Submissions for variant NM_004415.4(DSP):c.522T>C (p.Cys174=)

gnomAD frequency: 0.00124  dbSNP: rs144781697

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150558	SCV000197790	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Cys174Cys in Exon 04 of DSP: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.3% (13/3738) of Afri can American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs144781697).
Ambry Genetics	RCV000251541	SCV000318427	likely benign	Cardiovascular phenotype	2016-05-25	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.
GeneDx	RCV001534586	SCV000518101	likely benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV000472500	SCV000555741	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150558	SCV000919284	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: DSP c.522T>C alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.00041 in 277036 control chromosomes, predominantly at a frequency of 0.0046 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 184 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.522T>C 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. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV001190178	SCV001357610	benign	Cardiomyopathy	2018-11-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498691	SCV002802750	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-09-20	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000150558	SCV001917054	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001534586	SCV001963297	likely benign	not provided		no assertion criteria provided	clinical testing