ClinVar Miner

Submissions for variant NM_000551.3(VHL):c.491A>G (p.Gln164Arg) (rs267607170)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002326 SCV000697523 pathogenic Von Hippel-Lindau syndrome 2021-01-19 criteria provided, single submitter clinical testing Variant summary: VHL c.491A>G (p.Gln164Arg) results in a conservative amino acid change located in the alpha domain, which is known to interact with Elongin C (IPR024048). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple patients/families affected with Von Hippel-Lindau Syndrome (VHL) or with VHL-related tumors, including at least one individual with de novo occurrence (e.g. Chen_1995, Zbar_1996, Webster_1999, Mattocks_2000, Ong_2007, Sovinz_2010, de Cubas_2013, Neumann_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that while this variant didn't affect elongin B and C binding in an in vitro peptide-binding assay, the Q164R mutant full-length protein had reduced binding ability to elongin B and Cul2 in transiently transfected renal carcinoma cells (Ohh_1999). In addition, another study also reported that though the variant protein had retained elongin C binding, the variant significantly reduced the intracellular stability of VHL protein (Park_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000002326 SCV000897835 pathogenic Von Hippel-Lindau syndrome 2018-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023261 SCV001185112 pathogenic Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing The p.Q164R (also known as c.491A>G) pathogenic mutation, located in coding exon 3 of the VHL gene, results from an A to G substitution at nucleotide position 491. The glutamine at codon 164 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in patients with clinical diagnoses of von Hippel-Lindau syndrome (VHL), or VHL related tumors (Chen F et al. Hum. Mutat. 1995;5:66-75; Webster AR et al. Arch. Ophthalmol. 1999 Mar;117:371-8; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5; de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20:477-93; Fallon SC et al. J. Pediatr. Surg. 2013 Jun;48:1422-5; Krauss T et al. Endocr. Relat. Cancer. 2018 Sep;25:783-793). In one case, this variant was identified in a 2-year-old child with pheochromocytoma. It was found to be de novo in the patient's father, who also had pheochromocytoma, retinal angioma, and an adrenal adenoma (Sovinz P et al. Am. J. Med. Genet. A. 2010 Jul;152A:1752-5). In vitro functional studies do not show specific impaired functions, including elongin C binding, however, one study showed a shorter protein half-life than wild type leading the authors to speculate that the protein may be unstable (Ohh M et al. J. Clin. Invest. 1999 Dec;104:1583-91; Maynard MA et al. J. Biol. Chem. 2003 Mar;278:11032-40; Park KS et al. BMC Cancer. 2015 Oct;15:800). Another alteration at the same codon, ​p.Q164H (c.492G>C) , has been reported in a family diagnosed with PGLs and PCCs (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75), and internal structural analysis indicated the alteration disrupts the fold of the elongin binding domain of VHL (Ambry internal data; Van Molle I et al. Chem. Biol. 2012 Oct;19:1300-12). In addition, the p.Q164R variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001052383 SCV001216592 pathogenic Erythrocytosis, familial, 2; Von Hippel-Lindau syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 164 of the VHL protein (p.Gln164Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau disease (PMID: 7728151, 20583150, 17024664). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 2238). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Gln164 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24102379, 22517557, 19215943, 12807974, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002326 SCV000022484 pathogenic Von Hippel-Lindau syndrome 2010-07-01 no assertion criteria provided literature only

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