ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.533G>C, Arg178Pro, and Arg148Pro; This variant is associated with the following publications: (PMID: 12624160, 22825683, 9829911, 20151405, 22683710, 9143408, 32860304)

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 107 of the VHL protein (p.Arg107Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau (VHL) syndrome (PMID: 9829911, 12624160; Invitae). This variant is also known as 533G>C. ClinVar contains an entry for this variant (Variation ID: 36900). 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%. This variant disrupts the p.Arg107 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 19336503, 21362373, 22799452), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Variant summary: VHL c.320G>C (p.Arg107Pro) results in a non-conservative amino acid change located in the beta domain (IPR024053) 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 221140 control chromosomes (gnomAD). c.320G>C has been reported in the literature in individuals affected with Von Hippel-Lindau Syndrome (e.g., Stolle_1998, Rocha_2003, Ricketts_2015, Dallagnol_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36625343, 22683710, 18836774, 26484545, 12624160, 9829911, 19996202). Additionally, different missense variants affecting the same codon, namely c.319C>G (p.Arg107Gly) and c.320G>A (p.Arg107His), have been reported in the literature in many individuals affected with VHL-related disorders (PMIDs: 12000816, 21362373, 33720516, 19336503, 12202531, 32739800). ClinVar contains an entry for this variant (Variation ID: 36900). Based on the evidence outlined above, the variant was classified as pathogenic.

The p.R107P pathogenic mutation (also known as c.320G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 320. The arginine at codon 107 is replaced by proline, an amino acid with dissimilar properties. This alteration has been identified in numerous families meeting diagnostic criteria for von Hippel-Lindau (VHL) disease that have been affected with lesions such as CNS hemangioblastoma, retinal angioma, renal cell carcinoma, pancreatic and renal cysts, and pheochromocytoma (Stolle et al. Hum Mutat. 1998;12(6): 417-23; Rocha et al. J Med Genet. 2003;40(3): e31; Ambry Internal Data). Furthermore, three other mutations (p.R107C, p.R107H and p.R107G) at the same codon have been associated with VHL and pheochromocytoma. 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.