ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.872C>T (p.Thr291Met) (rs774563205)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658206 SCV000779977 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing The T291M variant of uncertain significance in the DSG2 gene has not been published as pathogenic or been reported as benign to our knowledge. T291M was observed in 4/30,780 (0.01%) alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). The T291M 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, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Color Health, Inc RCV001182734 SCV001348291 likely benign Cardiomyopathy 2018-11-29 criteria provided, single submitter clinical testing
Invitae RCV001240164 SCV001413088 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 291 of the DSG2 protein (p.Thr291Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs774563205, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 546345). 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 methionine 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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