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

gnomAD frequency: 0.00006  dbSNP: rs551034751

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656844	SCV000233464	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000688119	SCV000815719	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 548 of the DSG2 protein (p.Arg548His). This variant is present in population databases (rs551034751, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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 Diagnostics, LLC DBA Color Health	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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000656844	SCV001927088	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656844	SCV001951483	likely benign	not provided		no assertion criteria provided	clinical testing