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NM_000551.4(VHL):c.397A>C (p.Thr133Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 6, 2015
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:
RCV000492347.3

Allele description [Variation Report for NM_000551.4(VHL):c.397A>C (p.Thr133Pro)]

NM_000551.4(VHL):c.397A>C (p.Thr133Pro)

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.397A>C (p.Thr133Pro)
HGVS:
  • NC_000003.12:g.10146570A>C
  • NG_008212.3:g.9936A>C
  • NG_046756.1:g.4332A>C
  • NM_000551.4:c.397A>CMANE SELECT
  • NM_001354723.2:c.*18-3217A>C
  • NM_198156.3:c.341-3217A>C
  • NP_000542.1:p.Thr133Pro
  • NP_000542.1:p.Thr133Pro
  • LRG_322t1:c.397A>C
  • LRG_322:g.9936A>C
  • LRG_322p1:p.Thr133Pro
  • NC_000003.11:g.10188254A>C
  • NM_000551.3:c.397A>C
Protein change:
T133P
Links:
dbSNP: rs1131690961
NCBI 1000 Genomes Browser:
rs1131690961
Molecular consequence:
  • NM_001354723.2:c.*18-3217A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3217A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.4:c.397A>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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000580986Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Mar 6, 2015) 		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, SCV000580986.6

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

Description

The p.T133P variant (also known as c.397A>C), located in coding exon 2 of the VHL gene, results from an A to C substitution at nucleotide position 397. The threonine at codon 133 is replaced by proline, an amino acid with highly similar properties. This variant has been described in two individuals with VHL (http://www.freidok.uni-freiburg.de/volltexte/3040/pdf/Dissertation_Hader_Claudia.pdf). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4300 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. Structural analysis indicates proline introduces local strain and is destabilizing to the VHL fold (Nguyen HC et al Structure 2015 Mar;23(3):441-449)(Internal Ambry Data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: May 1, 2024