ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.500G>T (p.Arg167Leu) (rs5030821)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631284 SCV000752312 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2017-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 167 of the VHL protein (p.Arg167Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two families affected with von Hippel-Lindau syndrome, and to segregate with disease in one of these families (PMID: 21463266). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Codon 167 is located in the alpha domain of the VHL protein and is reported to be important in maintaining protein structure. This codon is the most frequently mutated residue in the VHL gene, accounting for 46% of the mutations in patients with type 2 von Hippel-Lindau syndrome in one study (PMID: 22799452, 9829911). For these reasons, this variant has been classified as Pathogenic.

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