Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000557226 | SCV000641960 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2017-02-02 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with valine at codon 426 of the DSG2 protein (p.Ala426Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. 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 valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSG2-related disease. In summary, this variant is a novel missense change that is not predicted to affect protein function but to affect mRNA splicing. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. |