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 1 annotations for this variant. Register or sign in to see them.
VIP Variant in TPMT
The TPMT*4 allele includes a G to A transition at the final splice acceptor nucleotide in TPMT intron 9 [Article:9486974]. This mutation disrupts the intron 9-exon 10 acceptor splice site and results in two abnormal transcripts, one that results from the activation of a cryptic splice site in intron 9, leading to the inclusion of 330 nucleotides of intron sequence, and another that uses a novel splice acceptor site located one nucleotide 3' downstream from the original splice junction. The latter situation results in a single nucleotide deletion and a frameshift in the portion of the mRNA encoded by exon 10 [Article:9486974]. Presence of TPMT*4 in an extended kindred uniformly resulted in very low TPMT activity in subjects carrying this allele [Article:9486974].
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
*4. TPMT:4
| Genomic Variant & GenBank ID:* | 8,989,263 C >T on NT_007592.14 |
|---|---|
| mRNA Variant & GenBank ID: | Not Available |
| Protein Variant & GenBank ID: | Not Available |
| GoldenPath Position: | Chr6:18,238,991 (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 | |
| thioguanine |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| VIP Annotation | purine analogues |
Publications related to rs1800584 at chr6:18131012: 1
| Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. The Journal of clinical investigation. 1998. Otterness D M, et al. [Article:9486974@PubMed] |
Cross-References
- UCSC Golden Path:
- chr6:18131012
- dbSNP:
- rs1800584
- HapMap:
- rs1800584
Platform Availability
- Illumina