Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000226491 | SCV000285497 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 143 of the VHL protein (p.Asp143His). This variant is present in population databases (rs372757722, gnomAD 0.007%). 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: 238108). 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 with a positive predictive value of 80%. 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 | RCV000492555 | SCV000580961 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-19 | criteria provided, single submitter | clinical testing | The p.D143H variant (also known as c.427G>C), located in coding exon 2 of the VHL gene, results from a G to C substitution at nucleotide position 427. The aspartic acid at codon 143 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV003228918 | SCV003925940 | uncertain significance | not provided | 2023-05-03 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Baylor Genetics | RCV003463662 | SCV004208776 | uncertain significance | Chuvash polycythemia | 2023-11-02 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003998849 | SCV004824838 | uncertain significance | Von Hippel-Lindau syndrome | 2023-05-30 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with histidine at codon 143 of the VHL protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 1/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |