NM_000551.4(VHL):c.452T>C (p.Ile151Thr) AND Von Hippel-Lindau syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 26, 2019
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:
RCV000590238.3

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:
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
SCV000697512Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Feb 26, 2019)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

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

Genotype-phenotype correlations in von Hippel-Lindau disease.

Ong KR, Woodward ER, Killick P, Lim C, Macdonald F, Maher ER.

Hum Mutat. 2007 Feb;28(2):143-9.

PubMed [citation]
PMID:
17024664
See all PubMed Citations (11)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697512.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

Variant summary: The variant, VHL c.452T>C (p.Ile151Thr, also known as c.655T>C, p.Ile222Thr) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain and von Hippel-Lindau disease tumour suppressor, beta/alpha domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246370 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Hes_2007, Ong_2007, Sriphrapradang_2017, Krauss_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence assessing the variant effect on the downstream signaling mechanism of VHL but does not allow convincing conclusions about the variant effect (Walmsley_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: May 1, 2024