NM_000551.3(VHL):c.598C>T (p.Arg200Trp) AND Erythrocytosis, familial, 2

Clinical significance:Pathogenic (Last evaluated: Mar 25, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
4 submissions [Details]
Record status:

Allele description [Variation Report for NM_000551.3(VHL):c.598C>T (p.Arg200Trp)]

NM_000551.3(VHL):c.598C>T (p.Arg200Trp)

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000551.3(VHL):c.598C>T (p.Arg200Trp)
  • NC_000003.12:g.10149921C>T
  • NG_008212.3:g.13287C>T
  • NM_000551.3:c.598C>T
  • NP_000542.1:p.Arg200Trp
  • LRG_322t1:c.598C>T
  • LRG_322:g.13287C>T
  • LRG_322p1:p.Arg200Trp
  • NC_000003.11:g.10191605C>T
  • NM_000551.2:c.598C>T
  • P40337:p.Arg200Trp
  • p.R200W:CGG>TGG
  • p.[Arg200Trp]
Protein change:
R200W; ARG200TRP
UniProtKB: P40337#VAR_005779; OMIM: 608537.0019; dbSNP: 28940298
NCBI 1000 Genomes Browser:
Allele Frequency:
0.0002, GO-ESP
Molecular consequence:
  • NM_000551.3:c.598C>T - missense variant - [Sequence Ontology: SO:0001583]


Erythrocytosis, familial, 2 (ECYT2)
Gene: 8056; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Age of onset:

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000022478OMIMno assertion criteria providedPathogenic
(Jun 19, 2011)
germlineliterature only

PubMed (11)
[See all records that cite these PMIDs]

Percy, M. J., McMullin, M. F., Treacy, M., Potter, M., Watson, W. H., Jowitt, S. N., Lappin, T. R. J. Identification of the Chuvash-type congenital polycythemia in patients of Asian and Western European ancestry. Blood 100: 660-only, 2002.,

SCV000053268LabCorpno assertion criteria providedPathogenic
(Apr 3, 2015)
germlineclinical testing

SCV000253857Invitaecriteria provided, single submitter
(Mar 25, 2016)
germlineclinical testing

Citation Link,

SCV000264776Division of Genomic Diagnostics,The Children's Hospital of Philadelphiano assertion criteria providedPathogenic
(Feb 26, 2016)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknown9not providednot providednot providednot providedclinical testing



Endemic polycythemia in Russia: mutation in the VHL gene.

Ang SO, Chen H, Gordeuk VR, Sergueeva AI, Polyakova LA, Miasnikova GY, Kralovics R, Stockton DW, Prchal JT.

Blood Cells Mol Dis. 2002 Jan-Feb;28(1):57-62.

PubMed [citation]

Localization of the gene responsible for familial benign polycythemia to chromosome 11q23.

Vasserman NN, Karzakova LM, Tverskaya SM, Saperov VN, Muchukova OM, Pavlova GP, Efimova NK, Vankina NN, Evgrafov OV.

Hum Hered. 1999 Jun;49(3):129-32.

PubMed [citation]
See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000022478.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (11)


Chuvash polycythemia, familial erythrocytosis-2 (263400) caused by this specific mutation, is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin (EPO; 133170) levels and ruled out a location of the gene on chromosome 11 as had been reported previously by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene (603348), which is located in 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a 598C-T transition in the VHL gene, resulting in an arg200-to-trp (R200W) mutation in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations.

Pastore et al. (2003) evaluated the role of the VHL gene in 8 children with a history of polycythemia and an elevated serum EPO level and identified 3 different germline VHL mutations in 4 of them. One child was homozygous for the R200W mutation, and another was compound heterozygous for the R200W mutation and a val130-to-leu mutation (V130L; 608537.0021). Of 2 sibs who were heterozygous for an asp126-to-tyr mutation (D126Y; 608537.0022), 1 fulfilled some criteria of VHL syndrome (193300); a pulmonary angioma was discovered at 10 years of age and treated by coil embolization without effect on the polycythemia, and at 15 years of age nephrectomy was performed for a subcapsular hemangioma.

Percy et al. (2002) observed homozygosity for the R200W mutation in 3 Bangladeshi families with Chuvash-type congenital polycythemia living in the United Kingdom.

By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago.

In a matched cohort study, Gordeuk et al. (2004) found that homozygosity for the 598C-T transition in the VHL gene was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF concentrations (p less than 0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of HIF1-alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in 598C-T homozygotes than in controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.

Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted.

Perrotta et al. (2006) found that the R200W missense mutation (598C-T) causing Chuvash polycythemia is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003).

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From LabCorp, SCV000053268.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000253857.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


This sequence change replaces arginine with tryptophan at codon 200 of the VHL protein (p.Arg200Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This pathogenic 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 worldwide its frequency is lower (rs28940298, 0.06%). 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). ClinVar contains an entry for this variant (Variation ID: 2232). Experimental studies have shown that this missense change disrupts the normal regulation of the hypoxia response pathway (PMID: 15574766, 19030229, 12415268). Mice homozygous for the Arg200Trp missense change develop polycythemia, mimicking the human disease. Of note, these mice were not predisposed to develop tumors (PMID: 17992257). For these reasons, this variant has been classified as Pathogenic for familial erythrocytosis, type 2. However, this missense change is not likely to confer risk for von Hippel-Lindau syndrome.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Division of Genomic Diagnostics,The Children's Hospital of Philadelphia, SCV000264776.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not providednot providedclinical testingnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided9not providednot providednot provided

Last Updated: Dec 17, 2016