ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.538A>G (p.Ile180Val) (rs377715747)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524495 SCV000259642 uncertain significance Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 180 of the VHL protein (p.Ile180Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs377715747, ExAC 0.002%). This variant has been reported in individuals with suspected von Hipple-Lindau (VHL) disease (PMID: 7987306, 9681856, 19408298, 17024664). This variant is also known as 751A>G, Ile251Val in the literature. ClinVar contains an entry for this variant (Variation ID: 161401). An experimental study has shown that this variant does not alter downstream protein complexes regulated by the VHL protein (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 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted VHL c.538A>G at the cDNA level, p.Ile180Val (I180V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant, also published as VHL 751A>G (Ile251Val) using alternate nomenclature, was observed in at least two individuals with von Hippel-Lindau (VHL) disease (Crossey 1994, Ong 2007). This variant was reported to have thermodynamic stability and to degrade HIF1a similar to wild type, but was associated with a decreased ability to degrade HIF2a compared to wild type in in vitro assays (Rechsteiner 2011). VHL Ile180Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the elongin C binding region (Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether VHL Ile180Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569566 SCV000675791 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148921 SCV000190678 likely benign Von Hippel-Lindau syndrome 2014-06-01 no assertion criteria provided research

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