Submissions for variant NM_024422.6(DSC2):c.172T>G (p.Phe58Val)

gnomAD frequency: 0.00061  dbSNP: rs138749562

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150527	SCV000197734	uncertain significance	not specified	2014-07-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Phe58Val varian t in DSC2 has been reported in 1 individual with DCM (Elliot 2010) and in 1/1254 control chromosomes (Kapplinger 2011). This variant has also been identified in 0.16% (7/4406) of African American chromosomes by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS/; dbSNP rs138749562). Phenylalanine (Phe ) at position 58 is not conserved in evolution and 2 mammals (rabbit, pika) carr y a valine (Val) at this position, suggesting that this change may be tolerated. In summary, while the clinical significance of the Phe58Val variant is uncertai n, these data suggest that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000725685	SCV000338592	uncertain significance	not provided	2016-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000725685	SCV000512857	likely benign	not provided	2021-05-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25351510, 20716751, 21636032)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083970	SCV000561706	likely benign	Arrhythmogenic right ventricular dysplasia 11	2025-01-23	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000150527	SCV000747971	likely benign	not specified	2017-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177334	SCV001341529	likely benign	Cardiomyopathy	2019-04-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177334	SCV002043568	benign	Cardiomyopathy	2019-12-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408665	SCV002716718	likely benign	Cardiovascular phenotype	2018-12-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150527	SCV004099534	likely benign	not specified	2025-01-27	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.172T>G (p.Phe58Val) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 250736 control chromosomes, predominantly at a frequency of 0.0019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11.69 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016). To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 163193). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV003998188	SCV004819371	likely benign	Familial isolated arrhythmogenic right ventricular dysplasia	2024-08-06	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000725685	SCV001918078	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000725685	SCV001932955	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907419	SCV004724003	likely benign	DSC2-related disorder	2022-06-02	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).