Submissions for variant NM_001943.5(DSG2):c.905G>A (p.Gly302Asp)

dbSNP: rs1338174918

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001177712	SCV001341974	uncertain significance	Cardiomyopathy	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 302 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 DSG2-related disorders in the literature. This variant has been identified in 1/249410 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	RCV001326290	SCV001517314	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 302 of the DSG2 protein (p.Gly302Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 919478). 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.
Ambry Genetics	RCV002555477	SCV003581170	uncertain significance	Inborn genetic diseases	2021-10-20	criteria provided, single submitter	clinical testing	The c.905G>A (p.G302D) alteration is located in exon 8 (coding exon 8) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 905, causing the glycine (G) at amino acid position 302 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.0004% (1/249,410) total alleles studied. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003325547	SCV004031962	uncertain significance	not provided	2023-08-23	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 (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
CeGaT Center for Human Genetics Tuebingen	RCV003325547	SCV004140912	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	DSG2: PM2, BP4