chr3-10149861-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000551.4(VHL):āc.538A>Gā(p.Ile180Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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VHL | NM_000551.4 | c.538A>G | p.Ile180Val | missense_variant | Exon 3 of 3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_198156.3 | c.415A>G | p.Ile139Val | missense_variant | Exon 2 of 2 | NP_937799.1 | ||
VHL | NM_001354723.2 | c.*92A>G | 3_prime_UTR_variant | Exon 3 of 3 | NP_001341652.1 | |||
VHL | NR_176335.1 | n.867A>G | non_coding_transcript_exon_variant | Exon 4 of 4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251436Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135906
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461886Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 727242
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Uncertain:2Benign:1
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ACMG Criteria: PM1, PM2, PP3; Variant was found in a heterozygous state -
Hereditary cancer-predisposing syndrome Uncertain:2
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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. Based on the available evidence, the clinical significance of this variant remains unclear. -
Enchondromatosis Pathogenic:1
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not specified Uncertain:1
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. -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
not provided Uncertain:1
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) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at