ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1130T>A (p.Val377Asp) (rs794728085)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181215 SCV000233493 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing p.Val377Asp (GTC>GAC): c.1130 T>A in exon 9 of the DSG2 gene (NM_001943.3). A variant of unknown significance has been identified in the DSG2 gene. The V377D variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V377D variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A missense mutation in a nearby residue (N381Y) has been reported in association with ARVC, supporting the functional importance of this region of the protein. The V377D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not well conserved across species.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Homozygosity for V377D could be observed if one DSG2 allele was missing (intragenic deletion) and in cases of parental consanguinity. ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to--cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). Although rare, mutations in the DSC2 gene have been reported in association with ARVC (McNally E et al., 2009). At least 12% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy have been reported to have a mutation in the DSG2 gene (McNally E et al., 2009). The variant is found in ARVC panel(s).
Invitae RCV000462054 SCV000551008 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 377 of the DSG2 protein (p.Val377Asp). The valine residue is moderately conserved and there is a large physicochemical difference between valine and aspartic acid. 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. ClinVar contains an entry for this variant (Variation ID: 199806). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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