ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.907G>A (p.Val303Met)

gnomAD frequency: 0.00021  dbSNP: rs145560678
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039445 SCV000063129 likely benign not specified 2016-11-15 criteria provided, single submitter clinical testing p.Val303Met in exon 7 of DSC2: This variant has been identified in 0.7% (120/165 12) of South Asian chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145560678). This vari ant was previously reported in 1 individual with DCM (Garcia-Pavia 2011). Howeve r, given the high frequency of this variant in the general population, it is not expected to have clinical significance.
GeneDx RCV000039445 SCV000233423 benign not specified 2017-02-03 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.
Invitae RCV000227622 SCV000290740 benign Arrhythmogenic right ventricular dysplasia 11 2024-01-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621747 SCV000736344 likely benign Cardiovascular phenotype 2018-09-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000227622 SCV000743496 likely benign Arrhythmogenic right ventricular dysplasia 11 2017-07-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000771128 SCV000902897 likely benign Cardiomyopathy 2018-03-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000039445 SCV000919275 likely benign not specified 2020-11-02 criteria provided, single submitter clinical testing Variant summary: DSC2 c.907G>A (p.Val303Met) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 252686 control chromosomes, predominantly at a frequency of 0.0068 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 680-fold the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.907G>A has been reported in the literature in at least one individual affected with cardiomyopathy (e.g. Garcia-Pavia_2011), but also in healthy controls (e.g. Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign/likely benign (n=8) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen RCV000858410 SCV001151502 likely benign not provided 2022-12-01 criteria provided, single submitter clinical testing DSC2: BP4
Illumina Laboratory Services, Illumina RCV000227622 SCV001281728 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000771128 SCV001334028 benign Cardiomyopathy 2018-03-20 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV000227622 SCV001984560 benign Arrhythmogenic right ventricular dysplasia 11 2020-01-08 criteria provided, single submitter clinical testing
Clinical Genetics, Academic Medical Center RCV000039445 SCV001921757 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000858410 SCV001954595 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000858410 SCV001964350 likely benign not provided no assertion criteria provided clinical testing

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