Submissions for variant NM_001943.5(DSG2):c.1642C>T (p.Arg548Cys)

gnomAD frequency: 0.00003  dbSNP: rs550400909

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551660	SCV000641965	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 548 of the DSG2 protein (p.Arg548Cys). This variant is present in population databases (rs550400909, gnomAD 0.005%). This missense change has been observed in individual(s) with sudden cardiac arrest (PMID: 30975432). ClinVar contains an entry for this variant (Variation ID: 466332). 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 not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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	RCV001186978	SCV001353617	uncertain significance	Cardiomyopathy	2022-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 548 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a sudden cardiac arrest survivor (PMID: 30975432). This variant has been identified in 6/279360 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.
Ambry Genetics	RCV002395392	SCV002703988	uncertain significance	Cardiovascular phenotype	2022-01-25	criteria provided, single submitter	clinical testing	The p.R548C variant (also known as c.1642C>T), located in coding exon 11 of the DSG2 gene, results from a C to T substitution at nucleotide position 1642. The arginine at codon 548 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a sudden cardiac arrest cohort (Asatryan B et al. Am J Cardiol, 2019 06;123:2031-2038). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999233	SCV004819566	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 548 of the DSG2 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 a sudden cardiac arrest survivor (PMID: 30975432). This variant has been identified in 6/279360 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.