ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.547C>T (p.Arg183Trp) (rs368082152)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000558579 SCV000645019 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 183 of the DSC2 protein (p.Arg183Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs368082152, ExAC 0.01%) but has not been reported in the literature in individuals with a DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 228624). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare 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.

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