Important Variant Information for CYP2C19
Submitted by: Jason Robarge, Rebecca Fletcher, Anne Nguyen (COBRA), Caroline F. Thorn (PharmGKB)
Reviewed by: Under Review
Submitted date: September 30, 2006
There are Two Important Variants for CYP2C19.
| Gene HGNC Name: | CYP2C19 |
|---|---|
| Variant Summary: | The G>A change at position 636 in the cDNA results in a premature termination codon at amino acid 212 (W212X) [PMID: 7969038]. CYP2C19: 636G>A is the defining SNP of the CYP2C19*3 haplotype. |
| Key PubMed IDs: | 7969038; 7586932 |
| GoldenPath Position: | Chr10:96530400 (hg18) |
| mRNA Variant & GenBank ID: | G>A at 636 on NM_000769 |
| Genomic Variant & GenBank ID: | G>A at 19952 on AY796203.1 |
| Protein Variant & GenBank ID: | Trp>Ter at 212 on NP_000760 |
| dbSNP rs#: | rs4986893 |
| Key Drugs/Substrates: | lansoprazole; omeprazole; pantoprazole; rabeprazole; phenytoin; mephenytoin; phenobarbitone; amitriptyline; carisoprodol; citalopram; clomipramine; cyclophosphamide; hexobarbital; imipramine; indomethacin; mephobarbital; moclobemide; nelfinavir; nilutamide; primidone; progesterone; proguanil; propranolol; teniposide; warfarin |
| Key Phenotypes/Diseases: | Phenotypes: Mephenytoin poor metabolizer (OMIM: 124020); Omeprazole poor metabolizer (OMIM: 124020); Proguanil poor metabolizer (OMIM: 124020) |
| Key Haplotypes | CYP2C19*3 |
| Gene HGNC Name: | CYP2C19 |
|---|---|
| Variant Summary: | The CYP2C19:681G>A variant introduces a splicing defect altering the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non-functional protein responsible for the poor metabolizer phenotype [PMID: 8195181]. This SNP is the defining SNP of the CYP2C19*2 haplotype. Clopidogrel must be metabolized into an active metabolite by liver cytochrome P-450 enzymes. CYP2C19 is one of the enzymes involved in this formation. The CYP2C19*2 loss of function variant was significantly associated with lower exposure to active metabolite in subjects treated with clopidogrel [PMID: 17900275, 19106084]. Furthermore, this variant has been associated with decreased platelet responsiveness to clopidogrel ex vivo [PMID: 16772608, 18004210, 19106084] and increased cardiovascular event rates in patients on clopidogrel [PMID: 19106083, 19106084, 19108880, 20351750]. A genome-wide association analysis identified that the loss-of-function variant CYP2C19*2 accounted for most of all the association with diminished platelet response to clopidogrel [PMID: 19706858]. The extension and replication of these results in a population with high risk of cardiovascular disease showed an association of CYP2C19*2 with poorer cardiovascular outcomes [PMID: 19706858]. Information regarding CYP2C19 genotyping has been added to the clopidogrel label (see Clinical PGx for clopidogrel ). |
| Key PubMed IDs: | 8195181; 9732415 ; 19706858 |
| GoldenPath Position: | Chr10:96531606 (hg18) |
| mRNA Variant & GenBank ID: | G>A at 681 on NM_000769 |
| Genomic Variant & GenBank ID: | G>A at 21158 on AY796203.1 |
| Protein Variant & GenBank ID: | Pro>Pro at 227 on NP_000760 |
| dbSNP rs#: | rs4244285 |
| Key Drugs/Substrates: | lansoprazole; omeprazole; pantoprazole; rabeprazole; phenytoin; mephenytoin; phenobarbitone; amitriptyline; carisoprodol; clopidogrel; citalopram; clomipramine; cyclophosphamide; hexobarbital; imipramine; indomethacin; mephobarbital; moclobemide; nelfinavir; nilutamide; primidone; progesterone; proguanil; propranolol; teniposide; warfarin |
| Key Phenotypes/Diseases: | Phenotypes: Mephenytoin poor metabolizer (OMIM: 124020); Omeprazole poor metabolizer (OMIM: 124020); Proguanil poor metabolizer (OMIM: 124020); Clopidogrel poor metabolizer (OMIM: 124020); (OMIM: 609535) |
| Key Haplotypes | CYP2C19*2 |
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