Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001929631 | SCV002202207 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2021-09-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 7987306, 10567493). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 32420132; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with threonine at codon 65 of the VHL protein (p.Ser65Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. |