Submissions for variant NM_001943.5(DSG2):c.877A>T (p.Ile293Leu)

dbSNP: rs2230234

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212490	SCV000233461	likely benign	not specified	2014-09-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212490	SCV000697890	uncertain significance	not specified	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The DSG2 c.877A>T (p.Ile293Leu) variant causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120730 (1/60365), which exceeds the estimated maximal expected allele frequency for a pathogenic DSG2 variant of 1/100000, however, this observation needs to be cautiously considered due to the cohort potentially harboring phenotypes that could be caused by a DSG2 mutation. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a clinical laboratory cites the variant as "likely benign," without additional information for an independent evaluation. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Ambry Genetics	RCV000621307	SCV000736753	uncertain significance	Cardiovascular phenotype	2021-06-30	criteria provided, single submitter	clinical testing	The p.I293L variant (also known as c.877A>T), located in coding exon 8 of the DSG2 gene, results from an A to T substitution at nucleotide position 877. The isoleucine at codon 293 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other 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 variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001184306	SCV001350254	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 293 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 3/280772 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.
Invitae	RCV001225861	SCV001398155	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 293 of the DSG2 protein (p.Ile293Leu). This variant is present in population databases (rs2230234, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 36014). 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.