ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2074A>G (p.Lys692Glu) (rs997161591)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522812 SCV000617101 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The K692E variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K692E 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. However, this substitution occurs at a position that is not conserved across species and glutamic acid (E) is the wild-type residue at this position in at least two non-mammalian species. Finally, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000700688 SCV000829455 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-05-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 692 of the DSG2 protein (p.Lys692Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 449228). 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 tolerated, but 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.
Color Health, Inc RCV001191878 SCV001359799 uncertain significance Cardiomyopathy 2020-01-15 criteria provided, single submitter clinical testing

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