ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.499C>G (p.Arg167Gly) (rs5030820)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002304 SCV000897839 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000466046 SCV000553389 likely pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 167 of the VHL protein (p.Arg167Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (rs5030820, ExAC no frequency). This variant has been reported in individuals affected with von Hippel–Lindau disease and sporadic pheochromocytoma (PMID: 7987306, 19574279). This variant is also known as 712C>G, p.Arg238Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 2219). 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. Two different missense substitutions at this codon, p.Arg167Trp and p.Arg167Gln, are reported to be deleterious. The arginine 167 residue is known to be among the most frequently mutated codons in VHL. Codon 167 missense variants are mainly associated with type 2B VHL, with a high incidence of pheochromocytoma within the families (PMID: 14987375, 20151405). This indicates that the Arg167 residue is important for VHL protein function. In summary, this variant has been reported in affected individuals, altering an amino acid residue known to be essential for protein function. In the absence of conclusive genetic and/or functional evidence, it has been classified as Likely Pathogenic.
OMIM RCV000002304 SCV000022462 pathogenic Von Hippel-Lindau syndrome 1995-06-01 no assertion criteria provided literature only

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