3-10149921-C-T

Position:

chr3-10149921-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3

The NM_000551.4(VHL):c.598C>T(p.Arg200Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

VHL
NM_000551.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:3B:3O:2

Conservation

PhyloP100: 3.36

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000551.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-10149922-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 840517.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VHL	NM_000551.4 linkuse as main transcript	c.598C>T	p.Arg200Trp	missense_variant	3/3	ENST00000256474.3
VHL	NM_198156.3 linkuse as main transcript	c.475C>T	p.Arg159Trp	missense_variant	2/2
VHL	NM_001354723.2 linkuse as main transcript	c.*152C>T		3_prime_UTR_variant	3/3
VHL	NR_176335.1 linkuse as main transcript	n.927C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3 linkuse as main transcript	c.598C>T	p.Arg200Trp	missense_variant	3/3	1	NM_000551.4	P1	P40337-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251358

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000240

AC:

351

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000258

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:3Benign:3Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chuvash polycythemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: VHL c.598C>T (p.Arg200Trp) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain (IPR024048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251358 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in VHL causing Congenital Polycythemia (0.00021 vs 0.02), allowing no conclusion about variant significance. c.598C>T has been reported in the literature, primarily in the homozygous state, in multiple individuals affected with autosomal recessive Congenital Polycythemia, also referred to as familial erythrocytosis type 2 (Chuvash polycythemia) (e.g. Ang_2002, Pastore_2003, Percy_2003, Perrotta_2006). These data indicate that the variant is very likely to be associated with Congenital Polycythemia. In the heterozygous state, the variant is not expected to cause Von Hippel-Lindau Syndrome, as reported by multiple studies (e.g. Ang_2002, Pastore_2003, Gordeuk_2004, Miasnikova_2011). Experimental evidence demonstrated the variant reduced the affinity of VHL for HIF1-alpha, resulting in a reduced rate of ubiquitination under non-hypoxic conditions (Ang_2002). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Additionally, two ClinVar submitters (evaluation after 2014) cite it as likely benign for the condition of von Hippel-Lindau syndrome. Based on the evidence outlined above, the variant was classified as pathogenic for Congenital Polycythemia (familial erythrocytosis type 2). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 19, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Mar 23, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -

Von Hippel-Lindau syndrome

Uncertain:1Benign:3Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 10-29-2020 by Lab or GTR ID 507401. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with tryptophan at codon 200 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). **Functional studies have reported that this variant partially impacted VHL functions to varying degrees in binding and ubiquitination of HIF1alpha and the regulation of genes in the VHL-HIF and VHL-JAK2 pathways (PMID: 12415268, 15574766, 17992257, 19304954, 21685897) and partial to no impact on VHL binding to Elongin B, Elongin C, cullen and ROC/Rbx1 (PMID: 15574766, 19030229). Homozygous and compound heterozygous carriers of this variant have been reported in individuals affected with recessive Chuvash polycythemia and/or erythrocytosis (PMID: 11987242, 12415268, 12393546, 12702509, 12844285, 14726398, 15642664, 16210343, 23403324, 31132167), and haplotype analysis has found that one haplotype with this variant is a founder mutation for recessive Chuvash polycythemia (PMID: 14604959). However, these individuals and heterozygous family members are not known to exhibit multiple CNS and retinal hemangioblastomas and clear cell renal cell carcinomas that are characteristic of VHL hereditary cancer predisposition syndrome. One carrier family that was originally reported to be affected with isolated central nervous system hemangioblastoma (PMID: 17264095) was found to have this variant, p.Arg200Trp, in cis with p.Arg161Gln, and the haplotype of both variants in cis and in heterozygous state segregated with family members affected with CNS and retinal hemangioblastoma, clear cell renal cell carcinoma, pheochromocytoma and pancreatic neuroendocrine tumor (PMID: 25371412). Furthermore, functional study found that both variants in cis has an additive deleterious impact on VHL function in HIF1alpha peptide binding and deregulated expression of genes in the VHL-HIF pathway, suggesting the that the haplotype with both variants in cis is associated with autosomal dominant cancer predisposition (PMID: 25371412). This variant is common and has been identified in 57/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, the heterozygous state for this variant per se may not be associated with the autosomal dominant VHL hereditary cancer predisposition syndrome. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Arg200Trp variant in VHL has not been reported in the heterozygous state in individuals with paragangliomas, pheochromocytomas, or von Hippel-Lindau syndrome (Ang 2002 PMID: 12415268, Pastore 2003 PMID: 12393546, Gordeuk 2004 PMID: 14726398, Miasnikova 2011 PMID: 21606165) or in individuals with haemangioblastoma (Woodward 2007 PMID: 17264095). However, it is a well-established pathogenic variant in the homozygous state for autosomal recessive familial erythrocytosis, also known as Chuvash polycythemia (Ang 2002 PMID: 12415268, Gordeuk 2004 PMID: 14726398, Perrota 2006 PMID: 16210343, Mallik 2019 PMID: 31132167). It has also been identified in 0.065% (20/30604) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 2232). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg200Trp variant is uncertain as it relates to paragangliomas, pheochromocytomas, and von Hippel-Lindau syndrome. ACMG/AMP Criteria applied: PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2024	Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (PMID: 17992257); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Chuvash polycythemia, there is no evidence that it causes increased risk for von Hippel Lindau disease (PMID: 12393546, 12844285, 17264095, 21606165); This variant is associated with the following publications: (PMID: 27568332, 15574766, 25637381, 21876117, 21993671, 27518686, 11987242, 29489754, 33033909, 31132167, 35220195, 19030229, 23015148, 18836774, 24728327, 8956040, 25371412, 12415268, 21606165, 23403324, 9829912, 27651169, 12844285, 12393546, 14726398, 28400504, 28104701, 26556299, 29741264, 29790589, 16210343, 19494350, 31568062, 12702509, 30787465, 35142155, 34308104, 35767051, 17264095, 17992257, 38390862, 37317877, 37553354, 37833987, 36744932, 37946251) -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 200 of the VHL protein (p.Arg200Trp). This variant is present in population databases (rs28940298, gnomAD 0.07%). This variant has been observed in a family affected with von Hippel-Lindau syndrome without pheochromocytoma (PMID: 8956040), however, several studies have reported that this variant does not cause von Hippel-Lindau syndrome (PMID: 14726398, 21606165). It has also been observed to segregate with disease in related individuals. This variant is a known common cause of autosomal recessive, familial erythrocytosis type 2 (Chuvash polycythemia) in the Chuvash population of Russia and the Italian island of Ischia (PMID: 11987242, 19494350, 9058738, 16210343). In the Chuvash population, an estimated 1/20 individuals is a carrier of this variant (PMID: 12415268), while the worldwide carrier frequency is lower (rs28940298, 0.06%). ClinVar contains an entry for this variant (Variation ID: 2232). 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: 12415268, 15574766, 17992257, 19030229). For these reasons, this variant has been classified as Pathogenic. -

Nonpapillary renal cell carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2022

The p.R200W pathogenic mutation (also known as c.598C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 598. The arginine at codon 200 is replaced by tryptophan, an amino acid with dissimilar properties. The p.R200W alteration has been established as a founder mutation known to cause autosomal recessive Chuvash polycythemia, a condition characterized by increased red blood cell mass and high risk of peripheral thrombosis and cerebrovascular events (Ang SO et al. Nat. Genet. 2002 Dec;32:614-21; Liu E et al. Blood. 2004 Mar;103:1937-40; Gordeuk VR et al. Blood. 2004 May;103:3924-32; Tomasic NL et al. Haematologica. 2013 Apr;98(4):560-7). Functional studies on this alteration have yielded varying results on different aspects of VHL function linked to tumor formation or erythropoeisis, such as increased angiogenesis and increased hypoxia-inducible factor (HIF1a and HIF2a) expression, but retention of interaction with Elongin C (Ang SO et al. Nat. Genet. 2002 Dec;32:614-21; Rathmell WK et al. Cancer Res. 2004 Dec;64:8595-603; Hickey MM et al. J. Clin. Invest. 2007 Dec;117:3879-89; Hacker KE et al. PLoS ONE. 2008 Nov;3:e3801; Gordeuk VR et al. Blood. 2011 Nov;118:5278-82; Couvé S et al. Cancer Res. 2014 Nov;74:6554-64). Although two unrelated individuals with isolated hemangioblastoma have been reported as p.R200W heterozygotes, the vast majority of carriers are not affected with von Hippel Lindau (VHL) lesions (Pastore Y et al. Am. J. Hum. Genet. 2003 Aug;73:412-9; Woodward ER et al. Brain. 2007 Mar;130(Pt 3):836-42). In addition, one family with a clinical diagnosis of VHL was initially reported as being heterozygous for p.R200W (Olschwang S et al. Hum. Mutat. 1998;12:424-30); however, further studies of this family found that they actually carried two VHL alterations in cis (p.R200W and p.R161Q) (Couvé S et al. Cancer Res. 2014 Nov;74:6554-64). By evaluating structural stability in areas of domain interaction, pVHL-HIF1a binding ability, and expression gradients of genes regulated by VHL, the authors were able to demonstrate that the impact of the double mutant allele was more disruptive to structural and functional roles of VHL than the impact of either alteration alone. They proposed that the p.R200W alteration was not sufficient in causing classic VHL disease. 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 available evidence, p.R200W is interpreted as a disease-causing mutation. At this time, individuals who are heterozygous for the p.R200W alteration can be interpreted as carriers for Chuvash polycythemia; however, it is unlikely that this alteration causes von Hippel Lindau disease. -

Acute leukemia of ambiguous lineage

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jan 20, 2017

This is a missense alteration in which a C is replaced by a T at coding nucleotide 598 and is predicted to change an Arginine to a Tryptophan at amino acid codon 200. Classification criteria: PS1 (associated with Chuvash syndrome, only in homozygous state), PS3, PM2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.52

MVP

1.0

MPC

1.1

ClinPred

0.66

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.84

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