rs5030821

Positions:

• chr3-10149823-G-A
• chr3-10149823-G-C
• chr3-10149823-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PS3_Supporting PM6 PP3 PM2_Supporting PS4

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: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:18 U:1
• Conservation: PhyloP100: 7.78

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.500G>A	p.Arg167Gln	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.377G>A	p.Arg126Gln	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2	c.*54G>A		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.829G>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.500G>A	p.Arg167Gln	missense_variant	3/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251434 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	May 10, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	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). -
Pathogenic, criteria provided, single submitter	curation	CIViC knowledgebase, Washington University School of Medicine	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	May 21, 2023	- -

not provided Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 11, 2016

- -

Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 22, 2024

- -

Pheochromocytoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2023

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). 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 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

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, 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 mutation has also been reported in some literature as p.R238Q ( c.713G>A). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.97		Gain of ubiquitination at K171 (P = 0.0397);.;
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5030821; hg19: chr3-10191507; COSMIC: COSV56547786;