ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.136C>T (p.Arg46Trp)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001069981 SCV001235186 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 46 of the DSG2 protein (p.Arg46Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs752522753, ExAC 0.009%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 30790397, 24585727, 29178656, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 863095). 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 and their clinical significance is uncertain. This variant disrupts the p.Arg46 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30790397, 23071725). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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