Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Mendelian Genomics, |
RCV000414987 | SCV000493062 | uncertain significance | Hypertrophic cardiomyopathy | 2021-05-01 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000642321 | SCV000763990 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 198 of the DSG2 protein (p.Tyr198Cys). This variant is present in population databases (rs786204291, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of DSG2-related conditions (PMID: 24125834, 27055156, 29456632, 30830208, 32659924, 33460606). ClinVar contains an entry for this variant (Variation ID: 188451). 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. 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, |
RCV000777716 | SCV000913660 | uncertain significance | Cardiomyopathy | 2023-12-13 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 198 of the DSG2 protein. Computational prediction suggests that this variant may have 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 been reported in at least six unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27055156, 29750433, 33460606, 37418234), including one individual who carried a second pathogenic variant in the DSG2 gene (PMID: 29750433). This variant was also reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 30847666, 32659924). This variant has been identified in 5/280796 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. |
Centre for Mendelian Genomics, |
RCV000642321 | SCV001369277 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2021-05-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002354411 | SCV002650431 | uncertain significance | Cardiovascular phenotype | 2019-07-01 | criteria provided, single submitter | clinical testing | The p.Y198C variant (also known as c.593A>G), located in coding exon 6 of the DSG2 gene, results from an A to G substitution at nucleotide position 593. The tyrosine at codon 198 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cadherin 2 domain. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Xiang R et al. Int. J. Cardiol., 2016 Jul;214:1-3). This amino acid position is well conserved in available vertebrate species. 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. |
Fulgent Genetics, |
RCV002485048 | SCV002782927 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB | 2022-02-14 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003995631 | SCV004819456 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2024-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 198 of the DSG2 protein. Computational prediction suggests that this variant may have 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 been reported in at least six unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27055156, 29750433, 33460606, 37418234), including one individual who carried a second pathogenic variant in the DSG2 gene (PMID: 29750433). This variant was also reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 30847666, 32659924). This variant has been identified in 5/280796 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. |
Clinical Genetics, |
RCV001698985 | SCV001920276 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV001698985 | SCV001930425 | uncertain significance | not provided | no assertion criteria provided | clinical testing |