ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2019-11-04 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.
Ambry Genetics RCV000563066 SCV000664511 pathogenic Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing 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)
PreventionGenetics,PreventionGenetics RCV000161092 SCV000805352 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000208848 SCV001362035 pathogenic Von Hippel-Lindau syndrome 2019-08-18 criteria provided, single submitter clinical testing Variant summary: VHL c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.482G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (example Chen_1995, Zbar_1996, Stolle_1998, Santarpia_2007, Olschwang_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of binding to elongin and an unstable VHL protein that is susceptible to proteasomal degradation (Schoenfeld_2000). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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

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