ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2318G>C (p.Gly773Ala) (rs749174176)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181163 SCV000233440 uncertain significance not provided 2015-05-21 criteria provided, single submitter clinical testing p.Gly773Ala (GGA>GCA): c.2318 G>C in exon 15 of the DSC2 gene (NM_024422.3). The Gly773Ala variant in the DSC2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly773Ala results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is mostly conserved across species. The Gly773Ala variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with ARVC, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Gly773Ala is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000526044 SCV000645008 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 773 of the DSC2 protein (p.Gly773Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs749174176, ExAC 0.009%) but has not been reported in the literature in individuals with a DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 199773). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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