3-10149822-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000551.4(VHL):c.499C>T(p.Arg167Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 3.37

Variant links:

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]

VHL links:

ENSG00000287086 (HGNC:):

ENSG00000287086 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 11) in uniprot entity VHL_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_000551.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-10149823-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 3-10149822-C-T is Pathogenic according to our data. Variant chr3-10149822-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149822-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4 link	c.499C>T	p.Arg167Trp	missense_variant	Exon 3 of 3	ENST00000256474.3	NP_000542.1	P40337-1A0A024R2F2
VHL	NM_198156.3 link	c.376C>T	p.Arg126Trp	missense_variant	Exon 2 of 2		NP_937799.1	P40337-2A0A0S2Z4K1
VHL	NM_001354723.2 link	c.*53C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1 link	n.828C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3 link	c.499C>T	p.Arg167Trp	missense_variant	Exon 3 of 3	1	NM_000551.4	ENSP00000256474.3		P40337-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251448

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727230

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome

Pathogenic:7

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The VHL c.499C>T (p.Arg167Trp) variant located in the alpha domain (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. This variant was found in 1/121114 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic VHL variant (0.0000208). Multiple publications have cited the variant in affected individuals ranging in phenotypes from VHL, renal carcinoma, hemangioblastoma and pheochromocytoma. Functional study, Schoenfield_2000, indicates the variant disrupts the elongin binding capability to VHL, a function that is essential for the tumor suppressor function of VHL. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

May 09, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 24, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 01, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2015

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant has been previously reported as disease-causing and was found twice in our study in patients with pheochromocytoma and family history of VHL. -

not provided

Pathogenic:5

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2018

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.499C>T; p.Arg167Trp variant (rs5030820), also reported as p.Arg238Trp, is a common pathogenic variant in individuals and families affected with Von Hippel-Lindau syndrome (Crossey 1994, Fishbein 2013, Peng 2017, Wang 2018, Zhang 2015). This variant is reported in ClinVar (Variation ID: 2218), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 167 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of elongin binding leading to VHL protein degradation (Leonardi 2011, Ohh 1999, Peng 2017, Schoenfeld 2000). Additionally, other amino acid substitutions at this codon (Gln, Gly, Leu, Pro) have been reported in individuals with Von Hippel-Lindau syndrome and are considered pathogenic (Crossey 1994, Zhang 2015). Based on available information, this variant is considered to be pathogenic. References: 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;3(8):1303-1308. Fishbein L et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450. Leonardi E et al. Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. Ann Hum Genet. 2011;75(4):483-496. Ohh M et al. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest. 1999;104(11):1583-1591. Peng S et al. Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. Oncotarget. 2017;8(24):38456-38465. Schoenfeld AR et al. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci U S A. 2000;97(15):8507-8512. Wang Y et al. Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. Oncol Lett. 2018;15(4):4882-4890. Zhang J et al. Clinical and genetic investigation of a multi-generational Chinese family afflicted with Von Hippel-Lindau disease. Chin Med J (Engl). 2015;128(1):32-38. -

May 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: Variant does not bind to elongin B or elongin C, resulting in an unstable protein that is rapidly degraded by the proteasome (Schoenfeld 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as p.(R208W) and p.(R238W); This variant is associated with the following publications: (PMID: 28873162, 14973063, 10205047, 9156047, 21519372, 23512077, 18836774, 12000816, 25119015, 19602254, 10900011, 7987306, 25563310, 27539324, 27527340, 27682873, 28944243, 28094316, 9829912, 22799452, 9829911, 8956040, 29124493, 25390905, 16042317, 29616089, 30522901, 30042107, 20233476, 29625052, 33745191, 32561571, 31589614, 30787465, 34377882, 34439168, 33828526, 34036514) -

Jul 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PM1, PM2, PS3_supporting, PS4_very_strong -

Pheochromocytoma

Pathogenic:2

Jan 20, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the VHL protein (p.Arg167Trp). This variant is present in population databases (rs5030820, gnomAD 0.0009%). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome and pheochromocytoma (PMID: 28873162, 14973063, 10205047, 9156047, 21519372, 23512077, 18836774, 12000816, 25119015, 19602254, 10900011, 7987306, 25563310, 27539324, 27527340, 27682873, 28944243, 28094316, 9829912, 22799452, 9829911, 8956040, 29124493, 25390905, 16042317, 29616089, 30522901, 30042107, 20233476, 29625052, 33745191, 32561571, 31589614, 30787465, 34377882, 34439168, 33828526, 34036514). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2218). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. 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, 9829911, 19574279, 21463266, 22799452). 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. -

May 09, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Chuvash polycythemia

Pathogenic:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

May 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 167 of the VHL protein (p.Arg167Trp). This variant is present in population databases (rs5030820, gnomAD 0.0009%). This missense change has been observed in individual(s) with von Hippel-Lindau syndrome and pheochromocytoma (PMID: 7987306, 9829912, 12000816, 15300849, 19464396, 23512077, 25563310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2218). 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: 14973063). 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, 9829911, 19574279, 21463266, 22799452). 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. -

Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma

Pathogenic:1

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 15, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R167W pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 499. The arginine at codon 167 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R167W mutation has been reported in multiple patients and families with von Hippel-Lindau (VHL) syndrome (Babinska A et al. Neuro Endocrinol. Lett. 2015 Dec;36:517-20; Vikkath N et al. Fam. Cancer. 2015 Dec;14:585-94; Lee JS et al. BMC Med. Genet. 2016 Jul;17:48; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607) and is considered one of the most common mutations in the VHL gene. Available evidence suggests that germline mutations at codon 167 convey an increased risk for developing pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug;3:1303-8; Chen F et al. Hum. Mut. 1995;5:66-75; Zbar B et al. Hum. Mutat. 1996;8:348-57; Olschwang S et al. Hum. Mut. 1998;12:424-30; Fishbein L et al. Ann. Surg. Oncol. 2013 May;20:1444-50). In one study of sporadic versus hereditary pancreatic islet cell tumors (ICTs), ICTs were found in 7 of 15 individuals (47%) with this mutation. In contrast, ICTs were found in only 1% of individuals with the p.Y98H founder mutation, suggesting an increased risk for ICTs in carriers of the p.R167W mutation (Erlic Z et al. Endocr. Relat. Cancer. 2010 Oct;17:875-83). The p.R167W mutation has been shown in transfection assays to prevent elongin-mediated stabilization of the VHL protein (Schoenfeld AR et al. Proc. Natl. Acad. Sci .USA. 2000 Jul;97:8507-12). Of note, this mutation is also designated as p.R238W (c.712C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.96

Loss of helix (P = 0.0138);.;

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over