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NM_000551.4(VHL):c.496G>T (p.Val166Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 14, 2016
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000220823.4

Allele description [Variation Report for NM_000551.4(VHL):c.496G>T (p.Val166Phe)]

NM_000551.4(VHL):c.496G>T (p.Val166Phe)

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.496G>T (p.Val166Phe)
HGVS:
  • NC_000003.12:g.10149819G>T
  • NG_008212.3:g.13185G>T
  • NG_046756.1:g.7581G>T
  • NM_000551.4:c.496G>TMANE SELECT
  • NM_001354723.2:c.*50G>T
  • NM_198156.3:c.373G>T
  • NP_000542.1:p.Val166Phe
  • NP_000542.1:p.Val166Phe
  • NP_937799.1:p.Val125Phe
  • LRG_322t1:c.496G>T
  • LRG_322:g.13185G>T
  • LRG_322p1:p.Val166Phe
  • NC_000003.11:g.10191503G>T
  • NM_000551.3:c.496G>T
  • P40337:p.Val166Phe
Protein change:
V125F; VAL166PHE
Links:
UniProtKB: P40337#VAR_005759; OMIM: 608537.0013; dbSNP: rs104893825
NCBI 1000 Genomes Browser:
rs104893825
Molecular consequence:
  • NM_001354723.2:c.*50G>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.496G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.373G>T - 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; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000274633Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 14, 2016) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein.

Ohh M, Takagi Y, Aso T, Stebbins CE, Pavletich NP, Zbar B, Conaway RC, Conaway JW, Kaelin WG Jr.

J Clin Invest. 1999 Dec;104(11):1583-91.

PubMed [citation]
PMID:
10587522
PMCID:
PMC481054

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

Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Béroud 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 (8)

Details of each submission

From Ambry Genetics, SCV000274633.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The p.V166F pathogenic mutation (also known as c.496G>T), located in coding exon 3 of the VHL gene, results from a G to T substitution at nucleotide position 496. The valine at codon 166 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of Von Hippel-Lindau syndrome; including personal histories of pheochromocytoma (Cruz JB et al, Arq Bras Endocrinol Metabol 2007 Dec; 51(9):1463-7; Gross DJ et al. J. Clin. Endocrinol. Metab. 1996 Jan; 81(1):147-9; Nordstrom-O'Brien M et al. Hum. Mutat. 2010 May;31(5):521-37; Maher ER et al. J. Med. Genet. 1996 Apr; 33(4):328-32); head and neck paraganglioma, pheochromocytoma and CNS hemangiblastoma (Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94(6):1938-44); as well as retinal hemangioblastoma (Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep; 43(9):3067-74). In addition, in vitro experiments suggest that mutations affecting residue 166, such as p.V166F, lead to a partial loss of elongin-binding activity (Ohh M et al. J. Clin. Invest. 1999 Dec; 104(11):1583-91). Of note, this alteration is also referred to as 709G>T in published literature. This alteration has been determined to be de novo in an affected individual in our cohort (Ambry internal data). Based on the available evidence, p.V166F is classified as a pathogenic mutation.

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

Last Updated: Sep 29, 2024