ClinVar Miner

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

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Total submissions: 15
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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 2020-10-19 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 The p.R167Q pathogenic mutation (also known as c.500G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 500. The arginine at codon 167 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been described in numerous VHL families from various ethnic backgrounds (Zbar B et al. Hum. Mutat. 1996;8:348-57; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Zhou J et al. Pathol. Int. 2010 Jun;60:452-8; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Wang X et al. Urology. 2014 Mar;83:675.e1-5; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Furthermore, codon 167 is a VHL mutation hotspot; substitutions at this position impact a highly-conserved protein surface residue and have been reported to confer high pheochromocytoma risk (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Cybulski C et al. J. Med. Genet. 2002 Jul;39:E38; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9). Of note, this mutation has also been reported in the literature as p.R238Q ( c.713G>A). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000325074 SCV000329564 pathogenic not provided 2021-07-15 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: disrupts HIF1-alpha hypoxia responsive regulation and impairs binding with Elongin C resulting in partial or unstable pVHL E3 (VBC) complex formation (Rathmell 2004, Hacker 2008, Lee 2009); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.713G>A (R238Q); This variant is associated with the following publications: (PMID: 27535533, 32742360, 29625052, 11510758, 29871882, 10205047, 20518900, 17024664, 10567493, 8956040, 28469506, 8730290, 28114281, 7784063, 27527340, 27539324, 25563310, 24352051, 21528828, 19252526, 19030229, 9106522, 17264095, 24712571, 15300849, 25562111, 19215943, 24301059, 24581539, 19464396, 22517557, 20151405, 21386872, 12202531, 17661816, 12114495, 18836774, 7987306, 25371412, 12000816, 15574766, 19602254, 23990666, 11354926, 29124493, 29616089, 31447099)
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 ( 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
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002300 SCV000264765 pathogenic Von Hippel-Lindau syndrome 2016-02-26 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000325074 SCV001932766 pathogenic not provided no assertion criteria provided clinical testing
University Health Network Clinical Genomics Labs,University Health Network RCV000002300 SCV001950141 pathogenic Von Hippel-Lindau syndrome 2019-05-10 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000325074 SCV001957608 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000325074 SCV001969275 pathogenic not provided no assertion criteria provided clinical testing

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