Submissions for variant NM_000551.4(VHL):c.266T>C (p.Leu89Pro)

dbSNP: rs5030807

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000161087	SCV000276228	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-03-07	criteria provided, single submitter	clinical testing	The p.L89P variant (also known as c.266T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 266. The leucine at codon 89 is replaced by proline, an amino acid with similar properties. This variant has been reported in numerous VHL kindreds to date (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Zbar B et al. Hum. Mutat. 1996;8:348-57; Glavac D et al. Hum. Genet. 1996 Sep;98:271-80; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Klein B et al. Hum. Genet. 2001 May;108:376-84; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Rajasekaran R et al. Mamm. Genome. 2008 Sep;19:654-61; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31:521-37). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000817709	SCV000958287	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-11-21	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 89 of the VHL protein (p.Leu89Pro). 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: 7987306, 8707293, 11309459, 17024664, 20151405). It has also been observed to segregate with disease in related individuals. This variant is also known as 479T>C and Leu160Pro. ClinVar contains an entry for this variant (Variation ID: 182979). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208869	SCV002051311	pathogenic	Von Hippel-Lindau syndrome	2021-12-21	criteria provided, single submitter	clinical testing	Variant summary: VHL c.266T>C (p.Leu89Pro) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225978 control chromosomes (gnomAD). c.266T>C has been reported in the literature in multiple individuals and families affected with Von Hippel-Lindau Syndrome (e.g. Crossey_1994, Glavac_1996, Chacon-Camacho_2010, Liu_2018). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000208869	SCV004930927	pathogenic	Von Hippel-Lindau syndrome	2024-02-20	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: 8707293, 20447124, 17024664, 31620170]. This variant is expected to disrupt protein structure [Myriad internal data].
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208869	SCV000264689	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing