Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000467837 | SCV000553413 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 202 of the VHL protein (p.Thr202Ile). This variant is present in population databases (rs779514074, 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: 411984). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on VHL protein function. 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 | RCV002356705 | SCV002659827 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-24 | criteria provided, single submitter | clinical testing | The p.T202I variant (also known as c.605C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 605. The threonine at codon 202 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well 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. |
| St. |
RCV003153642 | SCV003843005 | uncertain significance | Von Hippel-Lindau syndrome | 2023-01-19 | criteria provided, single submitter | clinical testing | The VHL c.605C>T (p.Thr202Ile) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. A VHL-specific in silico multiparametric scoring algorithm indicated that this variant is more likely to be associated with disease (PMID: 33151962). To our knowledge, this variant has not been reported in individuals with Von Hippel-Lindau disease. In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. |
| Baylor Genetics | RCV003463964 | SCV004208766 | uncertain significance | Chuvash polycythemia | 2023-07-03 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV003480645 | SCV004226049 | uncertain significance | not provided | 2022-09-23 | criteria provided, single submitter | clinical testing |