ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.875G>T (p.Arg292Leu)

dbSNP: rs185821167
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181210 SCV000233488 likely pathogenic not provided 2012-10-12 criteria provided, single submitter clinical testing p.Arg292Leu (CGC>CTC):c.875 G>T in exon 8 of the DSG2 gene (NM_001943.3). The Arg292Leu variant in the DSG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg292Leu results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Leucine at a position that is conserved across species. A mutation at the same codon (Arg292Cys) and mutations in nearby residues (Lys294Glu, Asp297Gly) have been reported in association with ARVC, further supporting the functional importance of this codon and this region of the protein. In silico analysis predicts Arg292Leu is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Arg292Leu was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Arg292Leu is a good candidate for a disease-causing mutation.The variant is found in ARVC panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000465847 SCV000551020 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2022-07-20 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 199802). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 292 of the DSG2 protein (p.Arg292Leu). 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 RCV003372639 SCV004096431 uncertain significance Cardiovascular phenotype 2023-08-08 criteria provided, single submitter clinical testing The p.R292L variant (also known as c.875G>T), located in coding exon 8 of the DSG2 gene, results from a G to T substitution at nucleotide position 875. The arginine at codon 292 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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