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 29 annotations for this variant. Register or sign in to see them.
There are 3 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ABCB1
Note: The ABCB1 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.
A thymine (T) - cytosine © transition at nucleotide 1236 in exon 13 of ABCB1 (per ENST00000265724;vdb=variation;vf=10286490] in Ensembl) results in a synonymous change (GGT glycine, GGC glycine) at residue 412 in a cytoplasmic loop of the ATP-dependent membrane transporter, P-glycoprotein (P-gp) (see location per Fung et al. [Article:19285158] as adapted from Ambudkar et al. [Article:10331089]). This single nucleotide polymorphism (SNP) is one of three coding SNPs in ABCB1 with a high minor allele frequency; and the valence of the minor differs by ethnicity. According to dbSNP, the ancestral C allele ranges in frequency from 30% to 93% depending on the population, with C being the minor allele in Asians, and T being the minor allele in Africans.
Although many studies have studied potential phenotypic associations for this silent SNP, the literature bears no consensus [Article:16969364]. As a brief illustration, studies found increased drug exposure or drug response associated with the 1236 CC genotype [Article:18687982], the 1236 TT genotype [Articles:12960109, 18717915], or no genetic effect was found with regard to rs1128503 [Article:19207033].
The rs1128503 T allele is reference, and the C allele is non-reference, on the minus strand of the sequence in UCSC Genome browser (hg18), which is in the 5' to 3' orientation of the ABCB1 gene.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (4)
|
| Phenotype Datasets | Pharmacokinetics of irinotecan in cancer patients |
Appendix
| Genomic Variant & GenBank ID: | 84224 is reference A on AC005068 (hg18 plus strand) |
|---|---|
| mRNA Variant & GenBank ID: | 1654 is reference T on NM_000927.3 (hg18 minus strand) |
| Protein Variant & GenBank ID: | 412 is glycine on NP_000918.2 (hg18 minus strand) This synonymous SNP does not result in a variation in protein sequence. |
| GoldenPath Position: | chr7:87017537 (hg18) |
Positive and negative findings for drugs/substrates:
| Drug/substrate | Positive findings | Negative findings |
|---|---|---|
| Cyclosporine A | The TT genotype of this variant (1236 SNP) associated with increased drug levels in myasthenia gravis [Article:18717915] | |
| Irinotecan and SN-38 | TT genotype of this variant (1236 SNP) associated with increased drug exposure in cancer (PharmGKB data set: PA129966511) [Article:12960109] | |
| Lopinavir | This variant (1236 SNP) not associated with drug levels in HIV [Article:19207033] | |
| Nelfinavir | This variant (1236 SNP) marginally associated with increased drug response in HIV [Article:15651752] | |
| Ritonavir | This variant (1236 SNP) not associated with drug levels in HIV [Article:19207033] | |
| Temozolomide | The CC genotype of this variant (1236 SNP) associated with increased drug response in glioblastoma [Article:18687982] |
Key Phenotypes/Diseases: Negative findings
| Drug resistance: This variant (1236 SNP) not associated in drug response in pediatric epilepsy in Indians [Article:19571437] |
| Pediatric epilepsy: This variant (1236 SNP) not associated with disease risk in Indians [Article:19571437] |
| Systemic lupus erythematosus: This variant (1236 SNP) not associated with disease risk [Article:18820766] |
ABCB1 haplotypes
Variant alleles in the common coding SNPs at nucleotides 1236 (rs1128503), 2677 (rs2032582), and 3435 (rs1045642) are in high linkage disequilibrium [Article:16708052], and are observed as common haplotypes in the population [Articles:11503014, 12893986, 19072639]. Variant alleles for 1236-2677-3435 commonly occur as the 893Ala-containing CGC haplotype and the 893Ser-containing TTT haplotype in most ethnic groups [Articles:11503014, 12172212, 12893986]. The vast majority of haplotypic studies for ABCB1 do not take into account all segregating sites that are used to distinguish ABCB1 star alleles (see below), but interrogate a select few variants.
ABCB1 star alleles
Sequence analysis of ABCB1 in different ethnic groups has been performed [Articles:11503014, 12172212, 12893986, 14646693, 15692830, 16708052, 17187507] and led to the designation of "star alleles" [Articles:14646693, 11503014, 12893986], as explained by Robarge et al. [Article:17700589]. ABCB1 star allele designations are currently not harmonized in the literature, and thus are specific to the citation referenced.
Connected Drugs
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Variant Annotation | antiepileptics |
Connected Diseases
Publications related to rs1128503 at chr7:87179601: 28
Cross-References
- UCSC Golden Path:
- chr7:87179601
- dbSNP:
- rs1128503
- HapMap:
- rs1128503
- JSNP:
- ssj0000017
Platform Availability
- Illumina