ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.547C>T (p.Arg183Trp)

gnomAD frequency: 0.00013  dbSNP: rs368082152
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Total submissions: 9
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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 RCV000215449 SCV000271707 uncertain significance not specified 2015-06-12 criteria provided, single submitter clinical testing The p.Arg183Trp variant in DSC2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66612 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 368082152). Computational prediction tools and conservation analysis suggest tha t the variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. In summary, the clinical significance of t he p.Arg183Trp variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000558579 SCV000645019 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DSC2 protein (p.Arg183Trp). This variant is present in population databases (rs368082152, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 228624). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000215449 SCV000919278 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: DSC2 c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the first 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 4.3e-05 in 277034 control chromosomes. The observed variant frequency is approximately 1.7-fold above the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), suggesting the variant may be benign. To our knowledge, no occurrence of c.547C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852738 SCV000995453 likely benign Hypertrophic cardiomyopathy 2019-06-03 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001182795 SCV001348376 uncertain significance Cardiomyopathy 2022-12-20 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 183 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 13/282690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV001658017 SCV001873741 uncertain significance not provided 2023-10-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002347840 SCV002648190 likely benign Cardiovascular phenotype 2022-11-28 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.
All of Us Research Program, National Institutes of Health RCV003997726 SCV004819338 uncertain significance Familial isolated arrhythmogenic right ventricular dysplasia 2023-10-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 183 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/282690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV003967589 SCV004779838 uncertain significance DSC2-related disorder 2023-12-20 no assertion criteria provided clinical testing The DSC2 c.547C>T variant is predicted to result in the amino acid substitution p.Arg183Trp. This variant was reported in an individual with dilated cardiomyopathy (Table S7, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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