Submissions for variant NM_001943.5(DSG2):c.2341G>T (p.Ala781Ser)

gnomAD frequency: 0.00005  dbSNP: rs760402926

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001042489	SCV001206171	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-06-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 781 of the DSG2 protein (p.Ala781Ser). 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: 840487). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs760402926, gnomAD 0.008%).
Color Diagnostics, LLC DBA Color Health	RCV001188803	SCV001355947	uncertain significance	Cardiomyopathy	2019-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 781 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/280362 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.
GeneDx	RCV003225143	SCV003921346	uncertain significance	not provided	2022-10-26	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
Ambry Genetics	RCV003372950	SCV004096434	uncertain significance	Cardiovascular phenotype	2023-08-07	criteria provided, single submitter	clinical testing	The p.A781S variant (also known as c.2341G>T), located in coding exon 15 of the DSG2 gene, results from a G to T substitution at nucleotide position 2341. The alanine at codon 781 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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.