Submissions for variant NM_001943.5(DSG2):c.770A>G (p.Gln257Arg)

gnomAD frequency: 0.00001  dbSNP: rs765118809

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483702	SCV000569736	uncertain significance	not provided	2016-03-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The Q257R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q257R variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q257R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved in mammals. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Color Diagnostics, LLC DBA Color Health	RCV001191862	SCV001359778	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 257 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 5/280270 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	RCV001851194	SCV002109320	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-05-30	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: 420771). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs765118809, gnomAD 0.002%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 257 of the DSG2 protein (p.Gln257Arg).