ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2084C>T (p.Thr695Met) (rs200137091)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757179 SCV000885315 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing The DSG2 c.2084C>T; p.Thr695Met variant (rs200137091), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 4 out of 246,042 chromosomes). The threonine at position 695 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Thr695Met variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Thr695Met variant cannot be determined with certainty.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781332 SCV000919283 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: DSG2 c.2084C>T (p.Thr695Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2084C>T has not been reported in the literature in individuals affected with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001065502 SCV001230461 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 695 of the DSG2 protein (p.Thr695Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs200137091, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 618607). 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.
Color Health, Inc RCV001180343 SCV001345252 uncertain significance Cardiomyopathy 2019-05-03 criteria provided, single submitter clinical testing

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