Submissions for variant NM_001943.5(DSG2):c.782G>A (p.Arg261His)

gnomAD frequency: 0.00001  dbSNP: rs727502984

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150534	SCV000197748	likely benign	not specified	2014-08-07	criteria provided, single submitter	clinical testing	Arg261His in exon 7 of DSG2: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , 6 mammals (dolphin, killer whale, white rhinoceros, shrew, aardvark, and armad illo) have a histidine (His) at this position despite high nearby amino acid con servation. Additional computational prediction tools do not suggest a high likel ihood of impact to the protein.
Invitae	RCV000642316	SCV000763985	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 261 of the DSG2 protein (p.Arg261His). This variant is present in population databases (rs727502984, gnomAD 0.004%). 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: 163202). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001526076	SCV001736352	uncertain significance	Cardiomyopathy	2021-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 261 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 2/248768 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.