ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.394C>T (p.Arg132Cys) (rs727504578)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155749 SCV000205460 uncertain significance not specified 2018-10-24 criteria provided, single submitter clinical testing The p.Arg132Cys variant in DSC2 has been identified in 3 individuals with ARVC, one of whom carried a likely pathogenic variant in PKP2 and another of whom also carried a frameshift variant in DSC2 (Fressart 2010, Ohno 2013, Wada 2017, LMM data). This variant has been identified in 10/282564 chromosomes by the gnomAD ( Computational prediction tools and conservati on analysis suggest that the p.Arg132Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , the clinical significance of the p.Arg132Cys variant is uncertain. ACMG/AMP Cr iteria applied: PP3.
Invitae RCV000230389 SCV000290741 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2016-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 132 of the DSC2 protein (p.Arg132Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs727504578, ExAC 0.02%). This variant has been reported in individuals with affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 23414727). ClinVar also contains an entry for this variant (Variation ID: 178972). 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 disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on splicing and protein function. While this variant has been reported in the literature in affected individuals, the available evidence is insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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