Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165891 | SCV000216644 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-20 | criteria provided, single submitter | clinical testing | The p.E70G variant (also known as c.209A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 209. The glutamic acid at codon 70 is replaced by glycine, an amino acid with similar properties. This alteration has not been reported in the literature to date, however an alteration at the same codon, p.E70K, has been observed in multiple individuals with a history of hemangioblastoma and has been shown to cause a modest reduction (20%) in the ability of the VHL protein to bind with the alpha subunit of the hypoxia-inducible transcription factor (Olschwang S et. al, Hum. Mut. 1998;12:424-30; Hes FJ et. al. Clin. Genet. 2007 Aug;72:122-9; Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Miller F et al. J Biol Chem. 2005 Mar;280:7986-96). One study using a multiparametric in silico prediction based on overall structure and stability of pVHL classified this missense alteration as "high risk" (Fields FR et al. PLoS One, 2020 Nov;15:e0234100). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000227354 | SCV000285491 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-07-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 70 of the VHL protein (p.Glu70Gly). This variant is present in population databases (rs786202857, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 186316). 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. This variant disrupts the p.Glu70 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 17661816, 19270817, 19408298, 25078357, 25562111, 25715769, 27439424; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001545934 | SCV001765359 | uncertain significance | not provided | 2022-12-30 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.422A>G, p.E141G and p.E111G; Observed in an individual with pheochromocytoma (Parisien-La Salle et al., 2022); This variant is associated with the following publications: (PMID: 34750850) |
| Baylor Genetics | RCV003462191 | SCV004206468 | uncertain significance | Chuvash polycythemia | 2023-10-16 | criteria provided, single submitter | clinical testing |