ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.6700G>A (p.Val2234Met) (rs112084407)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035252 SCV000058898 uncertain significance not specified 2011-07-01 criteria provided, single submitter clinical testing The 6700G>A (Val2234Met) variant has been reported in the literature in one indi vidual meeting the Ghent clinical criteria for Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007). However, this individual also carried a second FBN1 varia nt (Asp1113Gly) that was found in four affected family members and who were all negative for the Val2234Met variant (Rand-Hendriksen 2007). This variant has bee n identified by our laboratory in one family; two family members that are report edly minimally affected with some clinical features of Marfan syndrome carry thi s variant. Valine (Val) at amino acid position 2234 is not completely conserved in other mammals or distantly related species (cow, dog, elephant, chicken and f rog carry an alanine; opossum carries an isoleucine; fish carries a threonine). Furthermore, this variant has been reported in dbSNP (rs112084407) with a minor allele frequency of 0.002. Collectively, these data reduce the likelihood that t his change is pathogenic. However, in the absence of additional data, we cannot conclusively determine the clinical significance of this variant at this time, t hough we lean towards a likely benign role.
GeneDx RCV000035252 SCV000233880 likely benign not specified 2018-02-28 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.
Ambry Genetics RCV000245529 SCV000317882 benign Cardiovascular phenotype 2014-10-29 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with complete penetrance)
Illumina Clinical Services Laboratory,Illumina RCV000273547 SCV000392196 likely benign Geleophysic dysplasia 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000310000 SCV000392197 likely benign Acromicric dysplasia 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000029766 SCV000392198 likely benign Marfan syndrome 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000270709 SCV000392199 likely benign Ectopia lentis, isolated, autosomal dominant 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae RCV001081774 SCV000557055 likely benign Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-12-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726908 SCV000704103 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659568 SCV000781402 likely benign Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000029766 SCV000807914 likely benign Marfan syndrome 2018-06-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769627 SCV000901025 benign Familial thoracic aortic aneurysm and aortic dissection 2018-03-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769627 SCV000903361 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-04-26 criteria provided, single submitter clinical testing
Mendelics RCV000029766 SCV001139590 uncertain significance Marfan syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726908 SCV001149448 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283418 SCV001157313 likely benign none provided 2020-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029766 SCV000052419 benign Marfan syndrome 2015-06-12 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000029766 SCV000190200 likely benign Marfan syndrome 2016-08-15 no assertion criteria provided research Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing for an unrelated indication. No known history of Marfan syndrome.
Broad Institute Rare Disease Group, Broad Institute RCV000035252 SCV001422582 benign not specified 2020-01-22 no assertion criteria provided curation The p.Val2234Met variant in FBN1 has been reported in at least 1 Norwegian and 1 other individual with Marfan Syndrome (PMID: 17663468, 17253931; Lazalde et al. 2017), but has been identified in 0.1281% (165/128814) of European (non-Finnish) chromosomes, 0.09601% (34/35414) of Latino chromosomes, and 0.01602% (4/24966) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112084407). This variant has also been reported benign, likely benign, and a VUS in ClinVar (Variation ID: 36104). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Val2234Met variant did not segregate with Marfan Syndrome in 4 affected relatives of an individual with the variant, suggesting that this variant is not pathogenic for Marfan Syndrome (PMID: 17663468). Marfan Syndrome has been reported to have high clinical penetrance (PMID: 20301510) and the p.Val2234Met variant has been reported in the literature in at least 4 individuals without Marfan Syndrome, increasing the chance that this variant is benign (PMID: 25812041, 25637381; Variation ID: 36104). Two affected individuals with this variant have an alternative molecular basis for Marfan Syndrome, suggesting that this variant may not be pathogenic (PMID: 17663468; Lazalde et al. 2017). The number of missense variants reported in FBN1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as benign for Marfan Syndrome in an autosomal dominant manner based on its frequency in the general population and multiple occurrences in individuals without Marfan Syndrome. ACMG/AMP Criteria applied: BS2, BS4, BS1, BP5 (Richards 2015).

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