Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000220823 | SCV000274633 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-06-14 | criteria provided, single submitter | clinical testing | The p.V166F pathogenic mutation (also known as c.496G>T), located in coding exon 3 of the VHL gene, results from a G to T substitution at nucleotide position 496. The valine at codon 166 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of Von Hippel-Lindau syndrome; including personal histories of pheochromocytoma (Cruz JB et al, Arq Bras Endocrinol Metabol 2007 Dec; 51(9):1463-7; Gross DJ et al. J. Clin. Endocrinol. Metab. 1996 Jan; 81(1):147-9; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31(5):521-37; Maher ER et al. J. Med. Genet. 1996 Apr; 33(4):328-32); head and neck paraganglioma, pheochromocytoma and CNS hemangiblastoma (Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94(6):1938-44); as well as retinal hemangioblastoma (Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep; 43(9):3067-74). In addition, in vitro experiments suggest that mutations affecting residue 166, such as p.V166F, lead to a partial loss of elongin-binding activity (Ohh M et al. J. Clin. Invest. 1999 Dec; 104(11):1583-91). Of note, this alteration is also referred to as 709G>T in published literature. This alteration has been determined to be de novo in an affected individual in our cohort (Ambry internal data). Based on the available evidence, p.V166F is classified as a pathogenic mutation. |
| Labcorp Genetics |
RCV001851578 | SCV002123712 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-05-22 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 2224). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 8550742, 19336503, 25720320; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 166 of the VHL protein (p.Val166Phe). 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. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV002288459 | SCV002578799 | pathogenic | not provided | 2022-04-15 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.709G>T; p.V237F; This variant is associated with the following publications: (PMID: 24969085, 24155122, 8550742, 8730290, 9681856, 19336503, 25720320, 8956040, 10587522, 7728151, 33745191, 20151405, 9829912, 28650583, 32241160, 18209888, 10408776, 34439168, 32576040, 12202531) |
| OMIM | RCV000002310 | SCV000022468 | pathogenic | Von Hippel-Lindau syndrome | 1996-01-01 | no assertion criteria provided | literature only |