Submissions for variant NM_004415.4(DSP):c.5555G>A (p.Arg1852His)

gnomAD frequency: 0.00005  dbSNP: rs193922669

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000623709	SCV000052333	likely benign	not specified	2019-02-13	criteria provided, single submitter	clinical testing	Variant summary: DSP c.5555G>A (p.Arg1852His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 277212 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of 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 South Asian origin. c.5555G>A has been reported in the literature in a study that attempted to estimate the cardiovascular genetic risk in the Pakistani population in comparison with other continental populations using the 1000 genomes and the ExAC datasets. As this constitues the South Asian population referred above, this report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Furthermore, the Atlas of Cardiac Genetic Variation cites this variant as unlikely to be pathogenic based on its ExAC population frequency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these labs classified the variant as likely benign while the other two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000618287	SCV000736004	likely benign	Cardiovascular phenotype	2022-02-11	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623709	SCV000740336	likely benign	not specified	2025-02-17	criteria provided, single submitter	clinical testing	BS1, BP6
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641842	SCV000763492	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777717	SCV000913661	likely benign	Cardiomyopathy	2018-10-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777717	SCV002043296	benign	Cardiomyopathy	2019-09-23	criteria provided, single submitter	clinical testing