Submissions for variant NM_001943.5(DSG2):c.2471G>A (p.Arg824His)

gnomAD frequency: 0.00005  dbSNP: rs376858770

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000590938	SCV000700130	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Diagnostics, LLC DBA Color Health	RCV001188902	SCV001356077	uncertain significance	Cardiomyopathy	2023-05-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 824 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 14/280730 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.
Fulgent Genetics, Fulgent Genetics	RCV002497242	SCV002778750	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-10-26	criteria provided, single submitter	clinical testing
Invitae	RCV002530948	SCV003456859	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-10-12	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 824 of the DSG2 protein (p.Arg824His). This variant is present in population databases (rs376858770, gnomAD 0.03%). 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: 496663). 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.
Ambry Genetics	RCV003160005	SCV003858272	likely benign	Cardiovascular phenotype	2022-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.