Submissions for variant NM_004415.4(DSP):c.4775A>G (p.Lys1592Arg)

gnomAD frequency: 0.00016  dbSNP: rs200421954

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001847799	SCV000233684	uncertain significance	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Reported in association with HCM, ARVC, and sudden unexplained death (Cox et al., 2011; Bagnall et al., 2014; Bhonsale et al., 2015; Lopes et al., 2015); Reported in a male with sudden cardiac arrest at 28 years old, unrelated to exercise; this individual had no clear cardiac phenotype and also harbored a novel splice site variant in the TTN gene (Asatryan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 24440382, 25616645, 21606396, 27153395, 30975432)
Invitae	RCV000464510	SCV000543219	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168648	SCV000698437	likely benign	not specified	2022-01-24	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4775A>G (p.Lys1592Arg) results in a conservative amino acid change in 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 0.00023 in 250148 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 41 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.4775A>G has been reported in the literature in one individual affected with ARVD, one individual with a history of syncope and one individual with sudden cardiac arrest (Cox_2011, Bagnall_2014, Asatryan_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At-least one co-occurrence with another pathogenic variant has been observed in an individual undergoing evaluation on a Familial Arrhythmia Panel at our laboratory ( KCNQ1 c.1124_1127delTTCA, p.Ile375fs, Long QT syndrome), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000778012	SCV000914122	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1592 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396), in an individual with sudden death (PMID: 24440382), and in a sudden cardiac arrest survivor (PMID: 30975432). This variant occurs at an elevated allele frequency in the general population and has been identified in 65/281550 chromosomes by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000778012	SCV001332689	likely benign	Cardiomyopathy	2022-03-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336384	SCV002638683	likely benign	Cardiovascular phenotype	2023-05-03	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.
CeGaT Center for Human Genetics Tuebingen	RCV001847799	SCV004163054	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	DSP: PM2, BP4