Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 10 annotations for this variant. Register or sign in to see them.
VIP Variant in TPMT
TPMT cDNA from a TPMT-deficient patient who had developed severe hematopoietic toxicity during mercaptopurine therapy was cloned. Sequencing of the mutant TPMT cDNA revealed a single point mutation (G238->C, where 238 refers to the coding sequence), leading to an amino acid substitution at codon 80 (Ala80->Pro). When assessed in a yeast heterologous expression system, this mutation led to a 100-fold reduction in TPMT catalytic activity relative to the wild-type cDNA, despite a comparable level of mRNA expression. *2 is a relatively rare allele. It is degraded rapidly when transiently expressed in both yeast and mammalian cells.
This allele results in low TPMT protein and catalytic activity in blood and cell culture. Therefore, if patients who carry this allele are treated with standard dose of thiopurine drugs, they might have increased 6-TGN level and develop drug-related toxicity such as myelosuppression.
Note: The TPMT gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Appendix
*1. TPMT:2
| Genomic Variant & GenBank ID:* | 9,002,206 C>G on NT_007592.14 |
|---|---|
| mRNA Variant & GenBank ID:* | 393 G>C on NM_000367.2 |
| Protein Variant & GenBank ID:* | 80 Ala>Pro on NP_000358.1 |
| GoldenPath Position: | Chr6:18,251,934 (hg18) |
Other Variants of Known or Suspected Functional Significance
| Allele | Common Name(s) | Variant Information |
|---|---|---|
| TPMT*3D | 292G>T+460G>A+719A>G (Glu98Stop+Ala154Thr+Tyr240Cys) | Identified in a clinical sample demonstrating intermediate TPMT activity [Article:9246020]. |
| TPMT*5 | 146T>C(Leu49Ser) | Present in a patient (*1/*5) demonstrating intermediate TPMT activity [Article:9246020]. When \*5 was expressed in COS-1 cells, enzyme activity level was almost undetectable [Article:16220112]. |
| TPMT*6 | 539A>T(Tyr180Phe) | Present in a Korean subject demonstrating low RBC TPMT activity [PMID: 9246020\]. When \*6 was expressed in COS-1 cells, enzyme activity level was about a third of wild-type [Article:16220112]. |
| TPMT*7 | 681T>G(His227Gln) | First detected in a European subject (*1/*7) who was an intermediate methylator [Article:9711875]. Present in a European patient (*1/*7) treated with azathiopurine who developed severe leukopenia. In a recombinant yeast expression system, intrinsic clearance rate for the \*7 allele was about 10-fold lower than that for \*1 \PMID: 13679074]. In another report, enzyme activity when expressed in COS-1 cells was essentially at wild-type level [Article:16220112]. |
| TPMT*8 | 644G>A(Arg215His) | \*8 found in one African-American heterozygote (*1/*8) who demonstrated intermediate TPMT activity [Article:9931346]. |
| TPMT*9 | 356A>C(Lys119Thr) c.356A>C(p.Lys119Thr) | \*1/*9 German-Caucasian subject had intermediate TPMT activity [Article:15226673] . Noted in a Caucasian subject with intermediate TPMT activity [Article:18602085]. However, when \*9 was expressed in vitro, the catalytic activity of the variant protein was not significantly affected PMIDs: 16220112, 18602085, and \*9 was found in one subject defined as a normal methylator [Article:15226673]. |
| TPMT*10 | 430G>C(Gly144Arg) | Present in a patient (*1/*10) treated with azathiopurine who developed severe leukopenia. In a recombinant yeast expression system, intrinsic clearance rate for the \*10 allele was about 3.5-fold lower than that for \*1 [Article:13679074]. In another report, expression in COS-1 cells resulted in enzyme activity at about 70% that of wild-type [Article:16220112]. |
| TPMT*11 | 395G>A(Cys132Tyr) | Identified in a patient of Spanish origin (*3A/*11) who demonstrated very low RBC TPMT activity [Article:12835738]. Expression of the \*11 allele in COS-1 cells resulted in low enzyme activity [Article:16220112]. |
| TPMT*12 | 374C>T(Ser125Leu) | Present in an azathiopurine-treated patient (*1/*12) who developed severe leukopenia. In a recombinant yeast expression system, intrinsic clearance rate for the \*12 allele was about 3.5-fold lower than that for \*1 [Article:13679074]. In another report, expression in COS-1 cells resulted in enzyme activity of about 40% of wild-type [Article:16220112]. |
| TPMT*13 | 83A>T(Glu28Val) | Identified in an azathiopurine-treated patient (*1/*13) who developed severe leukopenia. In vitro, enzyme activity for the \*13 allele was about 60% that of \*1 [Article:13679074, 16220112]. |
| TPMT*14 | 1A>G(Met1Val) | Identified in a Northern European patient who demonstrated low RBC TPMT activity [Article:15083071]. |
| TPMT*15 | intron VII/exon VIII (IVS7-1G>A)(splice site) | Identified in a Northern European patient who demonstrated low RBC TPMT activity [Article:15083071]. |
| TPMT*16 | 488G>A(Arg163His) | In vitro, decreased the intrinsic clearance value with respect to 6-TG methylation three-fold. A Morrocan patient (*1/*16) was an intermediate methylator [Article:15652243].*1/*16 German-Caucasian heterozygote had intermediate TPMT activity [Article:15226673]. |
| TPMT*17 | 124C>G(Gln42Glu) | \*1/*17 German-Caucasian subject had intermediate TPMT activity [Article:15226673]. |
| TPMT*18 | 211G>A(Gly71Arg) | \*1/*18 German-Caucasian subject had intermediate TPMT activity [Article:15226673]. |
| TPMT*20 (vs.1-[Article:16946561]) (this is termed \*24 in [Article:18708949]) | 106G>A(Gly36Ser) | Identified in a Japanese subject (TPMT status not indicated) [Article:16946561]. When expressed in COS-7 cells, the intrinsic clearance of 6-TG S-methylation was less than 10% of wild-type TPMT [Article:18708949]. |
| TPMT*20 (vs.2\- [Article:16917910]) | 712A>G (Lys238Glu)(c.712A>G) | Identified in a Caucasian subject with intermediate RBC TPMT activity [Article:16917910]. |
| TPMT*21 | 205C>G(Leu69Val) c.205C>G(p.Leu69Val) | Noted in a Caucasian subject with intermediate TPMT activity [Article:16917910]. When \*21 was expressed in a recombinant yeast expression system, the resulting enzyme had significantly reduced intrinsic clearance when compared to wild-type protein [Article:18602085]. |
| TPMT*22 | 488G>C (Arg163Pro)(c.488G>C) | Identified in a Caucasian subject with intermediate RBC TPMT activity [Article:16917910]. |
| TPMT*23 | 500C>G(Ala167Gly) | Identified in a Caucasian subject with very low RBC TPMT activity [Article:17885628]. |
| TPMT*24 [Article:18602085]; also see \*20 information | 537G>T(Gln179His) c.537G>T(p.Gln179His) | Identified in a Caucasian subject having intermediate methylator phenotype. However, when \*24 was expressed in a recombinant yeast expression system, the catalytic activity of the variant protein was not significantly affected [Article:18602085]. |
| TPMT*25 | 634T>C (Cys212Arg) c.634T>C(p.Cys212Arg) | Identified in two Caucasian subjects demonstrating intermediate thiopurine drug methylation activity. In a recombinant yeast expression system, the recombinant enzyme had significantly decreased intrinsic clearance rate when compared to wild-type protein [Article:18602085]. |
Connected Drugs
| Evidence | Drug |
|---|---|
| azathioprine | |
| mercaptopurine | |
| s-adenosylmethionine | |
| thioguanine |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Clinical Annotation, Variant Annotation, VIP Annotation | purine analogues |
Connected Diseases
| Evidence | Disease |
|---|---|
| Drug Toxicity | |
| Precursor Cell Lymphoblastic Leukemia-Lymphoma |