UniProtKB/SwissProt variant VAR

Variant information

Variant position:

49

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 Leucine (L) to Serine (S) at position 49 (L49S, p.Leu49Ser).

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 medium size and hydrophobic (L) to small size and polar (S)

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: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:

Allele TPMT*5; has very low activity when expressed in a heterologous system.

Any additional useful information about the variant.

Other resources:

Links to websites of interest for the variant.

Variant rs72552740 [ dbSNP | Ensembl ]

Sequence information

Variant position:

49

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:

WQDKWVNGKTAFHQEQGHQL L KKHLDTFLKGKSGLRVFFPL

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                         WQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGKSGLRVFFPL

Gorilla                       WQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGKSGLRVFFPL

                              WQEKWVSRRIGFHQEQGHKLLKKHLDTFLKGENGLRVFFPL

Chimpanzee                    WQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGKSGLRVFFPL

Mouse                         WKEKWVTRHISFHQEQGHQLLKKHLDTFLKGQSGLRVFFPL

Rat                           WQDKWVTRHIAFHQEQGHQLLKKHFDTFLKGQSGLRVFFPL

Bovine                        WQEKWVNHKTGFHQEQGHQLLKKYLDTFLKGEKALRVFFPL

Rabbit                        WQDKWVSHKIGFHQEQGHKLLKKHLDAFLKGESGLRVFFPL

Cat                           WREKWVDGKIGFHQEQGHQLLKKHLDTFLKGENVLRVFFPL

Horse                         WQGKWVTGKTIFHQEQGHQLLKKHLDAFLKGESGLKVFFPL

Zebrafish                     WENRWQEGRTGFHRSDVHNLLKANVDKLICGRREVRFFFPL

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
Binding site	40 – 40	Substrate
Binding site	69 – 69	S-adenosyl-L-methionine; via carbonyl oxygen
Modified residue	58 – 58	N6-acetyllysine
Helix	47 – 57

Literature citations

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;

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;

UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P51580: Variant p.Leu49Ser