Submissions for variant NM_000551.4(VHL):c.538A>G (p.Ile180Val)

gnomAD frequency: 0.00001  dbSNP: rs377715747

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524495	SCV000259642	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2024-01-24	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000480432	SCV000565831	uncertain significance	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies are inconclusive: thermodynamic stability and degradation of HIF1a similar to wild type; decreased ability to degrade HIF2a compared to wild type (Rechsteiner et al., 2011); Observed in individuals with suspected VHL disease (Crossey et al., 1994; Ong et al., 2007); In silico analysis supports 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)
Ambry Genetics	RCV000569566	SCV000675791	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000148921	SCV001136313	uncertain significance	Von Hippel-Lindau syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569566	SCV002534183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387773	SCV004099642	uncertain significance	not specified	2023-09-08	criteria provided, single submitter	clinical testing	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.
CSER _CC_NCGL, University of Washington	RCV000148921	SCV000190678	likely benign	Von Hippel-Lindau syndrome	2014-06-01	flagged submission	research
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV002467588	SCV002764244	likely pathogenic	Enchondromatosis		flagged submission	research