Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001201863 | SCV001372954 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-02-02 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with VHL-related conditions. 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. This variant disrupts the p.Arg82 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23327821, 23626751, 24977658). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 933618). This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 82 of the VHL protein (p.Arg82Cys). |
| Ambry Genetics | RCV002447048 | SCV002732744 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-08 | criteria provided, single submitter | clinical testing | The p.R82C variant (also known as c.244C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 244. The arginine at codon 82 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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. |