Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781327 | SCV000919274 | likely benign | not specified | 2018-03-06 | criteria provided, single submitter | clinical testing | Variant summary: DSC2 c.2624G>A (p.Arg875Gln) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.2624G>A, was observed with an allele frequency of 2.8e-05 in 246040 control chromosomes (gnomAD). The observed variant frequency within the South Asian control individuals in the gnomAD database is approximately 6.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in population(s) of South Asian origin. To our knowledge, no occurrence of c.2624G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. |
| Invitae | RCV001059771 | SCV001224417 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2023-03-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 875 of the DSC2 protein (p.Arg875Gln). This variant is present in population databases (rs535014010, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 633190). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Color Diagnostics, |
RCV001182981 | SCV001348621 | likely benign | Cardiomyopathy | 2018-11-15 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV001507397 | SCV001712932 | uncertain significance | not provided | 2019-09-23 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002424776 | SCV002743117 | likely benign | Cardiovascular phenotype | 2021-08-26 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |