ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.482G>A (p.Arg161Gln) (rs730882035)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563066 SCV000664511 pathogenic Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s)
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000208848 SCV000264757 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
GeneDx RCV000161092 SCV000211827 pathogenic not provided 2015-12-30 criteria provided, single submitter clinical testing This variant is denoted VHL c.482G>A at the cDNA level and p.Arg161Gln (R161Q) at the protein level. The R161Q pathogenic missense variant in the VHL gene has been reported previously in association with von Hippel Lindau disease (Chen et al., 1995; Shah et al., 2014), and its presence is consistent with the diagnosis in this patient. Functional studies of R161Q shows this variant decreases the interactions responsible for stability of the interdomains creating an open conformation with greater rotation angle and moderately inhibits binding of VHL protein to proline-hydroxylated hypoxia-inducible Factor 1A (HIF1a) peptide (Couve et al., 2014).
Invitae RCV000456958 SCV000553385 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 161 of the VHL protein (p.Arg161Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with von Hippel-Lindau syndrome (PMID: 7728151, 24707167, 12000816, 15300849, 9829911, 21362373), including one individual where it was found to be de novo (PMID: 12000816). This variant has also been shown to segregate with disease in families (PMID: 23842656, 14767570, 20120764). In the literature, this variant is also known as c.695G>A. ClinVar contains an entry for this variant (Variation ID: 182983). Experimental studies demonstrated that this missense change disrupts the ability of VHL protein to bind and degrade HIF in vitro, which correlates with abnormal expression of HIF2-alpha regulated genes in vivo (PMID: 25371412, 21715564). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics RCV000161092 SCV000805352 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing

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