NM_000551.4(VHL):c.452T>C (p.Ile151Thr) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 27, 2020
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:
RCV000705307.6

Allele description [Variation Report for NM_000551.4(VHL):c.452T>C (p.Ile151Thr)]

NM_000551.4(VHL):c.452T>C (p.Ile151Thr)

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.452T>C (p.Ile151Thr)
HGVS:
  • NC_000003.12:g.10146625T>C
  • NG_008212.3:g.9991T>C
  • NG_046756.1:g.4387T>C
  • NM_000551.4:c.452T>CMANE SELECT
  • NM_001354723.2:c.*18-3162T>C
  • NM_198156.3:c.341-3162T>C
  • NP_000542.1:p.Ile151Thr
  • NP_000542.1:p.Ile151Thr
  • LRG_322t1:c.452T>C
  • LRG_322:g.9991T>C
  • LRG_322p1:p.Ile151Thr
  • NC_000003.11:g.10188309T>C
  • NM_000551.3:c.452T>C
Protein change:
I151T
Links:
dbSNP: rs869025655
NCBI 1000 Genomes Browser:
rs869025655
Molecular consequence:
  • NM_001354723.2:c.*18-3162T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3162T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.4:c.452T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Chuvash polycythemia
Synonyms:
POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
Identifiers:
MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Name:
Von Hippel-Lindau syndrome (VHLS)
Synonyms:
VHL syndrome; Von Hippel-Lindau
Identifiers:
MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000834297Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 27, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

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

Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients.

Wu P, Zhang N, Wang X, Ning X, Li T, Bu D, Gong K.

J Hum Genet. 2012 Apr;57(4):238-43. doi: 10.1038/jhg.2012.10. Epub 2012 Feb 23.

PubMed [citation]
PMID:
22357542
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000834297.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This variant has been reported in numerous individuals affected with von Hippel-Lindau (VHL) syndrome (PMID: 10567493, 28469506, 17661816, 17024664, 11309459). This variant is also known as 665T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 428803). For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Ile151Ser and p.Ile151Phe) have been reported in several individuals affected with VHL syndrome (PMID: 22357542, 25078357). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 151 of the VHL protein (p.Ile151Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

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

Last Updated: May 1, 2024