ClinVar Genomic variation as it relates to human health

The VHL c.499C>T; p.Arg167Trp variant (rs5030820), also reported as p.Arg238Trp, is a common pathogenic variant in individuals and families affected with Von Hippel-Lindau syndrome (Crossey 1994, Fishbein 2013, Peng 2017, Wang 2018, Zhang 2015). This variant is reported in ClinVar (Variation ID: 2218), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 167 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of elongin binding leading to VHL protein degradation (Leonardi 2011, Ohh 1999, Peng 2017, Schoenfeld 2000). Additionally, other amino acid substitutions at this codon (Gln, Gly, Leu, Pro) have been reported in individuals with Von Hippel-Lindau syndrome and are considered pathogenic (Crossey 1994, Zhang 2015). Based on available information, this variant is considered to be pathogenic. References: Crossey PA et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994;3(8):1303-1308. Fishbein L et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450. Leonardi E et al. Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. Ann Hum Genet. 2011;75(4):483-496. Ohh M et al. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999;104(11):1583-1591. Peng S et al. Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. Oncotarget. 2017;8(24):38456-38465. Schoenfeld AR et al. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci U S A. 2000;97(15):8507-8512. Wang Y et al. Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. Oncol Lett. 2018;15(4):4882-4890. Zhang J et al. Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease. Chin Med J (Engl). 2015;128(1):32-38.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Published functional studies demonstrate a damaging effect: Variant does not bind to elongin B or elongin C, resulting in an unstable protein that is rapidly degraded by the proteasome (Schoenfeld 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as p.(R208W) and p.(R238W); This variant is associated with the following publications: (PMID: 28873162, 14973063, 10205047, 9156047, 21519372, 23512077, 18836774, 12000816, 25119015, 19602254, 10900011, 7987306, 25563310, 27539324, 27527340, 27682873, 28944243, 28094316, 9829912, 22799452, 9829911, 8956040, 29124493, 25390905, 16042317, 29616089, 30522901, 30042107, 20233476, 29625052, 33745191, 32561571, 31589614, 30787465, 34377882, 34439168, 33828526, 34036514)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the VHL protein (p.Arg167Trp). This variant is present in population databases (rs5030820, gnomAD 0.0009%). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome and pheochromocytoma (PMID: 7987306, 9829912, 12000816, 15300849, 19464396, 23512077, 25563310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2218). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 14973063). This variant disrupts the p.Arg167 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7987306, 9829911, 19574279, 21463266, 22799452). 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.

Variant summary: The VHL c.499C>T (p.Arg167Trp) variant located in the alpha domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. This variant was found in 1/121114 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic VHL variant (0.0000208). Multiple publications have cited the variant in affected individuals ranging in phenotypes from VHL, renal carcinoma, hemangioblastoma and pheochromocytoma. Functional study, Schoenfield_2000, indicates the variant disrupts the elongin binding capability to VHL, a function that is essential for the tumor suppressor function of VHL. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R167W mutation has been reported in multiple patients and families with von Hippel-Lindau (VHL) syndrome (Babinska A et al. Neuro Endocrinol. Lett. 2015 Dec;36:517-20; Vikkath N et al. Fam. Cancer. 2015 Dec;14:585-94; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607) and is considered one of the most common mutations in the VHL gene. Available evidence suggests that germline mutations at codon 167 convey an increased risk for developing pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Chen F et al. Hum. Mut. 1995;5:66-75; Zbar B et al. Hum. Mutat. 1996;8:348-57; Olschwang S et al. Hum. Mut. 1998;12:424-30; Fishbein L et al. Ann. Surg. Oncol. 2013 May;20:1444-50). In one study of sporadic versus hereditary pancreatic islet cell tumors (ICTs), ICTs were found in 7 of 15 individuals (47%) with this mutation. In contrast, ICTs were found in only 1% of individuals with the p.Y98H founder mutation, suggesting an increased risk for ICTs in carriers of the p.R167W mutation (Erlic Z et al. Endocr. Relat. Cancer. 2010 Oct;17:875-83). The p.R167W mutation has been shown in transfection assays to prevent elongin-mediated stabilization of the VHL protein (Schoenfeld AR et al. Proc. Natl. Acad. Sci .USA. 2000 Jul;97:8507-12). Of note, this mutation is also designated as p.R238W (c.712C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.

This variant has been previously reported as disease-causing and was found twice in our study in patients with pheochromocytoma and family history of VHL.