ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.145C>A (p.Arg49Ser) (rs762526848)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526721 SCV000641963 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-01-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 49 of the DSG2 protein (p.Arg49Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSG2-related disease. 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. A different missense substitution at this codon (p.Arg49His) has been determined to be pathogenic (PMID: 16773573, 19151369). This suggests that the arginine residue is critical for DSG2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change with deleterious impact on protein function. In the absence of segregation or functional evidence, It has been classified as a Variant of Uncertain Significance.

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