Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001069981 | SCV001235186 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2023-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the DSG2 protein (p.Arg46Trp). This variant is present in population databases (rs752522753, gnomAD 0.003%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 24585727, 27532257, 29178656, 30790397, 31386562; Invitae). ClinVar contains an entry for this variant (Variation ID: 863095). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. This variant disrupts the p.Arg46 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23071725, 30790397). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| Ambry Genetics | RCV002379620 | SCV002702243 | pathogenic | Cardiovascular phenotype | 2022-04-18 | criteria provided, single submitter | clinical testing | The p.R46W pathogenic mutation (also known as c.136C>T), located in coding exon 3 of the DSG2 gene, results from a C to T substitution at nucleotide position 136. The arginine at codon 46 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, clinical details were limited for some cases (Fressart V et al. Europace, 2010 Jun;12:861-8; Vite A et al. PLoS ONE, 2013 Sep;8:e75082; Philips B et al. Circ Arrhythm Electrophysiol, 2014 Apr;7:230-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Wada Y et al. Mol Genet Genomic Med, 2017 11;5:639-651; Chen K et al. Clin Cardiol, 2018 May;41:615-622; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed). 2018 Dec;71(12):1018-1026; Hermida A et al. Eur J Heart Fail. 2019 06;21(6):792-800; Invitae pers. comm.). Another alteration at the same codon, p.R46Q (c.137G>A), has also been reported in association with ARVC and has shown segregation with disease (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Rasmussen TB et al. Hum Mutat, 2013 May;34:697-705). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |