Submissions for variant NM_000551.4(VHL):c.194C>G (p.Ser65Trp)

dbSNP: rs5030826

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497340	SCV000589600	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased VHL protein binding to HIF-1alpha, preventing ubiquitination (Miller 2005); Observed in multiple individuals with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Stolle 1998, Hes 2007, Dandanell 2012); 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; This variant is associated with the following publications: (PMID: 17661816, 20233476, 27527340, 26622630, 30731206, 23384228, 18544564, 15611064, 9829911, 19602254, 22799452, 10567493, 24444636, 8730290, 25563310, 7987306, 15881703, 31176917, 30522901, 31620170)
Invitae	RCV001219547	SCV001391491	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the VHL protein (p.Ser65Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 7987306, 8730290, 9829911, 10567493, 17024664, 22799452, 23384228). This variant is also known as Ser136Trp. ClinVar contains an entry for this variant (Variation ID: 43597). 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: 11331613, 15611064, 16669786, 18544564, 19602254). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10567493, 12114495, 15611064, 22799452, 25282218). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000497340	SCV002552398	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415465	SCV002718251	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	clinical testing	The p.S65W pathogenic mutation (also known as c.194C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 194. The serine at codon 65 is replaced by tryptophan, an amino acid with highly dissimilar properties This alteration has been reported as a germline mutation in many families affected with von Hippel-Lindau (VHL) syndrome that had no history of pheochromocytomas (Zbar et al. Hum Mutat. 1996;8(4):348-57; Crossey et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Ong et al. Hum Mutat. 2007 Feb;28(2):143-9; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Zhou et al. Pathol Int. 2010 Jun;60(6):452-8; Hes FJ et al. Clin. Genet., 2007 Aug;72:122-9). It has also been reported as a de novo alteration in a Chinese individual diagnosed with bilateral renal cell carcinoma at the age of 33 (Zhang L et al. Oncol Lett, 2015 Aug;10:1087-1090). Functional studies have indicated that the p.S65W mutation leads to severely compromised tight junctions and an unstable protein, therefore classifying it as a Type 1 VHL mutation (Bangiyeva et al. BMC Cancer. 2009 Jul 14;9:229). Note that this alteration is also referred to as c.407C>G in some published literature. Based on the available evidence, p.S65W is classified as a pathogenic mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036539	SCV000060194	pathogenic	Von Hippel-Lindau syndrome	2008-07-30	no assertion criteria provided	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000036539	SCV000264669	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000497340	SCV001931418	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000497340	SCV001970464	pathogenic	not provided		no assertion criteria provided	clinical testing