ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.613C>T (p.Pro205Ser) (rs200946320)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483311 SCV000573752 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing The P205S variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P205Svariant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at a position that isconserved through mammals, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, all of which would further clarify pathogenicity.
Invitae RCV000797576 SCV000937140 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-09-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 205 of the DSG2 protein (p.Pro205Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs200946320, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 423983). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C. The serine 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. 5

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