Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001921763 | SCV002206798 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 49 of the VHL protein (p.Gly49Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1424577). 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 not expected to disrupt VHL protein function with a negative predictive value of 95%. 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. |
| Ambry Genetics | RCV002388859 | SCV002702195 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-27 | criteria provided, single submitter | clinical testing | The p.G49D variant (also known as c.146G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 146. The glycine at codon 49 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Prevention |
RCV004728953 | SCV005339170 | uncertain significance | VHL-related disorder | 2024-08-12 | no assertion criteria provided | clinical testing | The VHL c.146G>A variant is predicted to result in the amino acid substitution p.Gly49Asp. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1424577/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |