ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.513G>T (p.Leu171Phe) (rs199926617)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700406 SCV000829159 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-03-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 171 of the DSG2 protein (p.Leu171Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs199926617, ExAC 0.02%). This variant has not been reported in the literature in individuals with DSG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 RCV001192198 SCV001360222 uncertain significance Cardiomyopathy 2019-09-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193615 SCV001362564 uncertain significance not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: DSG2 c.513G>T (p.Leu171Phe) results in a non-conservative amino acid change located in the second cadherin repeat (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248796 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.513G>T has been reported in the literature in an individual affected with exertional rhabdomyolysis, hematuria/proteinuria and episodic pain syndrome, who also carried other pathogenic and potentially pathogenic variants that could explain his phenotype (Sambuughin_2018). This report does not provide an unequivocal conclusion about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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