UniProtKB/Swiss-Prot P51580: Variant p.Tyr240Cys

Thiopurine S-methyltransferase
Gene: TPMT
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Variant information Variant position:

240 The position of the amino-acid change on the UniProtKB canonical protein sequence.
Type of variant:

LB/B The variants are classified into three categories: LP/P, LB/B and US.

LP/P: likely pathogenic or pathogenic.
LB/B: likely benign or benign.
US: uncertain significance

Residue change:

From Tyrosine (Y) to Cysteine (C) at position 240 (Y240C, p.Tyr240Cys). 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:

Change from large size and aromatic (Y) to medium size and polar (C) The physico-chemical property of the reference and variant residues and the change implicated.
BLOSUM score:

-2 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:8644731, PubMed:9177237).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:

Allele TPMT*3B and allele TPMT*3C; reduced activity; protein shows enhanced degradation. Any additional useful information about the variant.
Other resources:

Links to websites of interest for the variant.

Variant rs1142345 [ dbSNP | Ensembl ]

Sequence information Variant position:

240 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:

VDAFEERHKSWGIDCLFEKL Y LLTEK 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                         VDAFEERHKSWGIDCLFEKLYLLTEK--

Gorilla                       VDAFEERHKSWGIDCLFEKLYLLTEK

                              VDVFEEQHKSWGIDYIIEKLYLFTEK

Chimpanzee                    VDAFEERHKSWGIDCLFEKLYLLTEK

Mouse                         VDALEERHKAWGLDYLFEKLYLLTEK

Rat                           VDALEERHKTWGVDYFFEKLYLLTEK

Bovine                        VDVFEERHKSWGIDQIIERLYLFTEK

Rabbit                        VDAFEERHKSWGIDYIFEKLYLLTEK

Cat                           VDVFEERHKSWGIDYIVEKLYLLTEK

Horse                         VDALEERHKSWGIDYLVETLYLFTEK

Zebrafish                     VDGFEEKHRSWGLDSLTEKLYLLTTK

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.

Type	Positions	Description
Chain	1 – 245	Thiopurine S-methyltransferase
Beta strand	236 – 244

Literature citations
Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism.
Szumlanski C.; Otterness D.; Her C.; Lee D.; Brandriff B.; Kelsell D.; Spurr N.; Lennard L.; Wieben E.; Weinshilboum R.M.;
DNA Cell Biol. 15:17-30(1996)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS THR-154 AND CYS-240; Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.
Otterness D.; Szumlanski C.; Lennard L.; Klemetsdal B.; Aarbakke J.; Park-Hah J.O.; Iven H.; Schmiegelow K.; Branum E.; O'Brien J.; Weinshilboum R.M.;
Clin. Pharmacol. Ther. 62:60-73(1997)
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANTS SER-49; THR-154; PHE-180 AND CYS-240; Structural basis of allele variation of human thiopurine-S-methyltransferase.
Wu H.; Horton J.R.; Battaile K.; Allali-Hassani A.; Martin F.; Zeng H.; Loppnau P.; Vedadi M.; Bochkarev A.; Plotnikov A.N.; Cheng X.;
Proteins 67:198-208(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 16-245 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE; SUBUNIT; CHARACTERIZATION OF VARIANTS THR-154 AND CYS-240; Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.
Tai H.-L.; Krynetski E.Y.; Yates C.R.; Loennechen T.; Fessing M.Y.; Krynetskaia N.F.; Evans W.E.;
Am. J. Hum. Genet. 58:694-702(1996)
Cited for: VARIANTS THR-154 AND CYS-240; Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis.
Leipold G.; Schuetz E.; Haas J.P.; Oellerich M.;
Arthritis Rheum. 40:1896-1898(1997)
Cited for: VARIANTS THR-154 AND CYS-240; Thiopurine methyltransferase alleles in British and Ghanaian populations.
Ameyaw M.-M.; Collie-Duguid E.S.R.; Powrie R.H.; Ofori-Adjei D.; McLeod H.L.;
Hum. Mol. Genet. 8:367-370(1999)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.
Collie-Duguid E.S.R.; Pritchard S.C.; Powrie R.H.; Sludden J.; Collier D.A.; Li T.; McLeod H.L.;
Pharmacogenetics 9:37-42(1999)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES; Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population.
Hiratsuka M.; Inoue T.; Omori F.; Agatsuma Y.; Mizugaki M.;
Mutat. Res. 448:91-95(2000)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES; 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; Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C).
Kurzawski M.; Dziewanowski K.; Ciechanowski K.; Drozdzik M.;
Transpl. Int. 18:623-625(2005)
Cited for: VARIANTS THR-154 AND CYS-240; Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese.
Lu H.-F.; Shih M.-C.; Chang Y.-S.; Chang J.-Y.; Ko Y.-C.; Chang S.-J.; Chang J.-G.;
J. Clin. Pharm. Ther. 31:93-98(2006)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES; Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia.
Rossino R.; Vincis C.; Alves S.; Prata M.J.; Macis M.D.; Nucaro A.L.; Schirru E.; Congia M.;
J. Clin. Pharm. Ther. 31:283-287(2006)
Cited for: VARIANTS PRO-80; THR-154 AND CYS-240; FREQUENCY AND DISTRIBUTION OF ALLELES;

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.