ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.601G>A (p.Val201Ile) (rs202058544)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494438 SCV000583370 uncertain significance not provided 2017-05-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The V201I variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the V201I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution also occurs at a position where amino acids with similar properties to valine (V) are tolerated across species, and isoleucine (I) is the wild-type residue at this position in multiple species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000806197 SCV000946183 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 201 of the DSC2 protein (p.Val201Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs202058544, ExAC 0.001%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 430543). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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