ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2275G>A (p.Gly759Arg) (rs765793636)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481316 SCV000571596 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing The G759R variant of uncertain significance in the DSG2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 0.002%-0.008% alleles across ethnic groups in large population cohorts (Lek et al., 2016). The G759R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000529624 SCV000641972 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-02-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 759 of the DSG2 protein (p.Gly759Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs765793636, ExAC 0.002%) but has not been reported in the literature in individuals with a DSG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000529624 SCV001283589 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Health, Inc RCV001176559 SCV001340579 uncertain significance Cardiomyopathy 2020-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000529624 SCV001368394 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-03-12 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply.

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