NM_000551.3(VHL):c.571C>G (p.His191Asp) AND Erythrocytosis, familial, 2

Clinical significance:Pathogenic (Last evaluated: Apr 22, 2013)

Review status:(0/4)0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000002323.1

Allele description [Variation Report for NM_000551.3(VHL):c.571C>G (p.His191Asp)]

NM_000551.3(VHL):c.571C>G (p.His191Asp)

Gene:
VHL:von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.3
Genomic location:
Preferred name:
NM_000551.3(VHL):c.571C>G (p.His191Asp)
HGVS:
  • NC_000003.12:g.10149894C>G
  • NG_008212.3:g.13260C>G
  • NM_000551.3:c.571C>G
  • NP_000542.1:p.His191Asp
  • NC_000003.11:g.10191578C>G
Protein change:
H191D; HIS191ASP
Links:
OMIM: 608537.0024; dbSNP: 28940301
NCBI 1000 Genomes Browser:
rs28940301
Molecular consequence:
  • NM_000551.3:c.571C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Erythrocytosis, familial, 2 (ECYT2)
Synonyms:
ERYTHROCYTOSIS, AUTOSOMAL RECESSIVE BENIGN; POLYCYTHEMIA, CHUVASH TYPE; POLYCYTHEMIA, VHL-DEPENDENT; See all synonyms [MedGen]
Identifiers:
Gene: 8056; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Age of onset:
Neonatal/infancy

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000022481OMIMno assertion criteria providedPathogenic
(Apr 22, 2013)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.

Pastore Y, Jedlickova K, Guan Y, Liu E, Fahner J, Hasle H, Prchal JF, Prchal JT.

Am J Hum Genet. 2003 Aug;73(2):412-9. Epub 2003 Jul 3. Erratum in: Am J Hum Genet. 2004 Mar;74(3):598.

PubMed [citation]
PMID:
12844285
PMCID:
PMC1180379

Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.

Russell RC, Sufan RI, Zhou B, Heir P, Bunda S, Sybingco SS, Greer SN, Roche O, Heathcote SA, Chow VW, Boba LM, Richmond TD, Hickey MM, Barber DL, Cheresh DA, Simon MC, Irwin MS, Kim WY, Ohh M.

Nat Med. 2011 Jun 19;17(7):845-53. doi: 10.1038/nm.2370.

PubMed [citation]
PMID:
21685897
PMCID:
PMC3221316

Details of each submission

From OMIM, SCV000022481.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In a 17-year-old Croatian boy who presented at age 1 year with familial erythrocytosis (263400), Pastore et al. (2003) identified homozygosity for a 571C-G transversion in the VHL gene, resulting in a his191-to-asp (H191D) change.

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the H191D and R200W (608537.0019) VHL mutations result in polycythemia. In vitro studies showed that the H191D 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.

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

Last Updated: Feb 27, 2015