NM_000551.4(VHL):c.407T>G (p.Phe136Cys) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Feb 10, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000589290.1

Allele description [Variation Report for NM_000551.4(VHL):c.407T>G (p.Phe136Cys)]

NM_000551.4(VHL):c.407T>G (p.Phe136Cys)

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.407T>G (p.Phe136Cys)
HGVS:
  • NC_000003.12:g.10146580T>G
  • NG_008212.3:g.9946T>G
  • NG_046756.1:g.4342T>G
  • NM_000551.3:c.407T>G
  • NM_000551.4:c.407T>GMANE SELECT
  • NM_001354723.2:c.*18-3207T>G
  • NM_198156.3:c.341-3207T>G
  • NP_000542.1:p.Phe136Cys
  • NP_000542.1:p.Phe136Cys
  • LRG_322t1:c.407T>G
  • LRG_322:g.9946T>G
  • LRG_322p1:p.Phe136Cys
  • NC_000003.11:g.10188264T>G
Protein change:
F136C
Links:
dbSNP: rs5030833
NCBI 1000 Genomes Browser:
rs5030833
Molecular consequence:
  • NM_001354723.2:c.*18-3207T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3207T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.3:c.407T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000551.4:c.407T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000697514Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 10, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

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

Citations

PubMed

Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of followup.

Benhammou JN, Boris RS, Pacak K, Pinto PA, Linehan WM, Bratslavsky G.

J Urol. 2010 Nov;184(5):1855-9. doi: 10.1016/j.juro.2010.06.102. Epub 2010 Sep 17.

PubMed [citation]
PMID:
20846682
PMCID:
PMC3164541

Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein.

Corn PG, McDonald ER 3rd, Herman JG, El-Deiry WS.

Nat Genet. 2003 Nov;35(3):229-37. Epub 2003 Oct 12.

PubMed [citation]
PMID:
14556007
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697514.1

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

Description

Variant summary: VHL c.407T>G variant affects a conserved nucleotide, resulting in amino acid change from an aromatic Phe to a medium sized polar Cys. 4/4 in-silico tools predict damaging outcome for this variant (Mutation Taster not captured due to low p-value). Hif1-alpha regulation has been strongly correlated with hemangioblastoma susceptibility; and functional studies have shown that F136C disrupts binding to Hif1-alpha and elongin C, and reduces binding affinity for TBP-1 (Corn_NG_2003). This variant is not found in 121412 control chromosomes; however, it has been cited in at least 5 patients with pheochromocytoma and 1 patient with haemangioblastoma of the CNS. Taken together, this is a disease variant and was classified as pathogenic.

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

Last Updated: Oct 25, 2021

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