TPMT A154T - GET-Evidence

Curation:
Currentness:

TPMT A154T

(TPMT Ala154Thr)


Short summary

Usually this variant is found in combination Y240C, forming the TPMT*3A variant. When alone, this variant produces the *3B variant. Both variants are associated with loss of thiopurine methyltransferase (TPMT) activity. Inability to metabolize thiopurine drugs can lead to severe adverse reactions. Heterozygotes may be advised to take a reduced dosage due to reduced metabolism of the drug.

Variant evidence
Computational 1

Other variants in this gene cause the disease

Functional -
Case/Control 5

Well-established

Familial -
 
Clinical importance
Severity 4

Potentially lethal adverse reaction

Treatability 5

Halve dosage for carriers; avoid thiopurines or very low doses for homozygotes.

Penetrance 2

Homozygotes at severe risk, but most people never need to take thiopurine drugs

 

Impact

Low clinical importance, Likely pharmacogenetic

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr6:18139228: 2.8% (302/10756) in EVS
  • T @ chr6:18247206: 3.1% (4/128) in GET-Evidence
  • Frequency shown in summary reports: 2.8% (302/10756)

Publications
 

Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit. 2004 Apr;26(2):186-91. Review. PubMed PMID: 15228163.

 

Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004 Jul;41(Pt 4):294-302. Review. PubMed PMID: 15298741.

Authors report 50% enzyme activity for carriers and none for homozygotes. Report that a 50% dose of thiopurines results in normal response for carriers.

Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, Klein TE. Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenet Genomics. 2010 Jun;20(6):401-5. PubMed PMID: 20154640.

A review of the TPMT alleles.

Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol. 2010 Apr;63(4):288-95. PubMed PMID: 20354201.

Homozygotes are at severe risk of developing myelosuppression if treated with standard doses of thiopurine drugs, and deaths have occurred. Never-the-less, accounts for only 5–10% of adverse reactions to thiopurine drugs and about 30% cases of neutropenia. Non-genetic factors such as diet, drug interactions, and genetic variation of other enzymes involved in thiopurine drug metabolism have also been implicated.

Genomes
 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
hom T @ chr6:18139228

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het T @ chr6:18139228

 

 

GS19735 - var-GS19735-1100-36-ASM
het T @ chr6:18247207

 

Other external references
 

    dbSNP
  • rs1800460
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.667 (possibly damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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