ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.3509G>A (p.Arg1170His) (rs137854475)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000589339 SCV000603629 likely benign not provided 2017-11-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617054 SCV000317678 likely benign Cardiovascular phenotype 2017-02-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Subpopulation frequency in support of benign classification
Baylor Genetics RCV000148494 SCV000328720 pathogenic Marfan syndrome 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as causing Marfanoid-like features. It has been found 20 times in our laboratory, always inherited when parents are tested, and not always in patients with Marfanoid features.
Blueprint Genetics RCV000157227 SCV000206952 uncertain significance Marfanoid habitus 2014-03-25 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148494 SCV000190201 uncertain significance Marfan syndrome 2014-06-01 no assertion criteria provided research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767968 SCV000898695 uncertain significance Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-12-03 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon 29 p.Arg1170His (c.3509G>A): This variant has been reported in at least four individuals with incomplete/suspected Marfan syndrome, segregating with suspected features in at least two different families (Hayward 1994 PMID:7870075, Montgomery 1998 PMID:9837823, Comeglio 2007 PMID:17657824, Stavropoulos 2016 PMID:28567303). Of note, these reported probands presented with primarily skeletal abnormalities; none fully met Ghent criteria for Marfan syndrome. This variant is present in 0.2% (286/129170) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-48779352-C-T) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:16451). This variant amino acid Histidine (His) is present in several bird species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Medical Genetics Ghent,University of Ghent RCV000148494 SCV000786972 likely benign Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Color RCV000242225 SCV000911141 likely benign Thoracic aortic aneurysm and aortic dissection 2018-03-16 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000148494 SCV000257635 uncertain significance Marfan syndrome 2015-07-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589339 SCV000228689 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000154459 SCV000233791 likely benign not specified 2017-12-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
GenomeConnect, ClinGen RCV000845006 SCV000986836 not provided Marfan syndrome; MASS syndrome; Weill-Marchesani syndrome; Ectopia lentis; Familial thoracic aortic aneurysm no assertion provided phenotyping only Variant interpretted as Likely benign and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000154459 SCV000923434 uncertain significance not specified 2019-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290413 SCV000392418 likely benign Geleophysic dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000340663 SCV000392419 likely benign Ectopia lentis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000242225 SCV000392420 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305937 SCV000392421 likely benign Stiff skin syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000360569 SCV000392422 likely benign MASS syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148494 SCV000392423 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297783 SCV000392424 likely benign Weill-Marchesani syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000357267 SCV000392425 likely benign Acromicric dysplasia 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589339 SCV000695516 likely benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The p.Arg1170His variant has previously been reported in at least three individuals with clinical features of Incomplete Marfan Syndrome and to segregate in two families (Collod-Beroud 1998, Comeglio 2007, Hayward 1994, Montgomery 1998, Waldmuller 2007). However, based on the information reported in the papers, non-carrier members in those families presented with some skeletal features and early-onset myopia; other genes with mirror phenotype were not screened for mutations. In addition, this variant has been identified by our laboratory, in individuals who tested positive for known pathogenic variants, c.1633C>T (p.Arg545Cys) and c.4913delA (p.Tyr1638fsX2), that could have explained the clinical features in these pts. The observed allele frequency of 0.12% in the general population is significantly higher than the maximal expected allele frequency of a disease causing FBN1 allele 0.020%, supporting a benign classification with regard to MFS. The segregation data is not informative and there is not enough information to support pathogenicity in MFS diagnosis using the Ghent criteria. Nevertheless, it should not be ignored that the variant was also seen in multiple cases of atypical presentations overlapping the phenotypic spectrum of MFS and clinical diagnostic centers classify variant as a VUS via ClinVar. Considering all, this variant has been classified as a Probable Normal Variant/Likely Benign.
Invitae RCV000231987 SCV000283623 likely benign Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2017-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154459 SCV000204128 likely benign not specified 2015-03-24 criteria provided, single submitter clinical testing p.Arg1170His in exon 28 of FBN1: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (124/66684) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs137854475). Arginine (Arg) at position 1170 is not conserved in evolut ionarily distant species and at least 10 birds, reptiles, and fish carry a histi dine (His) at this position, supporting that this change may be tolerated. This variant has been identified by our laboratory in 6 individuals with features of Marfan syndrome; however, two of these individuals were compound heterozygotes f or a pathogenic variant sufficient to explain their disease. Although this varia nt has been reported in individuals with features of Marfan syndrome in the lite rature, this variant is likely benign based on its frequency in the general popu lation, lack of conservation, and the presence of other variants to explain dise ase in multiple individuals.
OMIM RCV000360569 SCV000038193 pathogenic MASS syndrome 1998-12-01 no assertion criteria provided literature only

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