Submissions for variant NM_000551.4(VHL):c.353T>C (p.Leu118Pro)

dbSNP: rs5030830

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492175	SCV000580985	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-02	criteria provided, single submitter	clinical testing	The p.L118P pathogenic mutation (also known as c.353T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 353. The leucine at codon 118 is replaced by proline, an amino acid with very few similar properties. This pathogenic mutation has been reported in numerous individuals diagnosed with VHL (Crossey PA et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Zbar B et al. Hum Mutat. 1996;8(4):348-57; Olschwang S et al. Hum. Mutat. 1998;12:424-30; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;91(2):204-12; Gallou C et al. Hum Mutat. 2004 Sep;24(3):215-24; Benhammou JN et al. J. Urol. 2010 Nov;184:1855-9; Dandanell M et al. BMC Med Genet. 2012 Jul 16;13:54; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Authors of another study concurred that missense mutations in the VHL gene are associated with a higher risk of pheochromocytomas, however they divided missense mutations into two subgroups:surface missense amino acid substitution mutations (SM) and deep missense mutations (DM). Missense mutations in the SM group were found to be at a significantly higher risk for pheochromocytomas than missense mutations in the DM group. The p.L118P variant was categorized as a DM due to its location in the protein core and the disruption of protein function (Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9). Of note, this pathogenic mutation is also referred to as 566T>C in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801496	SCV000941273	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 118 of the VHL protein (p.Leu118Pro). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 14973063). 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: 428807). This variant is also known as c.566T>C (p.Leu189Pro). This missense change has been observed in individuals with von Hippel-Lindau (VHL) syndrome and clinical features of VHL (PMID: 7987306, 8956040, 9829912, 12202531, 17024664, 22799452, 25952756, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Myriad Genetics, Inc.	RCV004591439	SCV005084510	pathogenic	Von Hippel-Lindau syndrome	2024-05-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 14636579]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 38595826, 17024664, 25952756, 9829912].
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702663	SCV001930739	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702663	SCV001955800	pathogenic	not provided		no assertion criteria provided	clinical testing