ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2441C>T (p.Thr814Met)

gnomAD frequency: 0.00001  dbSNP: rs756497616
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001189288 SCV001356548 uncertain significance Cardiomyopathy 2023-09-06 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 814 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 cardiovascular disorders in the literature. This variant has been identified in 5/251226 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 RCV001751344 SCV001988256 uncertain significance not provided 2021-01-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV001876213 SCV002151783 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 814 of the DSC2 protein (p.Thr814Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs756497616, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 926604). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Ambry Genetics RCV002451396 SCV002736743 likely benign Cardiovascular phenotype 2023-03-27 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.
Fulgent Genetics, Fulgent Genetics RCV001876213 SCV002816597 uncertain significance Arrhythmogenic right ventricular dysplasia 11 2021-11-20 criteria provided, single submitter clinical testing

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