ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2191G>A (p.Asp731Asn) (rs762055797)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482040 SCV000573082 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing The D731N variant in the DSC2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D731N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D731N as a variant of uncertain significance.
Invitae RCV000644636 SCV000766339 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 731 of the DSC2 protein (p.Asp731Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs762055797, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 423386). 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, 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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