Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000521284 | SCV000619108 | uncertain significance | not provided | 2017-07-13 | criteria provided, single submitter | clinical testing | The P474L variant has not been publishedas pathogenic or been reported as benign to our knowledge. Furthermore, it is not observed at a significant frequencyin large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). TheP474L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as theseresidues differ in some properties. However, this substitution occurs at a position that is not conserved across species,and in silico analysis predicts this variant likely does not alter the protein structure/function. |
Invitae | RCV001299593 | SCV001488691 | uncertain significance | Arrhythmogenic right ventricular dysplasia 11 | 2021-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with leucine at codon 474 of the DSC2 protein (p.Pro474Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs776398212, ExAC 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: 450512). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine 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, |
RCV003532155 | SCV004363093 | uncertain significance | Cardiomyopathy | 2023-08-02 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 474 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 hypertrophic cardiomyopathy (PMID: 32746448). This variant has been identified in 2/251200 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. |