ClinVar Genomic variation as it relates to human health

Variant summary: VHL c.538A>G (p.Ile180Val) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain (IPR022772) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251436 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.538A>G has been reported in the literature in individuals with a diagnosis of von Hipple-Lindau syndrome (VHL) (examples: Crossey_1994, Zbar_1996, Neuman_1998, Ong_2007) and Ollier disease (Poll_VHL_Plos Gen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Polycythemia. Using a HIF (1/2)alpha GFP reporter assay one study have shown that this missense change does not substantially affect VHL function (Rechsteiner_ 2011). The following publications have been ascertained in the context of this evaluation (PMID: 7987306, 9681856, 17024664, 21715564, 10088816, 8956040, 36480544). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 180 of the VHL protein (p.Ile180Val). This variant is present in population databases (rs377715747, gnomAD 0.003%). This missense change has been observed in individual(s) with von Hipple-Lindau (VHL) disease (PMID: 7987306, 9681856, 17024664, 19408298). This variant is also known as 751A>G, Ile251Val. ClinVar contains an entry for this variant (Variation ID: 161401). 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 does not substantially affect VHL function (PMID: 21715564). 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.

The p.I180V variant (also known as c.538A>G), located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 538. The isoleucine at codon 180 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in an individual with a diagnosis of von Hipple-Lindau syndrome (VHL) (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Zbar B et al. Hum. Mutat. 1996;8:348-57), as well as an individual with renal cell carcinoma (Ong KR et al. Hum. Mutat., 2007 Feb;28:143-9). However, a functional analysis has shown this alteration does not alter downstream protein complexes regulated by VHL protein and behaves as wild type VHL protein (Rechsteiner MP et al. Cancer Res. 2011 Aug;71:5500-11). This variant has also been detected in multiple individuals with no reported features of VHL-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies are inconclusive: decreased ability to degrade HIF2a, but thermodynamic stability and degradation of HIF1a similar to wildtype (PMID: 21715564); Observed in individuals with suspected VHL disease (PMID: 7987306, 17024664); Identified in an individual with Ollier disease (PMID: 36480544); In silico analysis indicates that this missense variant does not alter protein structure/function; Also reported as 751A>G (Ile251Val); This variant is associated with the following publications: (PMID: 23606570, 26659599, 25637381, 8956040, 9681856, 19408298, 24969085, 20151405, 26206375, 20978146, 27530247, 28166483, 17024664, 7987306, 21715564, 36480544, 37937776)

ACMG Criteria: PM1, PM2, PP3; Variant was found in a heterozygous state