Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
CSER _CC_NCGL, |
RCV000590953 | SCV000700122 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2016-10-01 | criteria provided, single submitter | research | Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. |
Invitae | RCV000693817 | SCV000822236 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2023-07-12 | 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 496660). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 28798025). This variant is present in population databases (rs769787593, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the DSC2 protein (p.Arg199Cys). |
Illumina Laboratory Services, |
RCV000693817 | SCV001282909 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Color Diagnostics, |
RCV001179075 | SCV001343660 | uncertain significance | Cardiomyopathy | 2023-02-16 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 199 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 observed in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 4/251394 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. |
Gene |
RCV001541214 | SCV001759185 | uncertain significance | not provided | 2020-09-16 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27054166, 28798025) |
MGZ Medical Genetics Center | RCV000693817 | SCV002581179 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2021-10-12 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002358651 | SCV002656379 | uncertain significance | Cardiovascular phenotype | 2023-06-12 | criteria provided, single submitter | clinical testing | The p.R199C variant (also known as c.595C>T), located in coding exon 5 of the DSC2 gene, results from a C to T substitution at nucleotide position 595. The arginine at codon 199 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a patient with hypertrophic cardiomyopathy and in a left ventricular non-compaction cohort; however clinical details were limited in the latter case (Bottillo I et al. Gene, 2016 Feb;577:227-35; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
All of Us Research Program, |
RCV004002450 | SCV004819336 | uncertain significance | Familial isolated arrhythmogenic right ventricular dysplasia | 2023-12-01 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 199 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 observed in an individual affected with left ventricular non-compaction (PMID: 28798025). This variant has been identified in 4/251394 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. |