ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2038C>A (p.Arg680Ser) (rs757253682)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481056 SCV000565785 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing The R680S variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition,R680S is a semi-conservative amino acid substitution, which may impact secondary protein structure as theseresidues differ in some properties. However, this substitution occurs at a position that is not conserved across species,and two of three in silico models predict this variant likely does not alter the protein structure/function.
Invitae RCV000531195 SCV000645000 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 680 of the DSC2 protein (p.Arg680Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs757253682, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 418603). 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.

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