Submissions for variant NM_024422.6(DSC2):c.1070G>A (p.Arg357His)

gnomAD frequency: 0.00011  dbSNP: rs201201194

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171892	SCV000050899	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000181148	SCV000233425	likely benign	not specified	2018-03-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087574	SCV000561705	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181148	SCV000917283	benign	not specified	2021-05-12	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.1070G>A (p.Arg357His) results in a non-conservative amino acid change located in the third cadherin-like repeat (IPR002126) of 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 0.00022 in 282370 control chromosomes, predominantly at a frequency of 0.0027 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 100-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1070G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three classifying the variant as likely benign, and one calling it a VUS. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001179307	SCV001343938	likely benign	Cardiomyopathy	2018-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415731	SCV002718829	benign	Cardiovascular phenotype	2021-10-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
PreventionGenetics, part of Exact Sciences	RCV003965231	SCV004784229	likely benign	DSC2-related disorder	2022-08-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).