Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002357396 | SCV002620641 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-29 | criteria provided, single submitter | clinical testing | The p.V130I variant (also known as c.388G>A), located in coding exon 2 of the VHL gene, results from a G to A substitution at nucleotide position 388. The valine at codon 130 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with a pheochromocytoma (Capodimonti S et al. J Clin Oncol, 2012 May;30:e137-9). 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. |
| Labcorp Genetics |
RCV003102470 | SCV003525039 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-08-31 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val130 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 10570625, 12202531, 12393546, 24581539). 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 VHL-related conditions (PMID: 22393103). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 130 of the VHL protein (p.Val130Ile). |