Submissions for variant NM_000551.4(VHL):c.257C>G (p.Pro86Arg)

dbSNP: rs730882034

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208868	SCV000697491	pathogenic	Von Hippel-Lindau syndrome	2016-02-02	criteria provided, single submitter	clinical testing
Invitae	RCV000631258	SCV000752286	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the VHL protein (p.Pro86Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 9829911, 11257211, 17024664, 19408298). ClinVar contains an entry for this variant (Variation ID: 223170). 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. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 10205047, 22799452, 27034144, 27057652, 27527340). 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 Human Genetics, Inc, Center for Human Genetics, Inc	RCV000208868	SCV000782418	pathogenic	Von Hippel-Lindau syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237772	SCV002011312	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426981	SCV002740355	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-28	criteria provided, single submitter	clinical testing	The p.P86R pathogenic mutation (also known as c.257C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 257. The proline at codon 86 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in numerous families with a diagnosis of Von Hippel-Lindau syndrome (VHL) (Stolle C et al. Hum. Mutat. 1998;12:417-23; Rothberg PG et al. Mol. Diagn. 2001 Mar;6:49-54; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Liu SJ et al. Genet. Med. 2018 10;20:1266-1273). Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. Several other alterations at the same codon (p.P86A, p.P86L, and p.P86S) have been detected in individuals with VHL syndrome suggesting this codon may represent a mutation hotspot. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV003237772	SCV004226809	likely pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	PP3, PP4, PM1, PM2, PM5
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208868	SCV000264686	likely pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing