ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1643G>A (p.Arg548His) (rs551034751)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656844 SCV000233464 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing The R548H variant of uncertain significance in the DSG2 gene has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been identified in several individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified both as a likely benign variant and a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000738038.1, SCV000263854.1, SCV000219454.2; Landrum et al., 2016). The R548H variant was observed in 4/18,818 (0.02%) alleles from individuals of East Asian ancestry, and globally in 17/275,406 (0.006%) alleles from individuals of varying ethnic backgrounds in large population cohorts (Lek et al., 2016). R548H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Blueprint Genetics RCV000208129 SCV000263854 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-11-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621270 SCV000738038 likely benign Cardiovascular phenotype 2017-05-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000688119 SCV000815719 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-04-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 548 of the DSG2 protein (p.Arg548His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs551034751, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 188453). 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 histidine 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 RCV000771882 SCV000904639 likely benign Cardiomyopathy 2018-05-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781331 SCV000919281 likely benign not specified 2018-10-08 criteria provided, single submitter clinical testing Variant summary: DSG2 c.1643G>A (p.Arg548His) 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 6.2e-05 in 275406 control chromosomes. The observed variant frequency is approximately 2.5-fold over the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. To our knowledge, no occurrence of c.1643G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as likely benign.

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