ClinVar Genomic variation as it relates to human health

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that while this missense change does not affect microtubule stabilization, it does exhibit disrupted microtubule turnover, reduced assembly of the VCB-Cul2 complex, and decreased HIF-1 alpha binding and ubiquitination (PMID: 11865071, 12510195, 20855504). Other missense substitutions at this codon (p.Gly114Arg and p.Gly114Cys) have been reported in individuals affected with VHL syndrome (PMID: 7728151, 27527340, 7987306). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in individuals and families affected with von Hippel-Lindau (VHL) syndrome, or VHL-associated lesions (PMID: 20660572, 23407287, 15002726, Invitae). This variant is also known as c.553G>A in the literature. This sequence change replaces glycine with serine at codon 114 of the VHL protein (p.Gly114Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 1 of the VHL coding sequence, which is part of the consensus splice site for this exon.

The p.G114S pathogenic mutation (also known as c.340G>A), located in coding exon 1 of the VHL gene, results from a G to A substitution at nucleotide position 340. The glycine at codon 114 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1 and may have some effect on normal mRNA splicing. In functional studies, this alteration was shown to reduce binding and decrease ability to ubiquinate a critical transcription factor HIF1-alpha (Hansen WJ et al. Mol Cell Biol, 2002 Mar;22:1947-60). In addition, this alteration was shown to moderately decrease microtubule regulatory functions compared to the wildtype VHL protein (Thoma CR et al. J Cell Biol, 2010 Sep;190(6):991-1003). This alteration has been reported in multiple individuals with features of VHL and/or a clinical diagnosis of VHL (Loughrey PB et al. Endocr Relat Cancer, 2022 Oct;29:R157-R172; Petenuci J et al. Clin Endocrinol (Oxf), 2021 Jul;95:117-124; Krauss T et al. Endocr Relat Cancer, 2018 Sep;25:783-793; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.