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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000274633	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10587522, 12202531, 18209888, 19336503, 20151405, 8550742, 8730290, 8956040 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000274633

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 14, 2016)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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