ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2314G>A (p.Val772Met) (rs146029947)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171889 SCV000050901 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000171889 SCV000233408 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The V772M variant was reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where Methionine is present as the wild type in multiple species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, this variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Ambry Genetics RCV000242264 SCV000317867 uncertain significance Cardiovascular phenotype 2016-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Invitae RCV000644644 SCV000766347 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 772 of the DSC2 protein (p.Val772Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs146029947, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 191620). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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