ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.907G>A (p.Val303Met) (rs145560678)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621747 SCV000736344 uncertain significance Cardiovascular phenotype 2016-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000771128 SCV000902897 likely benign Cardiomyopathy 2018-03-09 criteria provided, single submitter clinical testing
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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000227622 SCV000743496 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000039445 SCV000919275 likely benign not specified 2018-03-06 criteria provided, single submitter clinical testing Variant summary: DSC2 c.907G>A (p.Val303Met) results in a conservative amino acid change located in the second cadherin repeat domain (IPR002126) 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 0.001 in 278410 control chromosomes (in the gnomAD database and publication data), predominantly observed within the South Asian subpopulation at a frequency of 0.0068, including 1 homozygote. The observed variant frequency within South Asian control individuals is approximately 680 fold of 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. Though c.907G>A has been reported in the literature in an affected individual (Garcia-Pavia 2011), this report does 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000227622 SCV000290740 benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-11-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.

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