Submissions for variant NM_000551.4(VHL):c.482G>A (p.Arg161Gln)

dbSNP: rs730882035

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161092	SCV000211827	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: moderately inhibited binding to proline-hydroxylated hypoxia-inducible Factor 1A (HIF1a), increased HIF2a stability and target expression (PMID: 25371412); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.695G>A (p.Arg232Gln); This variant is associated with the following publications: (PMID: 21715564, 29022557, 33219105, 10587522, 14767570, 27539324, 27527340, 29124493, 19135659, 17102087, 28052007, 7728151, 9829912, 8956040, 21362373, 15300849, 9829911, 24466223, 20120764, 9215674, 24707167, 30877234, 31666924, 10900011, 32742360, 33745191, 32561571, 32901917, 30787465, 9497878, 12000816, 23842656, 25371412)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456958	SCV000553385	pathogenic	Chuvash polycythemia; Von Hippel-Lindau syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 161 of the VHL protein (p.Arg161Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 7728151, 9829911, 12000816, 14767570, 15300849, 20120764, 21362373, 23842656, 24707167). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.695G>A. ClinVar contains an entry for this variant (Variation ID: 182983). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564, 25371412). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000563066	SCV000664511	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	The p.R161Q pathogenic mutation (also known as c.482G>A), located in coding exon 3 of the VHL gene, results from a G to A substitution at nucleotide position 482. The arginine at codon 161 is replaced by glutamine, an amino acid with highly similar properties. This well-described mutation has been identified in kindreds with multiple von Hippel Lindau (VHL) tumors including hemangioblastoma, renal cell carcinoma, and pheochromocytoma (PCC), and has also been identified in individuals with isolated PCC (Chen F et al. Hum Mutat. 1995; 5: 66-75; Zbar et al. Hum Mutat. 1996; 8(4): 348-57; Woodward E et al. Hum Mol Genet. 1997; 6(7):1051-6; Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Stolle C et al. Hum Mutat, 1998;12:417-23; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Santarpia L et al. Ann N Y Acad Sci, 2006 Aug;1073:198-202; Tong A et al. Chin Med Sci J. 2009 Dec;24(4):197-201; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805; Crona J et al. PLoS ONE 2014 Jan;9(1):e86756; Shah V et al. Clin Ophthalmol 2014 Mar;8:623-8; Pandit R et al. Eur J Endocrinol, 2016 Oct;175:311-23; Igaki J et al. Clin Pediatr Endocrinol, 2018 Apr;27:87-93; Lomte N et al. Fam Cancer, 2018 07;17:441-449; Dadeviren Çakr A et al. J Clin Res Pediatr Endocrinol, 2018 06;10:179-182; Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931). It has been reported as a de novo finding in two individuals and segregated with disease in several families (Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Iida K et al. Int J Mol Med, 2004 Mar;13:401-4; Qi XP et al. Mol Med Rep 2013 Sep;8(3):799-805). Functional studies have shown that p.R161Q disrupts VHL function in hypoxia signaling pathways in vitro (Couvé S et al. Cancer Res. 2014 Nov;74(22):6554-64). Of note, this alteration is also designated as p.R232Q in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208848	SCV001362035	pathogenic	Von Hippel-Lindau syndrome	2019-08-18	criteria provided, single submitter	clinical testing	Variant summary: VHL c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes. c.482G>A has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (example Chen_1995, Zbar_1996, Stolle_1998, Santarpia_2007, Olschwang_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of binding to elongin and an unstable VHL protein that is susceptible to proteasomal degradation (Schoenfeld_2000). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000161092	SCV001500282	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000161092	SCV002067285	pathogenic	not provided	2019-03-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the VHL gene demonstrated a sequence change, c.482G>A, in exon 3 that results in an amino acid change, p.Arg161Gln. This sequence change is absent from large population databases such as ExAC and gnomAD. This pathogenic sequence change has previously been described in multiple patients and families with Von Hippel-Lindau syndrome (Igaki et al., 2018; Zhang et al., 2015; Iada et al., 2004). Functional analyses demonstrated that the p.Arg161Gln change inhibits the VHL protein from binding to proline-hydroxylated hypoxia-inducible factor 1A (HIF1a peptide (Couve et al., 2014). The p.Arg161Gln change affects a highly conserved amino acid residue located in a domain of the VHL protein that is known to be functional. The p.Arg161Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000208848	SCV003930412	pathogenic	Von Hippel-Lindau syndrome	2023-05-21	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000208848	SCV000264757	pathogenic	Von Hippel-Lindau syndrome	2016-02-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742286	SCV000805352	pathogenic	VHL-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The VHL c.482G>A variant is predicted to result in the amino acid substitution p.Arg161Gln. This variant was reported in numerous individuals with Von Hippel-Lindau syndrome and pheochromocytoma, and has been repeatedly shown to segregate with disease (see for example: Neumann et al. 2002. PubMed ID: 12000816; (described as c.695G>A) Iida et al. 2004. PubMed ID: 14767570; Qi et al. 2013. PubMed ID: 23842656; Couvé et al. 2014. PubMed ID: 25371412; Wong et al. 2016. PubMed ID: 27527340; Pandit et al. 2016. PubMed ID: 27539324; Olschwang et al. 1998. PubMed ID: 9829912). Functional studies suggest this variant decreases the ability of pVHL to bind to its expected substrate, hydroxylated hypoxia inducible factor (HIF-OH), compared to the wild type protein (Couvé et al. 2014. PubMed ID: 25371412). This variant has not been reported in a large population database, indicating this variant is rare. The VHL c.482G>A variant has been classified as pathogenic by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/). This variant is interpreted as pathogenic.
Clinical Genomics Labs, University Health Network	RCV000208848	SCV001950139	pathogenic	Von Hippel-Lindau syndrome	2017-02-22	no assertion criteria provided	clinical testing