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NM_000551.4(VHL):c.473T>C (p.Leu158Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 29, 2023
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:
RCV000492547.5

Allele description [Variation Report for NM_000551.4(VHL):c.473T>C (p.Leu158Pro)]

NM_000551.4(VHL):c.473T>C (p.Leu158Pro)

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.473T>C (p.Leu158Pro)
Other names:
p.L158P:CTG>CCG
HGVS:
  • NC_000003.12:g.10149796T>C
  • NG_008212.3:g.13162T>C
  • NG_046756.1:g.7558T>C
  • NM_000551.4:c.473T>CMANE SELECT
  • NM_001354723.2:c.*27T>C
  • NM_198156.3:c.350T>C
  • NP_000542.1:p.Leu158Pro
  • NP_000542.1:p.Leu158Pro
  • NP_937799.1:p.Leu117Pro
  • LRG_322t1:c.473T>C
  • LRG_322:g.13162T>C
  • LRG_322p1:p.Leu158Pro
  • NC_000003.11:g.10191480T>C
  • NM_000551.3:c.473T>C
  • P40337:p.Leu158Pro
  • p.[Leu158Pro]
Protein change:
L117P
Links:
UniProtKB: P40337#VAR_005748; dbSNP: rs121913346
NCBI 1000 Genomes Browser:
rs121913346
Molecular consequence:
  • NM_001354723.2:c.*27T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.473T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.350T>C - 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
SCV000580975Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Mar 29, 2023) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV000580975.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.L158P pathogenic mutation (also known as c.473T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 473. The leucine at codon 158 is replaced by proline, an amino acid with similar properties. This variant has been reported in several families with VHL (Whaley JM et al. Am. J. Hum. Genet. 1994 Dec;55(6):1092-102; Olschwang S et al. Hum Mutat. 1998;12(6):424-30; Ambry internal data). Of note, this variant may be referred to as c.686T>C in older literature.This alteration has been shown to disrupt the ability of the chaperone complex elongin-BC to bind to the VHL protein which leads to improper protein folding (McClellan AJ et al. Cell. 2005 Jun 3;121(5):739-48). One in vitro functional study showed that this variant produced an unstable VHL protein. The authors also show that a p.L158P mutant cell line displayed the same disorganized, fibroblastic morphology as seen in other VHL mutants, and classified this variant as a type 1 VHL mutation (Bangiyeva V et al.. BMC Cancer. 2009 Jul 14;9:229). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024