Submissions for variant NM_000551.4(VHL):c.435G>C (p.Gln145His)

dbSNP: rs771727849

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197591	SCV000254653	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 145 of the VHL protein (p.Gln145His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with VHL-related conditions. ClinVar contains an entry for this variant (Variation ID: 216479). 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%. Experimental studies have shown that this missense change affects VHL function (PMID: 15611064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002327050	SCV002632239	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-30	criteria provided, single submitter	clinical testing	The p.Q145H variant (also known as c.435G>C), located in coding exon 2 of the VHL gene, results from a G to C substitution at nucleotide position 435. The glutamine at codon 145 is replaced by histidine, an amino acid with highly similar properties. Functional in vitro studies indicate this alteration disrupts binding to HIF-2 alpha and fails to degrade HIF-2 alpha (Miller F et al. J Biol Chem, 2005 Mar;280:7985-96). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003997031	SCV004841652	uncertain significance	Von Hippel-Lindau syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 145 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant impairs HIF-2alpha degradation and alters binding specificity to HIF-1alpha (PMID: 15611064). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.