Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000123106 | SCV000166407 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-05-22 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 135955). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 25952756). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 94 of the VHL protein (p.Glu94Lys). |
| Ambry Genetics | RCV000166872 | SCV000217688 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-01 | criteria provided, single submitter | clinical testing | The p.E94K variant (also known as c.280G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 280. The glutamic acid at codon 94 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a male patient with a clinical diagnosis of VHL at age 25 (Vikkath N et al. Fam. Cancer, 2015 Dec;14:585-94). 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. |
| All of Us Research Program, |
RCV003997420 | SCV004820570 | uncertain significance | Von Hippel-Lindau syndrome | 2023-04-03 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with lysine at codon 94 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 been reported in one individual affected with von Hippel-Lindau syndrome (PMID: 25952756). This variant has been identified in 1/224192 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. |