(p13), NC_000020.10:g.61001_1041262del, which is found in a de novo state. This CNV encompasses 21 protein coding genes, including the CSNK2A1, SOX12, NRSN2 genes. Similar 20p13 microdeletions, including in a de novo state, have been reported in individuals with features including developmental delay, learning and intellectual disability, short stature, microcephaly, seizures, and variable facial dysmorphism (PMID: 19344873; 24019301; 31087544; 33678341). Similar CNVs have not been observed in controls (PMID: 21841781; 24174537). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448690 SCV004176332 uncertain significance not provided 2023-03-09 criteria provided, single submitter clinical testing This CNV is a 1.8 Mb duplication of 8p21.3, on chromosome 8, (seq[GRCh37]dup(8)(p21.3), chr8:g.20868762_22701502dup), which is found in a de novo state. This CNV constitutes a gain encompassing 26 protein coding genes, including full duplication of the BMP1 gene. Variants in the BMP1 gene are known to cause an autosomal recessive form of osteogenesis imperfecta (PMID: 33085247). However, there is no literature evidence to support triplosensitivity as a mechanism of disease for this gene. Patients with similar duplications in this region have not been reported in the peer-reviewed literature. A few similar sized de novo CNVs of uncertain significance or unconfirmed parentage with non-specific phenotypes have been reported in the DECIPHER database (PMID: 19344873). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448691 SCV004176333 uncertain significance not provided 2023-05-24 criteria provided, single submitter clinical testing This CNV is a 609 kb duplication of Xp11.22 on chromosome X, (seq[GRCh37]dup(X)(Xp11.22); NC_000023.10:g.54054624_54663870dup). This CNV encompasses the following six protein coding genes: FAM120C, FGD1, GNL3L, TSR2, WNK3, PHF8. The breakpoints lie within intron 2 of PHF8 and in an intergenic region. Loss of function variants in PHF8 are associated with an X-linked neurodevelopmental disorder in which males show a spectrum of developmental delay, speech delay, intellectual disability, and variable craniofacial features (PMID: 35469323). Duplications of a similar size and location to this event have been reported in individuals with variable features and have not been reported in controls (PMID: 19344873). This event also fully encompasses FGD1, a gene in which loss of function variants are associated with X-linked Aarskog-Scott syndrome. Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448692 SCV004176334 pathogenic not provided 2023-03-16 criteria provided, single submitter clinical testing This CNV is a 34.7 Mb duplication of 12p on chromosome 12, (seq[GRCh37]dup(12)(p13.33p11.1); chr12:g.188053_34856694dup), which is apparently mosaic. The CNV constitutes a gain encompassing 280 protein coding genes, and overlaps the critical region associated with both mosaic 12p trisomy and Pallister-Killian syndrome. This critical region is located at 12p13.31 and contains the candidate genes ING4, CHD4, and MAGP2, though causality has not yet been ascribed to a specific gene (PMID: 34073526). Similar mosaic CNVs have been reported in individuals with developmental delays, hypotonia, digital anomalies, congenital heart defects, and variable craniofacial features (PMID: 16502429; PMID: 31913574). The 12p duplication has not been reported in published controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448693 SCV004176335 pathogenic not provided 2023-08-17 criteria provided, single submitter clinical testing This CNV is a 31 Mb duplication of 8p23.1-p11.1 on chromosome 8, seq[GRCh37]dup(8)(p23.1p11.1), NC_000008.10:g.12530550_43483193dup, which is found in a de novo state. This CNV encompasses 180 protein coding genes. Duplications of 8p of a similar size and location to this event have been reported in individuals with features that include developmental and motor delay, neonatal feeding problems, hypotonia, structural brain abnormalities, and facial dysmorphism (PMID: 8256810; 8533823; 8599364; 19344873; 29165669; https://doi.org/10.1016/j.genrep.2017.11.006). In many cases, the duplication was shown to arise de novo. In addition, duplication of 8p was accompanied by deletion of 8p23.1 to 8pter in many individuals. This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448694 SCV004176336 pathogenic not provided 2023-05-23 criteria provided, single submitter clinical testing This CNV is a 7.2 Mb deletion of 3p26.3-p26.1 on chromosome 3, (seq[GRCh37]del(3)(3p26.3p26.1), NC_000003.11:g.61434_7264917del). This CNV constitutes a loss of 14 protein coding genes and has not been reported in controls. Deletions of a similar size occurring either de novo or as a result of a balanced translocation in an unaffected parent, have been reported in multiple individuals with developmental abnormalities and dysmorphic features (PMID: 19344873). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448695 SCV004176337 pathogenic not provided 2023-05-08 criteria provided, single submitter clinical testing This CNV is a 1.3 Mb deletion of 17p12 on chromosome 17 (seq[GRCh37]del(17)(p12); NC_000017.10:g.14098446_15442637del). This CNV overlaps the well-described 17p12 deletion associated with autosomal dominant hereditary neuropathy with liability to pressure palsies (HNPP) and encompasses the following protein coding genes: TVP23C-CDRT4, CDRT15, TEKT3, PMP22, CDRT4, TVP23C, HS3ST3B1, COX10. The 17p12 region is prone to rearrangements due to the presence of low copy repeats, referred to as the proximal CMT1A-REP and distal CMT1A-REP (PMID: 30258273). This deletion fully encompasses the PMP22 gene, which has been identified as the main candidate underlying HNPP. PMP22 encodes the peripheral myelin protein 22 which is associated with myelin organization in the peripheral nervous system (PMID: 23224996; 24697164). Deletions of approximately 1.4 Mb at 17p12 have been described in approximately 85-90% of individuals with clinical evidence of HNPP (PMID: 24646194). Based on the collective evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448696 SCV004176338 pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing This CNV is a 16.3 Mb deletion of 9p24.3-p22.3 on chromosome 9, seq[GRCh37]del(9)(p24.3p22.3), NC_000009.11:g.204064_16456192del. The CNV encompasses 49 protein coding genes including the NFIB gene and overlaps the proposed critical regions of the well described 9p deletion syndrome (PMID: 35047865). The NFIB gene encodes nuclear factor 1 B, a transcription factor that regulates mammalian development. Haploinsufficiency of NFIB is associated with acquired macrocephaly with impaired intellectual development (MIM 600728). The CNV has not been reported in published controls and is not present in the Database of Genomic Variants (PMID: 24174537). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448697 SCV004176339 pathogenic not provided 2023-04-25 criteria provided, single submitter clinical testing This CNV is a 10.4 Mb deletion of 15q15.1-q21.2, on chromosome 15, (seq[GRCh37]del(15)(q15.1q21.2);NC_000015.9:g.41321409_51718601del) that occurred de novo. This CNV encompasses 106 protein coding genes, including the FBN1 gene. Whole gene deletions of FBN1 are known to cause Marfan syndrome, which is a connective tissue disorder primarily characterized by ocular, skeletal and cardiovascular system involvement (PMID: 21063442; GeneReviews NBK1335; PMID: 34475413). Several de novo deletions overlapping 15q15.1-q21.2 regions have been reported in affected individuals (PMID: 19344873). This CNV has not been reported in controls (PMID: 24174537). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448698 SCV004176340 uncertain significance not provided 2023-08-24 criteria provided, single submitter clinical testing This CNV is a 5.7 Mb deletion of 5q21.3-q22.2 on chromosome 5, seq[GRCh37]del(5)(q21.3q22.2), NC_000005.9:g.106137712_111825745del. This CNV encompasses 13 protein-coding genes, with breakpoints in intergenic regions. There is limited evidence for an association of the CAMK4 gene with an autosomal dominant complex neurodevelopmental disorder (PMID: 33211350) and two genes, EFNA5 and FBLX17, are predicted to be intolerant to loss-of-function variation but to date do not have enough evidence for an association with disease. The SLC25A46 gene is associated with hereditary motor and sensory neuropathy type 6B and pontocerebellar hypoplasia type 1E, both of which follow an autosomal recessive pattern of inheritance. Similar deletions have been identified in two patients with syndromic neurodevelopmental phenotypes (PMID 19344873; 22970919). This CNV has not been reported in controls. Based on the available evidence, this CNV is classified as a variant of uncertain significance.
Illumina Laboratory Services, Illumina RCV003448699 SCV004176341 pathogenic not provided 2023-05-12 criteria provided, single submitter clinical testing This CNV is a 473 kb deletion of 15q11.2 on chromosome 15, seq[GRCh37]del(15)(q11.2), NC_000015.9:g.22750407_23223112del. This CNV encompasses the following protein coding genes: CYFIP1, NIPA1, NIPA2, and TUBGCP5. While the precise breakpoints of this CNV cannot be determined due to the presence of low copy repeats on both ends, their general locations correspond well with the recurrent BP1-BP2 breakpoints known to be associated with 15q11.2 microdeletion syndrome which is known to have low penetrance (PMID: 25689425). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina RCV003448700 SCV004176342 pathogenic not provided 2023-08-18 criteria provided, single submitter clinical testing This CNV is a 120 kb deletion of 2q13 on chromosome 2, seq[GRCh37]del(2)(q13), NC_000002.11:g.112687864_112808213del, which encompasses exons 3-19 of the MERTK gene and is predicted to disrupt the MERTK gene product. One of the breakpoints lies within intron 2 and the other in an intergenic region. Deletion of exons 3-19 has been reported in a homozygous state in an individual with cone-rod dystrophy (CRD) (PMID: 26103963). Additionally, this deletion is reported with a missense variant in an individual with retinal dystrophy, and with a splice region variant in an individual with retinitis pigmentosa (unconfirmed diagnosis). However, the phase of the variants identified in these individuals was not confirmed (PMID: 29074561; 32783370). Smaller deletions in this region have also been reported in individuals with retinopathies (PMID: 29659094). A similar deletion has been observed at a frequency of 0.001468 in the African/African American population of the Genome Aggregation Database (gnomAD SVs version 2.1). Based on the available evidence, this CNV is classified as pathogenic.
Illumina Laboratory Services, Illumina