Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000589319 | SCV000697886 | uncertain significance | not provided | 2017-03-13 | criteria provided, single submitter | clinical testing | Variant summary: The DSG2 c.2510C>A (p.Ala837Asp) variant located in the Catenin binding domain (via InterPro) involves the alteration of a conserved nucleotide that 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120474 (1/40160), which does exceed the estimated maximal expected allele frequency for a pathogenic DSG2 variant of 1/100000, suggesting this variant could be a rare benign polymorphism. However, this observation needs to be cautiously considered due to the cohort containing individuals that could harbor a DSG2 phenotype. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign (VUS)." |
| Color Diagnostics, |
RCV001185321 | SCV001351510 | uncertain significance | Cardiomyopathy | 2023-03-30 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with aspartic acid at codon 837 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 5/249138 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 | RCV001201605 | SCV001372682 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2023-05-26 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 496149). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs756338201, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 837 of the DSG2 protein (p.Ala837Asp). |
| Fulgent Genetics, |
RCV002483569 | SCV002787926 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB | 2021-08-18 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003159997 | SCV003859081 | uncertain significance | Cardiovascular phenotype | 2022-12-04 | criteria provided, single submitter | clinical testing | The p.A837D variant (also known as c.2510C>A), located in coding exon 15 of the DSG2 gene, results from a C to A substitution at nucleotide position 2510. The alanine at codon 837 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is conserved. 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. |