Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000631279 | SCV000752307 | uncertain significance | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 199 of the VHL protein (p.Glu199Ala). This variant is present in population databases (rs760690217, gnomAD 0.002%). 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: 526682). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 | RCV001024729 | SCV001186800 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-05 | criteria provided, single submitter | clinical testing | The p.E199A variant (also known as c.596A>C), located in coding exon 3 of the VHL gene, results from an A to C substitution at nucleotide position 596. The glutamic acid at codon 199 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is poorly 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 |
RCV001544814 | SCV001764018 | uncertain significance | not provided | 2024-08-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function |
| Baylor Genetics | RCV003459502 | SCV004208777 | uncertain significance | Chuvash polycythemia | 2024-01-30 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004002810 | SCV004841668 | uncertain significance | Von Hippel-Lindau syndrome | 2024-07-29 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with alanine at codon 199 of the VHL protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251404 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. |