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UniProtKB/Swiss-Prot P51580: Variant p.His227Gln

Thiopurine S-methyltransferase
Gene: TPMT
Chromosomal location: 6p22.3
Variant information

Variant position:  227
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Polymorphism
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Histidine (H) to Glutamine (Q) at position 227 (H227Q, p.His227Gln).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Similar physico-chemical property. Both residues are medium size and polar.
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Polymorphism:  Polymorphic variations define TPMT activity levels that are variable among ethnic groups. 90% of Caucasians have high TPMT activity, 10% have intermediate activity, and 1 in 300 individuals has low activity (PubMed:10208641). These differences influence the clinical use and therapeutic efficacy of thiopurine drugs, generally used as immunosuppressants or cytotoxic drugs in conditions including leukemia, autoimmune disease and organ transplantation. Intermediate or low TPMT activity is associated with thiopurine intolerance and patients are at risk of toxicity after receiving standard doses of thiopurine drugs [MIM:610460] (PubMed:10751626, PubMed:15819814, PubMed:16220112, PubMed:16476125, PubMed:16789994, PubMed:7862671, PubMed:8561894, PubMed:8644731, PubMed:9246020, PubMed:9336428, PubMed:9711875, PubMed:9931345, PubMed:9931346). The most prevalent TPMT alleles associated with TPMT deficiency are TPMT*2 and TPMT*3A. The proteins encoded by TPMT*2 and TPMT*3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway (PubMed:9177237, PubMed:8644731).TPMT*3A is the most common allele in the Caucasians and American Caucasians; it is the only mutant allele found in the South West Asians; it is not found in the Chinese. TPMT*3C is common in African-Americans and is the only allele in Chinese, Japanese and Taiwanese individuals. This allele is found at a low frequency in the Caucasians. This suggests that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. -
Additional information on the polymorphism described.

Variant description:  Polymorphism; allele TPMT*7; reduced activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  227
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  245
The length of the canonical sequence.

Location on the sequence:   LFGKICNIRCLEKVDAFEER  H KSWGIDCLFEKLYLLTEK
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         LFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLYLLTEK--

Gorilla                       LFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLYLLTEK

                              LFGSICNIHCLEKVDVFEEQHKSWGIDYIIEKLYLFTEK

Chimpanzee                    LFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLYLLTEK

Mouse                         LFGTKCSMQCLEEVDALEERHKAWGLDYLFEKLYLLTEK

Rat                           LFGTKCNMQCLEEVDALEERHKTWGVDYFFEKLYLLTEK

Bovine                        LFGSVCNIQCLEKVDVFEERHKSWGIDQIIERLYLFTEK

Rabbit                        LFDTKCKIHCLEKVDAFEERHKSWGIDYIFEKLYLLTEK

Cat                           LFGSTCNIHCLEKVDVFEERHKSWGIDYIVEKLYLLTEK

Horse                         LFDSVCNIRCLEKVDALEERHKSWGIDYLVETLYLFTEK

Zebrafish                     VFGGSCNIDLLQSVDGFEEKHRSWGLDSLTEKLYLLTTK

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 245 Thiopurine S-methyltransferase
Helix 225 – 230


Literature citations

Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis.
Spire-Vayron de la Moureyre C.; Debuysere H.; Sabbagh N.; Marez D.; Vinner E.; Chevalier E.D.; Lo-Guidice J.-M.; Broly F.;
Hum. Mutat. 12:177-185(1998)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 210-245; VARIANT GLN-227;

Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics.
Salavaggione O.E.; Wang L.; Wiepert M.; Yee V.C.; Weinshilboum R.M.;
Pharmacogenet. Genomics 15:801-815(2005)
Cited for: VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; GLN-227 AND CYS-240; CHARACTERIZATION OF VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; GLN-227 AND CYS-240;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.