ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.500G>A (p.Arg167Gln) (rs5030821)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627745 SCV000253856 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 167 of the VHL protein (p.Arg167Gln). 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 patients and families affected with pheochromocytoma, hemangioblastoma of the central nervous system and spinal cord, renal cell carcinoma, and pancreatic cyst (PMID: 8956040, 15300849, 12000816, 7987306, 19464396, 10567493). This variant is also known as p.Arg238Gln in the literature. ClinVar contains an entry for this variant (Variation ID: 2216). A different missense substitution at this codon (p.Arg167Trp) has been determined to be pathogenic (PMID: 8730290, 7987306). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change disrupts the normal function of the VHL protein (PMID: 19602254, 15574766, 19030229, 19252526). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000213850 SCV000273601 pathogenic Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing Well-characterized mutation at same position;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
GeneDx RCV000325074 SCV000329564 pathogenic not provided 2018-06-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted VHL c.500G>A at the cDNA level, p.Arg167Gln (R167Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also known as 713G>A and Arg238Gln using alternate nomenclature, has been observed in many individuals with von Hippel-Lindau disease and/or pheochromocytoma (Crossey 1994, Dollfus 2002, Neumann 2002, Ciotti 2009, Casey 2014, Sriphrapradang 2017). Functional studies show Arg167Gln disrupts HIF1-alpha hypoxia responsive regulation and leads to impaired binding with Elongin C resulting in partial or unstable pVHL E3 (VBC) complex formation (Rathmell 2004, Hacker 2008, Lee 2009). VHL Arg167Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). VHL Arg167Gln is located in the alpha domain of the elongin C binding region and is one of the most frequently mutated residues in the VHL gene (Stebbins 1999, Yuen 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506694 SCV000605562 pathogenic not specified 2016-10-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002300 SCV000711453 pathogenic Von Hippel-Lindau syndrome 2018-01-17 criteria provided, single submitter clinical testing The p.Arg167Gln variant in VHL (also described as p.Arg238Gln in the literature) has been reported in >15 individuals with von Hippel-Lindau syndrome (VHL) and is associated with a high incidence of pheochromocytomas (Crossey 1994, Neumann 2002, Park 2015, Sriphraprandang 2017; Zhuo 2010; Zbar 1996). It has also been r eported by other clinical laboratories in ClinVar (Variant ID: 2216). In vitro f unctional studies provide some evidence that the p.Arg167Gln variant may impact protein function (Rathmell 2004, Couve 2014). This variant has been identified i n 1/111702 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Co mputational prediction tools and conservation analysis suggest that the p.Arg176 Gln variant may impact the protein. Of note, other variants at this position (p. Arg167Gly, p.Arg167Leu, p.Arg167Trp) have been reported in individuals with VHL, suggesting that an alteration at this position is not tolerated. In summary, th is variant meets criteria to be classified as pathogenic for VHL in an autosomal dominant manner based upon multiple occurrences in affected individuals, very l ow frequency in the general population, presence of other pathogenic variants at the same amino acid position and computational and functional evidence. ACMG/AM P criteria applied: PS4, PM2, PM5, PS3_Supporting, PP3.
PreventionGenetics,PreventionGenetics RCV000325074 SCV000805355 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000325074 SCV001153781 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000002300 SCV001167284 pathogenic Von Hippel-Lindau syndrome 2019-09-25 criteria provided, single submitter clinical testing
CIViC knowledgebase,Washington University School of Medicine RCV000002300 SCV001192828 pathogenic Von Hippel-Lindau syndrome criteria provided, single submitter curation R167Q (c.500G>A) is a pathogenic variant for Von Hippel-Lindau. R167Q is the most common mutation associated with Von Hippel-Lindau syndrome. This variant is very rare in the general population at 4.061e-6 in the gnomAD exomes (v2.0.2) proving ACMG code PM2. The variant occurs within the functional domain, disrupting VHL binding to elongin C (ACMG code PM1). Additional codes are provided by the following EIDs. 4913 (PS4), 5062 (PP4), 5264 (PS4), 5354 (PP4), 5487 and 4913 (PP1).
OMIM RCV000002300 SCV000022458 pathogenic Von Hippel-Lindau syndrome 1995-06-01 no assertion criteria provided literature only
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000002300 SCV000264765 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing

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