NM_000551.4(VHL):c.486C>G (p.Cys162Trp) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 5, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000567560.1

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]
Observations:
1

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
SCV000664755Ambry Geneticscriteria provided, single submitter
Pathogenic
(Sep 5, 2017)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.

Gallou C, Joly D, Méjean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chrétien Y, Maréchal JM, Richard S, Junien C, Béroud C.

Hum Mutat. 1999;13(6):464-75.

PubMed [citation]
PMID:
10408776

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system.

Gläsker S, Bender BU, Apel TW, Natt E, van Velthoven V, Scheremet R, Zentner J, Neumann HP.

J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):758-62.

PubMed [citation]
PMID:
10567493
PMCID:
PMC1736691
See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000664755.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (13)

Description

The p.C162W pathogenic mutation (also known as c.486C>G), located in coding exon 3 of the VHL gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in multiple individuals with personal and/or family history consistent with von Hippel-Lindau disease (Chen F et al. Hum. Mutat., 1995;5:66-75; Glavac D et al. Hum. Genet., 1996 Sep;98:271-80; Olschwang S et al. Hum. Mutat., 1998;12:424-30; Stolle C et al. Hum. Mutat., 1998;12:417-23; Gallou C et al. Hum. Mutat., 1999;13:464-75; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr., 1999 Dec;67:758-62; Dollfus H et al. Invest. Ophthalmol. Vis. Sci., 2002 Sep;43:3067-74; Cho HJ et al. J. Korean Med. Sci., 2009 Feb;24:77-83; Wong M et al. Chin J Cancer, 2016 Aug;35:79). Further, one study has shown that this pathogenic mutation stabilized a variant of protein kinase C that suppresses epithelial cell polarization to the levels seen in the presence of a proteasome inhibitor suggesting this alteration results in a dominant-negative effect (Iturrioz X et al. FEBS Lett., 2007 Apr;581:1397-402). In addition, at least two other missense pathogenic mutations have been reported at this location including p.C162F (c.485G>T) and p.C162R (c.484T>C) (Hoffman MA et al. Hum. Mol. Genet., 2001 May;10:1019-27; Wong M et al. Chin J Cancer, 2016 Aug;35:79). Based on the available evidence, p.C162W is classified as a pathogenic mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Oct 30, 2021

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