ClinVar Genomic variation as it relates to human health

Variant summary: The variant, VHL c.452T>C (p.Ile151Thr, also known as c.655T>C, p.Ile222Thr) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain and von Hippel-Lindau disease tumour suppressor, beta/alpha domain 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 246370 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Hes_2007, Ong_2007, Sriphrapradang_2017, Krauss_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence assessing the variant effect on the downstream signaling mechanism of VHL but does not allow convincing conclusions about the variant effect (Walmsley_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant has been reported in numerous individuals affected with von Hippel-Lindau (VHL) syndrome (PMID: 10567493, 28469506, 17661816, 17024664, 11309459). This variant is also known as 665T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 428803). For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Ile151Ser and p.Ile151Phe) have been reported in several individuals affected with VHL syndrome (PMID: 22357542, 25078357). 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 variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 151 of the VHL protein (p.Ile151Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

The p.I151T pathogenic mutation (also known as c.452T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 452. The isoleucine at codon 151 is replaced by threonine, an amino acid with similar properties. The p.I151T alteration, also referred to as 665T>C in some literature, has been reported in individuals with a diagnosis or clinical features of VHL (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Gläsker S et al. J. Neurol. Neurosurg. Psychiatry. 2001 May;70:644-8; Hes FJ et al. Clin. Genet. 2007 Aug;72:122-9; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122; Krauss T et al. Endocr. Relat. Cancer. 2018 09;25:783-793; Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Testa A et al. J. Am. Chem. Soc., 2018 07;140:9299-9313). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation.

ACMG categories: PS1,PM2,PM7,PP3,PP4,PP5