rs5030821
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM2_SupportingPS4PM1PS3_SupportingPM6
This summary comes from the ClinGen Evidence Repository: The NM_000551.4(VHL):c.500G>A (p.Arg167Gln) variant in VHL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 167. This missense mutation has been identified in at least 19 unrelated individuals with von Hippel-Lindau disease. Mostly VHL Type 2 or 2B phenotypes are noted. However, some publications describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used (https://civicdb.org): 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4). Multiple publications (PMID:15574766, PMID:19030229) support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a (PS3_Supporting). A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID:30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo (PM6). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Arg167 is one of the germline hotspots outlined by the VHL VCEP, and it is in the Elongin binding domain (PM1). The computational predictor REVEL gives a score of 0.874, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). Per VHL VCEP specifications, this code is applied when the REVEL score is >=0.6. (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020454/MONDO:0008667/078
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.500G>A | p.Arg167Gln | missense_variant | Exon 3 of 3 | ENST00000256474.3 | NP_000542.1 | |
| VHL | NM_198156.3 | c.377G>A | p.Arg126Gln | missense_variant | Exon 2 of 2 | NP_937799.1 | ||
| VHL | NM_001354723.2 | c.*54G>A | 3_prime_UTR_variant | Exon 3 of 3 | NP_001341652.1 | |||
| VHL | NR_176335.1 | n.829G>A | non_coding_transcript_exon_variant | Exon 4 of 4 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:8
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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. -
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The NM_000551.4(VHL):c.500G>A (p.Arg167Gln) variant in VHL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 167. This missense mutation has been identified in at least 19 unrelated individuals with von Hippel-Lindau disease. Mostly VHL Type 2 or 2B phenotypes are noted. However, some publications describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used (https://civicdb.org): 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4). Multiple publications (PMID: 15574766, PMID: 19030229) support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a (PS3_Supporting). A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID: 30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo (PM6). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Arg167 is one of the germline hotspots outlined by the VHL VCEP, and it is in the Elongin binding domain (PM1). The computational predictor REVEL gives a score of 0.874, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). Per VHL VCEP specifications, this code is applied when the REVEL score is >=0.6. (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). -
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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). -
not provided Pathogenic:6Uncertain:1
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The VHL c.500G>A; p.Arg167Gln variant (rs5030821, ClinVar variation ID: 2216), also reported as p.Arg238Gln, is one of the most common pathogenic variants in hereditary von Hippel Lindau (VHL) disease (Ding 2014) and has been reported in numerous individuals and families with diagnoses or clinical suspicion of VHL disease (Chen 1995, Couve 2014, Crossey 1994, Lee 2016, Park 2015, Sriphrapradang 2017, Tomita 2001). In several families, this variant has been observed to cosegregate with disease (Couve 2014, Lee 2016, Tomita 2001). In cultured cells, the p.Arg167Gln variant exhibits diminished interaction with binding partners (Hacker 2008, Rathmell 2004), while a p.Arg167Gln mouse model develops renal neoplasias similar to human VHL patients (Lee 2009). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.874). Additionally, another variant at this codon (p.Arg167Trp) has been reported in numerous individuals with VHL disease and is considered pathogenic (Chen 1995, Crossey 1994, Lee 2016). Based on available information, the p.Arg167Gln variant is considered to be pathogenic. References: Chen F et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75. PMID: 7728151. Couve S et al. Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis. Cancer Res. 2014 Nov 15;74(22):6554-64. PMID: 25371412. Crossey PA et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994 Aug;3(8):1303-8. PMID: 7987306. Ding Z et al. Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein. Cancer Res. 2014 Jun 1;74(11):3127-36. PMID: 24755468. Hacker KE et al. VHL type 2B mutations retain VBC complex form and function. PLoS One. 2008;3(11):e3801. PMID: 19030229. Lee CM et al. VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene. 2009 Apr 9;28(14):1694-705. PMID: 19252526. Lee JS et al. Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-a binding site missense mutations elevate age-specific risk for CNS hemangioblastoma. BMC Med Genet. 2016 Jul 20;17(1):48. PMID: 27439424. Park TY et al. Clinical features of pancreatic involvement in von Hippel-Lindau disease: a retrospective study of 55 cases in a single center. Scand J Gastroenterol. 2015 Mar;50(3):360-7. PMID: 25562111. Rathmell WK et al. In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations. Cancer Res. 2004 Dec 1;64(23):8595-603. PMID: 15574766. Sriphrapradang C et al. Genotype-Phenotype Correlation in Patients With Germline Mutations of VHL, RET, SDHB, and SDHD Genes: Thai Experience. Clin Med Insights Endocrinol Diabetes. 2017 Apr 20;10:1179551417705122. PMID: 28469506. Tomita N et al. A family with von Hippel-Lindau disease revealed by pheochromocytoma. Hypertens Res. 2001 Jul;24(4):445-50. PMID: 11510758. -
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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 et al., 2004; Hacker et al., 2008; Lee et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.713G>A, p.(R238Q); This variant is associated with the following publications: (PMID: 21528828, 24352051, 18836774, 20151405, 19030229, 23990666, 29124493, 29616089, 11354926, 31447099, 19602254, 15574766, 12000816, 25371412, 7987306, 12114495, 17661816, 12202531, 21386872, 22517557, 19464396, 24581539, 24301059, 19215943, 25562111, 15300849, 24712571, 17264095, 9106522, 19252526, 25563310, 27539324, 27527340, 7784063, 28114281, 8730290, 28469506, 8956040, 10567493, 17024664, 20518900, 10205047, 29871882, 11510758, 29625052, 32742360, 33745191, 34122352, 32561571, 30787465, 35260109, 34923986) -
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Chuvash polycythemia Pathogenic:1
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Pheochromocytoma Pathogenic:1
The missense variant c.500G>A(p.Arg167Gln) in VHL gene has been observed in heterozygous state in multiple individual(s) with pheochromocytoma and VHL related disorders (Fagundes et. al., 2019; Tung et. al., 2022; Ciotti et. al., 2009). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects VHL function (Bangiyeva et. al., 2009). The p.Arg167Gln variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0004% in gnomAD exomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic (multiple submitters). The amino acid change p.Arg167Gln in VHL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 167 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 167 of the VHL protein (p.Arg167Gln). This variant is present in population databases (rs5030821, gnomAD 0.0009%). This missense change has been observed in individual(s) with pheochromocytoma, hemangioblastoma of the central nervous system and spinal cord, renal cell carcinoma, and pancreatic cyst (PMID: 7987306, 8956040, 10567493, 12000816, 15300849, 19464396). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg238Gln. ClinVar contains an entry for this variant (Variation ID: 2216). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 15574766, 19030229, 19252526, 19602254). This variant disrupts the p.Arg167 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7987306, 8730290). 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. -
Hereditary cancer-predisposing syndrome Pathogenic:1
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 variant 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, substitutions at codon 167 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 variant has also been reported in some literature as p.R238Q ( c.713G>A). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at