Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000620914 | SCV000736598 | uncertain significance | Cardiovascular phenotype | 2016-05-20 | criteria provided, single submitter | clinical testing | The p.I109L variant (also known as c.325A>C), located in coding exon 3 of the DSC2 gene, results from an A to C substitution at nucleotide position 325. The isoleucine at codon 109 is replaced by leucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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. |
| Invitae | RCV001855263 | SCV002193861 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 109 of the DSC2 protein (p.Ile109Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 518920). 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 with a negative predictive value of 80%. 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. |
| Fulgent Genetics, |
RCV001855263 | SCV002775747 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2021-10-05 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004002660 | SCV004817405 | uncertain significance | Familial isolated arrhythmogenic right ventricular dysplasia | 2023-03-09 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with leucine at codon 109 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 not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 2/282108 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. |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000786113 | SCV000924766 | uncertain significance | not provided | 2017-06-20 | no assertion criteria provided | provider interpretation |