Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000181170 | SCV000233447 | uncertain significance | not provided | 2022-09-01 | criteria provided, single submitter | clinical testing | Reported in one Danish individual fulfilling task force criteria for a diagnosis of ARVC (Christensen et al., 2010); Identified in 15 individuals from a cohort of 30,716 predominantly European individuals undergoing exome sequencing and review of available electronic health records indicated that none of these individuals had a documented diagnosis of ARVC (Haggerty et al., 2017), although specific clinical details and follow-up cardiac evaluations were not reported; Identified in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data are limited at this time; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23911551, 20864495, 26264440, 28471438, 31402444) |
Invitae | RCV000546172 | SCV000645018 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the DSC2 protein (p.Glu2Lys). This variant is present in population databases (rs762556795, gnomAD 0.03%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495). ClinVar contains an entry for this variant (Variation ID: 199776). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 | RCV000619111 | SCV000737951 | likely benign | Cardiovascular phenotype | 2021-10-04 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. |
Color Diagnostics, |
RCV000778023 | SCV000914134 | uncertain significance | Cardiomyopathy | 2023-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 2 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26264440). This variant has been identified in 16/149434 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. |
ARUP Laboratories, |
RCV001002111 | SCV001159958 | uncertain significance | not specified | 2018-10-05 | criteria provided, single submitter | clinical testing | The p.Glu2Lys variant (rs762556795) was reported in one patient with palpitation at 15 years age of onset without a family history (Christensen 2010). This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.02 percent in the European Non-Finnish population (identified on 12 out of 56,600 chromosomes) and has been reported to the ClinVar database (Variation ID: 199776). The glutamic acid at the second codon is weakly conserved and before the signal peptide which is cleaved off before insertion into the plasma membrane. Computational analyses of the p.Glu2Lys variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu2Lys variant with certainty. |
Illumina Laboratory Services, |
RCV000546172 | SCV001285910 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Fulgent Genetics, |
RCV000546172 | SCV002790099 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2021-11-10 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003996605 | SCV004819397 | uncertain significance | Familial isolated arrhythmogenic right ventricular dysplasia | 2024-01-11 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 2 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26264440). This variant has been identified in 16/149434 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. |