Submissions for variant NM_001943.5(DSG2):c.1843A>G (p.Ile615Val)

gnomAD frequency: 0.00001  dbSNP: rs794728087

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181224	SCV000233503	uncertain significance	not provided	2021-12-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199812; Landrum et al., 2016)
Color Diagnostics, LLC DBA Color Health	RCV001190476	SCV001357976	uncertain significance	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 615 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 2/248946 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003517142	SCV004353667	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-05-05	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 199812). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs794728087, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 615 of the DSG2 protein (p.Ile615Val).
Ambry Genetics	RCV004020185	SCV005017992	uncertain significance	Cardiovascular phenotype	2024-02-16	criteria provided, single submitter	clinical testing	The p.I615V variant (also known as c.1843A>G), located in coding exon 12 of the DSG2 gene, results from an A to G substitution at nucleotide position 1843. The isoleucine at codon 615 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004806168	SCV005428716	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 615 of the DSG2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/248946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.