Submissions for variant NM_004415.4(DSP):c.4489C>T (p.Arg1497Trp)

gnomAD frequency: 0.00178  dbSNP: rs148041814

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038045	SCV000061711	likely benign	not specified	2012-02-09	criteria provided, single submitter	clinical testing	Arg1497Trp in exon 23 of DSP: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (17/3738) of African American ch romosomes by the NHLBI Exome Sequencing Project in a broad population (http://ev s.gs.washington.edu/EVS; dbSNP rs148041814). Arg1497Trp in exon 23 of DSP (rs14 8041814; allele frequency = 0.4%, 17/3738) **
GeneDx	RCV000038045	SCV000168266	benign	not specified	2014-04-25	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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202877	SCV000257967	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-06-08	criteria provided, single submitter	clinical testing
Invitae	RCV001080732	SCV000288539	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000038045	SCV000333271	likely benign	not specified	2015-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619831	SCV000736005	likely benign	Cardiovascular phenotype	2018-10-04	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770246	SCV000901677	benign	Cardiomyopathy	2023-01-27	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845533	SCV000987647	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852995	SCV000995746	likely benign	Restrictive cardiomyopathy	2018-08-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770246	SCV001358195	benign	Cardiomyopathy	2018-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038045	SCV001363279	benign	not specified	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4489C>T (p.Arg1497Trp) results in a non-conservative amino acid change in 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 0.00033 in 250336 control chromosomes, predominantly at a frequency of 0.0047 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 24-folds over the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six ClinVar submissions (evaluation after 2014) cites the variant five times as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000845533	SCV002049354	likely benign	not provided	2021-05-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952433	SCV004769908	likely benign	DSP-related disorder	2023-10-19	criteria provided, single submitter	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).