Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588483 | SCV000697505 | pathogenic | Von Hippel-Lindau syndrome | 2016-02-05 | criteria provided, single submitter | clinical testing | Variant summary: The c.355T>C (F119L) in VHL is a missense variant involving a highly conserved nucleotide and 3/4 in silico tools predict this variant to be deleterious (no prediction for SIFT). The variant was not found in the general population but was reported in at least 3 VHL patients. Another variant, c.357C>G, leading to the same amino acid change (F119L) and c.356T>C (F119S) have been reported in multiple VHL pts, indicating that this codon is a mutation hotspot. Additionally this variant has been identified as a somatic mutation in multiple renal cell carcinomas. Taken together, this is a disease variant and was classified as Pathogenic. |
| Labcorp Genetics |
RCV000631289 | SCV000752317 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2022-07-19 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with VHL-related conditions (PMID: 7728151, 12000816, 16142346, 19270817). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564, 23840444). 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: 496059). This variant is also known as P190L. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the VHL protein (p.Phe119Leu). |
| Ambry Genetics | RCV002456285 | SCV002616639 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-29 | criteria provided, single submitter | clinical testing | The p.F119L pathogenic mutation (also known as c.355T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 355. The phenylalanine at codon 119 is replaced by leucine, an amino acid with highly similar properties. In one study, in silico, in vitro, and bacterial assays showed that the p.F119L alteration results in loss of folding, stability, and function of the VHL protein (Shmueli MD et al. PLoS ONE. 2013 Jun;8:e66333). This mutation has been identified in multiple individuals/families with a clinical diagnosis or suspicion of von-Hippel-Lindau (VHL) syndrome (Cho HJ et al. J. Korean Med. Sci., 2009 Feb;24:77-83; Klein B et al. Hum. Genet., 2001 May;108:376-84; Ambry internal data). It has also been reported in a patient with non-syndromic pheochromocytoma (Neumann HP et al. N. Engl. J. Med. 2002 May; 346:1459-66), a patient with bilateral pheochromocytomas (Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931), and a patient with bilateral adrenal pheochromocytoma and a carotid paraganglioma (Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94:1938-44). In one functional study, this alteration's interactions with hypoxia-inducible factors (HIF), which affect protein stability, were similar to at least one alteration classified as VLP at Ambry (W88C) (Rechsteiner MP et al. Cancer Res. 2011 Aug; 71(16):5500-11; Ambry internal data). Of note, this alteration is also designated as 568C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |