Submissions for variant NM_001943.5(DSG2):c.172C>G (p.Leu58Val)

dbSNP: rs780300040

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171304	SCV001334031	uncertain significance	Cardiomyopathy	2018-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV001202950	SCV001374085	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 58 of the DSG2 protein (p.Leu58Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 915834). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	RCV001171304	SCV002053144	uncertain significance	Cardiomyopathy	2021-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 58 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31404 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	RCV002411663	SCV002715651	uncertain significance	Cardiovascular phenotype	2022-08-11	criteria provided, single submitter	clinical testing	The p.L58V variant (also known as c.172C>G), located in coding exon 3 of the DSG2 gene, results from a C to G substitution at nucleotide position 172. The leucine at codon 58 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a Brugada syndrome cohort; however, clinical details were limited (Di Resta C et al. Hum Mol Genet, 2015 Oct;24:5828-35). This amino acid position is well 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.