Submissions for variant NM_001943.5(DSG2):c.2165G>A (p.Arg722Lys) (rs376819371)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484089	SCV000572052	uncertain significance	not provided	2016-10-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The R722K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R722K variant was not observed with any significant frequency in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. Nevertheless, the R722K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Addtionally, the majority of in silico analysis (2 out of 3) predict this variant likely does not alter the protein structure/function.
Color Health, Inc	RCV000772021	SCV000904977	uncertain significance	Cardiomyopathy	2020-10-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 722 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 5/249456 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	RCV001366209	SCV001562505	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy, type 10	2020-02-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with lysine at codon 722 of the DSG2 protein (p.Arg722Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs376819371, ExAC 0.003%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 422554). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.