NM_000551.4(VHL):c.445G>A (p.Ala149Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 30, 2017
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:: RCV002327073.2

Allele description [Variation Report for NM_000551.4(VHL):c.445G>A (p.Ala149Thr)]

NM_000551.4(VHL):c.445G>A (p.Ala149Thr)

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.445G>A (p.Ala149Thr)

HGVS:

NC_000003.12:g.10146618G>A
NG_008212.3:g.9984G>A
NG_046756.1:g.4380G>A
NM_000551.4:c.445G>AMANE SELECT
NM_001354723.2:c.*18-3169G>A
NM_198156.3:c.341-3169G>A
NP_000542.1:p.Ala149Thr
NP_000542.1:p.Ala149Thr
LRG_322t1:c.445G>A
LRG_322:g.9984G>A
LRG_322p1:p.Ala149Thr
NC_000003.11:g.10188302G>A
NM_000551.3:c.445G>A
P40337:p.Ala149Thr
p.[Ala149Thr]

Protein change:

A149T

Links:

UniProtKB: P40337#VAR_005740; dbSNP: rs587780077

NCBI 1000 Genomes Browser:

rs587780077

Molecular consequence:

NM_001354723.2:c.*18-3169G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3169G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.445G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002635995	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 30, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11865071, 15300849, 23102223 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002635995

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 30, 2017)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diverse effects of mutations in exon II of the von Hippel-Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity.

Hansen WJ, Ohh M, Moslehi J, Kondo K, Kaelin WG, Welch WJ.

Mol Cell Biol. 2002 Mar;22(6):1947-60.

PubMed [citation]

PMID:: 11865071
PMCID:: PMC135590

Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions.

Gallou C, Chauveau D, Richard S, Joly D, Giraud S, Olschwang S, Martin N, Saquet C, Chrétien Y, Méjean A, Correas JM, Benoît G, Colombeau P, Grünfeld JP, Junien C, Béroud C.

Hum Mutat. 2004 Sep;24(3):215-24. Erratum in: Hum Mutat. 2004 Nov;24(5):435-6.

PubMed [citation]

PMID:: 15300849

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002635995.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.A149T pathogenic mutation (also known as c.445G>A), located in coding exon 2 of the VHL gene, results from a G to A substitution at nucleotide position 445. The alanine at codon 149 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with a clinical diagnosis of von Hippel-Lindau (VHL) syndrome (Gallou C et al. Hum. Mutat., 2004 Sep;24:215-24; Ambry internal data). Functional analysis demonstrated a reduced affinity for and decreased ability to ubiquinate HIF-1α, a critical transcription factor activated during hypoxia, and regulated by VHL (Hansen WJ et al. Mol. Cell. Biol., 2002 Mar;22:1947-60). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). In addition, another alteration at this same amino acid position, p.A149S, has been shown to segregate with disease in two large VHL families (Mete T, et al. Endocrine 2014;45(1):128-35; Atuk NO, et al. J. Clin. Endocrinol. Metab. 1998;83(1):117-20). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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