ClinVar Genomic variation as it relates to human health

The Val84Leu variant has previously been reported in the literature in several i ndividuals with clinical features consistent with VHL syndrome. Six individuals with bilateral pheochromocytomas have been reported, four of whom had a family h istory (Abbott 2006, Crossey 1995, Klein 2001, Leonardi 2011). This variant segr egated with disease in two individuals from two families (Crossey 1995, Abbott 2 006) and is currently considered to be causative for VHL type 2C (Crossey 1995). In addition, this variant (caused by a different nucleotide change, 250G>C) was reported as a de novo variant in an individual with sporadic disease and was ab sent from 400 control chromosomes (Leonardi 2011). This variant is listed in dbS NP (rs5030827) as a clinically associated variant. In summary, this variant is h ighly likely to be pathogenic.

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). 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: 2236). This missense change has been observed in individual(s) with von Hipple Lindau type 2C (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu).

VHL: PS1, PM1, PM2, PM5, PP3

The p.V84L pathogenic mutation (also known as c.250G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 250. The valine at codon 84 is replaced by leucine, an amino acid with highly similar properties. This mutation has been reported in multiple families with early-onset and/or bilateral pheochromocytomas (Crossey PA et al. J Med Genet, 1995 Nov;32:885-6; Klein B et al. Hum Genet, 2001 May;108:376-84; Kang HC et al. Oncol Rep, 2005 Oct;14:879-83; Abbott MA et al. Am J Med Genet A, 2006 Apr;140:685-90). Structural analysis of this variant demonstrated impaired formation of stable pVHL-ElonginC-ElonginB (VCB) complexes in vitro and CBCVHL ubiquitin ligase complexes in vivo, and functional analyses indicated this variant is mildly defective in HIF-1α regulation, suggesting the possibility that a low level of HIF-1/2α dysregulation contributes to the pathogenesis of pheochromocytomas (Knauth K et al. J Biol Chem, 2009 Apr;284:10514-22). Another functional analysis showed low levels of HIF-2α similar to those observed with wild-type VHL but elevated levels of α5 integrin compared to wild-type VHL (Bangiyeva V et al. BMC Cancer, 2009 Jul;9:229). Another alteration at the same codon, p.V84M (c.250G>A), has been described in families with early-onset pheochromocytomas (Stanojevic BR et al. Neoplasma. 2007;54:402-6; Eisenhofer G et al. Horm. Metab. Res. 2012 May;44(5):343-8). Of note, this alteration is also designated as 463G>T in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.