ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1195G>A (p.Glu399Lys) (rs774863785)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181216 SCV000233495 uncertain significance not provided 2018-09-17 criteria provided, single submitter clinical testing The E399K variant in the DSG2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 7/246052 (0.0028%) alleles in large population cohorts. The E399K 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. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We now interpret E399K as a variant of uncertain significance.
Invitae RCV001341325 SCV001535193 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 399 of the DSG2 protein (p.Glu399Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs774863785, 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: 199807). 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 disruptive, 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.

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