Submissions for variant NM_000551.4(VHL):c.262T>C (p.Trp88Arg)

dbSNP: rs1553619431

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589476	SCV000697494	pathogenic	Von Hippel-Lindau syndrome	2016-02-03	criteria provided, single submitter	clinical testing	Variant summary: This c.262T>C variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102034 control chromosomes, including the large and broad populations from ExAC. This variant has been reported in at least seven unrelated VHL patients and VHL-related tumors. c.262T>A, another variant leading to the same amino acid change, is a pathogenic variant. This evidence strongly supports that variant of interest is also pathogenic. In addition, codon 88 is a mutational hot spot in which other potentially pathogenic variants such as .W88C, p.W88S, p.W88* (c.263G>A) and p.W88* (c.264G>A) have been reported in VHL disease or its related cancers. In a tumor cell containing this variant, vascular endothelial growth factor (VEGF) expression was significantly increased which suggests that this variant leads to functional impairment (although it is uncertain whether observed effect was solely due to this variant as they assay was from patient cells) (Na_2003). Taken together, this variant has been classified as a Pathogenic.
Invitae	RCV000631292	SCV000752320	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-08-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp88 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 10567493, 11309459, 17024664, 19996202, 21715564, 27530247). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 496053). This missense change has been observed in individuals with Von Hippel-Lindau syndrome (PMID: 7728151, 10567493, 11309459, 12624160, 17024664, 17688370, 19996202, 21715564, 27530247). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 88 of the VHL protein (p.Trp88Arg).
Myriad Genetics, Inc.	RCV000589476	SCV003806644	pathogenic	Von Hippel-Lindau syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31620170, 35448166, 12624160, 33720516, 17024664, 17688370]. Functional studies indicate this variant impacts protein function [PMID: 35448166]. This variant is expected to disrupt protein structure [internal Myriad data].