Submissions for variant NM_024422.6(DSC2):c.395G>A (p.Arg132His)

gnomAD frequency: 0.00003  dbSNP: rs375410133

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552860	SCV000645016	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2024-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 132 of the DSC2 protein (p.Arg132His). This variant is present in population databases (rs375410133, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 29750433). ClinVar contains an entry for this variant (Variation ID: 468383). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DSC2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001177624	SCV001341865	uncertain significance	Cardiomyopathy	2024-04-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 132 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiomyopathy (PMID: 29750433). This variant has been identified in 9/282578 chromosomes in the general population 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811054	SCV001472318	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing	The DSC2 c.395G>A; p.Arg132His variant (rs375410133) is reported in the literature in an individual affected with arrhythmogenic cardiomyopathy that also carried a second missense variant in DSC2 (Chen 2018). The p.Arg132His variant is found on only nine chromosomes (9/282578 alleles) in the Genome Aggregation Database. The arginine at codon 132 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Arg132Cys) has been reported in an individual with arrhythmogenic cardiomyopathy, although its clinical significance was not demonstrated (Fressart 2010). Given the lack of clinical and functional data, the significance of the p.Arg132His variant is uncertain at this time. References: Chen K et al. Absence of a primary role for TTN missense variants in arrhythmogenic cardiomyopathy: From a clinical and pathological perspective. Clin Cardiol. 2018 May;41(5):615-622. Fressart V et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 2010 Jun;12(6):861-8.
Ambry Genetics	RCV002358540	SCV002622973	likely benign	Cardiovascular phenotype	2024-04-23	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.
Fulgent Genetics, Fulgent Genetics	RCV000552860	SCV002777325	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-08-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999355	SCV004819351	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 132 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 cardiomyopathy (PMID: 29750433). This variant has been identified in 9/282578 chromosomes in the general population 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.