Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000465780 | SCV000553405 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 25 of the VHL protein (p.Pro25Ala). 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: 411976). 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 | RCV002383832 | SCV002671214 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-06-21 | criteria provided, single submitter | clinical testing | The p.P25A variant (also known as c.73C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 73. The proline at codon 25 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is not conserved on limited sequence alignment. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004701512 | SCV005202562 | uncertain significance | not specified | 2024-07-12 | criteria provided, single submitter | clinical testing | Variant summary: VHL c.73C>G (p.Pro25Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.73C>G in individuals affected with Congenital Polycythemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 411976). Based on the evidence outlined above, the variant was classified as uncertain significance. |