NM_000551.4(VHL):c.486C>G (p.Cys162Trp) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Oct 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000226031.4

Allele description [Variation Report for NM_000551.4(VHL):c.486C>G (p.Cys162Trp)]

NM_000551.4(VHL):c.486C>G (p.Cys162Trp)

Genes:
LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [Gene]
VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.3
Genomic location:
Preferred name:
NM_000551.4(VHL):c.486C>G (p.Cys162Trp)
HGVS:
  • NC_000003.12:g.10149809C>G
  • NG_008212.3:g.13175C>G
  • NG_046756.1:g.7571C>G
  • NM_000551.3:c.486C>G
  • NM_000551.4:c.486C>GMANE SELECT
  • NM_001354723.2:c.*40C>G
  • NM_198156.3:c.363C>G
  • NP_000542.1:p.Cys162Trp
  • NP_000542.1:p.Cys162Trp
  • NP_937799.1:p.Cys121Trp
  • LRG_322t1:c.486C>G
  • LRG_322:g.13175C>G
  • LRG_322p1:p.Cys162Trp
  • NC_000003.11:g.10191493C>G
  • P40337:p.Cys162Trp
  • p.[Cys162Trp]
Protein change:
C121W
Links:
UniProtKB: P40337#VAR_005756; dbSNP: rs5030622
NCBI 1000 Genomes Browser:
rs5030622
Molecular consequence:
  • NM_001354723.2:c.*40C>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.3:c.486C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000551.4:c.486C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.363C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Erythrocytosis, familial, 2 (ECYT2)
Synonyms:
POLYCYTHEMIA, CHUVASH TYPE; POLYCYTHEMIA, VHL-DEPENDENT
Identifiers:
MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Name:
Von Hippel-Lindau syndrome (VHLS)
Synonyms:
VHL syndrome; Von Hippel-Lindau
Identifiers:
MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000285499Invitaecriteria provided, single submitter
Pathogenic
(Oct 19, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.

Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G.

Hum Mutat. 1998;12(6):424-30.

PubMed [citation]
PMID:
9829912

Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.

Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, BĂ©roud C, Dureau P, Gaudric A, Landais P, Richard S.

Invest Ophthalmol Vis Sci. 2002 Sep;43(9):3067-74.

PubMed [citation]
PMID:
12202531
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000285499.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces cysteine with tryptophan at codon 162 of the VHL protein (p.Cys162Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with von Hippel-Lindau disease (PMID: 9829912, 12202531, 19270817, 25867206) and renal cell carcinoma (PMID: 10408776, 15177666). Currently there is insufficient evidence to conclude whether this variant segregates with disease or not. This variant is also known in the literature as c.699C>G (p.Cys233Trp). ClinVar contains an entry for this variant (Variation ID: 223227). One experimental study has shown that this missense change disrupts the VHL-dependent proteasomal degradation failing to induce ubiquination of targeted proteins (PMID: 17350623). This variant disrupts the p.Cys162 amino acid residue in VHL. Other variant that disrupt this residue have been observed in affected individuals (PMID: 11331612), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 30, 2021

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