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

dbSNP: rs1553619431

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000558602	SCV000626889	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2017-12-21	criteria provided, single submitter	clinical testing	A different variant (c.262T>C) giving rise to the same protein effect observed here (p.Trp88Arg) has been reported in individuals affected with Von Hippel-Lindau syndrome (PMID: 12624160, 17688370, Invitae). In addition, a different missense substitution at this codon (p.Trp88Cys) has been determined to be likely pathogenic (PMID: 10567493, 21715564). This suggests that the tryptophan residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces tryptophan with arginine at codon 88 of the VHL protein (p.Trp88Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Von Hippel-Lindau syndrome (PMID: 10567493, 7728151, 17024664, 8956040).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587190	SCV000697493	pathogenic	Von Hippel-Lindau syndrome	2016-02-03	criteria provided, single submitter	clinical testing	Variant summary: This c.262T>A variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg in beta domain of VHL protein. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102226 control chromosomes including the large and broad populations from ExAC. This variant has been reported in at least ten independent VHL patients, two of whom carried the variant as somatic occurrence. In a family, the variant was found in two affected members, suggesting a possible cosegregation of the variant with disease (Glasker_2001). Another nucleotide change leading to the same amino acid change c.262T>C is a pathogenic variant, a strong evidence that this nucleotide change 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. Taken together, this variant has been classified as a Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000679026	SCV000805333	pathogenic	not provided	2014-04-16	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000587190	SCV000897793	pathogenic	Von Hippel-Lindau syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431533	SCV002743251	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-21	criteria provided, single submitter	clinical testing	The p.W88R variant (also known as c.262T>A), located in coding exon 1 of the VHL gene, results from a T to A substitution at nucleotide position 262. The tryptophan at codon 88 is replaced by arginine, an amino acid with dissimilar properties. This alteration (also designated 475T>A) was detected in multiple patients who met clinical criteria or presented with clinical features of Von Hippel-Lindau (VHL) Syndrome (Chen F et al. Hum. Mutat., 1995;5:66-75; Gläsker S et al. J. Neurol. Neurosurg. Psychiatry, 1999 Dec;67:758-62; Jilg CA et al. Urol. Int., 2012 Dec;88:71-8; Ong KR et al. Hum. Mutat., 2007 Feb;28:143-9; Rocha JC et al. J. Med. Genet., 2003 Mar;40:e31; Stanojevic BR et al. Neoplasma, 2007;54:402-6; Zbar B et al. Hum. Mutat., 1996;8:348-57). In addition, a similar alteration resulting in the same amino acid change (W88R) but with a different nucleotide change (c.262T>C) has been reported in VHL patients (Hong B et al. Front Genet, 2019 Sep;10:867; Kim WT et al. J. Korean Med. Sci., 2009 Dec;24:1145-9). Based on internal structural analysis, W88R is at a putative HIF1 binding interface and the variant is moderately destabilizing to the local structure and more disruptive than known variants in the region (Shmueli MD et al. PLoS ONE, 2014 Oct;9:e109864; Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003459186	SCV004208763	pathogenic	Chuvash polycythemia	2023-07-21	criteria provided, single submitter	clinical testing
Clinical Genomics Labs, University Health Network	RCV000587190	SCV001950153	pathogenic	Von Hippel-Lindau syndrome	2019-10-16	no assertion criteria provided	clinical testing