Cytochrome P450 Genotyping
Indication for ordering:
- Assess genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5.
- May aid in drug selection and dose planning for many drugs that are either activated or inactivated by one or more CYP450 enzymes. Recommendations may include drug avoidance or nonstandard dosing.
- Report includes comprehensive medication guidance based on the genotypes detected and access to GeneDose Live, a cloud-based medication management and risk mitigation tool.
Indication for ordering:
Assess genetic risk of abnormal drug metabolism for CYP2C19 substrates. May aid in drug selection and dose planning.
Indication for ordering:
Assess genetic risk of abnormal drug metabolism for CYP2C8 and/or CYP2C9 substrates. May aid in drug selection and dose planning.
Indication for ordering:
Assess genetic risk of abnormal drug metabolism for CYP2D6 substrates. Includes detection of common copy number variations and gene hybrids. May aid in drug selection and dose planning.
Indication for ordering:
Assess genetic risk of abnormal drug metabolism for substrates of CYP3A4 and/or CYP3A5. May aid in drug selection and dose planning.
The cytochrome P450 (CYP) isozymes 2C19, 2C8, 2C9, 2D6, and the CYP3A subfamily are involved in the metabolism of many drugs. Variants in the genes that code for these enzymes will influence pharmacokinetics of the respective medications, and may predict or explain nonstandard dose requirements, therapeutic failure, or adverse reactions.
DISEASE OVERVIEW
Treatment Issues
- Actual metabolic phenotype is subject to drug/drug interactions, clinical factors, and other nongenetic factors.
- Therapeutic drug monitoring and/or metabolic ratios may be useful for evaluating the pharmacokinetics of a particular drug for a particular patient.
- See the ARUP Laboratory Test Directory (www.aruplab.com/) for a list of available drug-specific testing (search by test name or number).
- The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing guidelines involving CYP genotypes (https://cpicpgx.org/guidelines/), such as:
- Clopidogrel (eg, Plavix): refer to CPIC dosing guideline
- Codeine: refer to CPIC dosing guideline
- Ondansetron and Tropiesetron: refer to CPIC dosing guideline
- Phenytoin (eg, Dilantin): refer to CPIC dosing guideline
- Selective serotonin reuptake inhibitors (eg, citalopram): refer to CPIC dosing guideline
- Tacrolimus (eg, Prograf): refer to CPIC dosing guideline
- Tamoxifen: refer to CPIC dosing guideline
- Tricyclic antidepressants (eg, amitriptyline): refer to CPIC dosing guideline
- Voriconazole: refer to CPIC dosing guideline
- Warfarin (eg, Coumadin): refer to CPIC dosing guideline
GENETICS
Genes
CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5
Inheritance
Autosomal codominant
Variants Tested
Variants or groups of variants are classified as “star” (*) alleles, that are associated with predicted enzyme function, based on international consensus nomenclature. However, all variants are not detected and assumptions about phase are made, as shown below. More details about nomenclature, allele frequencies and phenotype predictions available at www.pharmvar.org or www.pharmgkb.org.
|
Gene (Transcript) |
Alleles |
Predicted Allele Function |
|---|---|---|
|
CYP2C19 (NM_000769) |
CYP2C19*2: rs4244285, c.681G>A; rs12769205, c.332-23A>G |
No function |
|
CYP2C19*3: rs4986893, c.636G>A |
No function |
|
|
CYP2C19*4: rs28399504, c.1A>G |
No function |
|
|
CYP2C19*5: rs56337013, c.1297C>T |
No function |
|
|
CYP2C19*6: rs72552267, c.395G>A |
No function |
|
|
CYP2C19*7: rs72558186, c.819+2T>A |
No function |
|
|
CYP2C19*8: rs41291556, c.358T>C |
No function |
|
|
CYP2C19*9: rs17884712, c.431G>A |
Decreased function |
|
|
CYP2C19*10: rs6413438, c.680C>T |
Decreased function |
|
|
CYP2C19*15: rs17882687, c.55A>C |
Functional |
|
|
CYP2C19*17: rs12248560, c.-806C>T |
Increased function |
|
|
CYP2C19*35: rs12769205, c.332-23A>G |
No function |
|
|
CYP2C8 (NM_000770) |
CYP2C8*1C: rs17110453, c.-370T>G |
Unclassified |
|
CYP2C8*2: rs11572103, c.805A>T |
Decreased function |
|
|
CYP2C8*3: rs10509681, c.1196A>G |
Decreased function |
|
|
CYP2C8*4: rs1058930, c.792C>G |
Probably decreased function |
|
|
CYP2C9 (NM_000771) |
CYP2C9*2: rs1799853, c.430C>T |
Decreased function |
|
CYP2C9*3: rs1057910, c.1075A>C |
Decreased function |
|
|
CYP2C9*4: rs56165452, c.1076T>C |
Decreased function |
|
|
CYP2C9*5: rs28371686, c.1080C>G |
Decreased function |
|
|
CYP2C9*6: rs9332131, c.818del |
No function |
|
|
CYP2C9*8: rs7900194, c.449G>A |
Decreased function |
|
|
CYP2C9*11: rs28371685, c.1003C>T |
Decreased function |
|
|
CYP2D6 (M33388 sequence) |
CYP2D6*2: rs16947, g.2850C>T; rs1135840, g.4180G>C | Functional |
| CYP2D6*2A: rs1080985, g.-1584C>G; rs16947, g.2850C>T; rs1135840, g.4180G>C | Functional | |
| CYP2D6*3: rs35743686, g.2549del | No function | |
|
CYP2D6*4: rs1065852, g.100C>T; rs3892097, g.1846G>A; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*5: gene deletion |
No function |
|
|
CYP2D6*6: rs5030655, g.1707del; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*7: rs5030867, g.2935A>C |
No function |
|
|
CYP2D6*8: rs5030865, g.1758G>T; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*9: rs5030656, g.2615_2617del |
Decreased function |
|
|
CYP2D6*10: rs1065852, g.100C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*11: rs1080985, g.-1584C>G; rs201377835, g.883G>C; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*12: rs5030862, g.124G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*13: a CYP2D7-derived exon 1 conversion |
No function |
|
|
CYP2D6*14: rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*15: rs774671100, g.137_138insT |
No function |
|
|
CYP2D6*17: rs28371706, g.1023C>T; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*29: rs16947, g.2850C>T; rs59421388, g.3183G>A; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*35: rs1080985, g.-1584C>G; rs769258, g.31G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Functional |
|
|
CYP2D6*36: a CYP2D6*10 carrying a CYP2D7-derived exon 9 conversion |
No function |
|
|
CYP2D6*36-*10: a CYP2D6*36 and a CYP2D6*10 in tandem |
Decreased function |
|
|
CYP2D6*41: rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*45: rs28371710, g.1716G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Functional |
|
|
CYP2D6*46: rs28371696, g.77G>A; rs28371710, g1716G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Functional |
|
|
CYP2D6*49: rs1065852, g.100C>T; rs1135822, g.1611T>A; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*53: rs1135822, g.1611T>A |
Functional |
|
|
CYP2D6*69: rs1065852, g.100C>T; rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g4180G>C |
No function |
|
|
CYP2D6*114: rs1065852, g.100C>T; rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
DUP: complete gene duplication |
Varies based on the allele that is duplicated |
|
|
CYP3A4 (NM_017460) |
CYP3A4*1B: rs2740574, c.-392G>A |
Unclassified |
|
CYP3A4*15: rs4986907, c.485G>A |
Unclassified |
|
|
CYP3A4*22: rs35599367, c.522-191C>T |
Decreased function |
|
|
CYP3A5 (NM_000777) |
CYP3A5*3: rs776746, c.219-237A>G |
Severely decreased function |
|
CYP3A5*6: rs10264272, c.624G>A |
Severely decreased function |
|
|
CYP3A5*7: rs41303343, c.1035dup |
Probably severely decreased function |
Results
- Genetic variant(s) detected: alleles detected are reported. The combination of alleles detected is used to predict metabolizer phenotype, and in the case of CYP2D6, the activity score. Phenotype predictions are subject to change as the scientific and clinical evidence evolves.
- No variants detected is predictive of *1 functional alleles.
TEST DESCRIPTION
- Polymerase chain reaction (PCR) and fluorescence monitoring
- Clinical sensitivity is drug dependent.
- Analytical sensitivity/specificity is greater than 99%.
Limitations
- Only the targeted CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and CYP3A5 variants will be detected by this this panel. Assumptions about phase and content are made to assign alleles.
- Diagnostic errors can occur due to rare sequence variations.
- A combination of the CYP2D6*5 (gene deletion) and a CYP2D6 gene duplication cannot be specifically identified; however, this combination is not expected to adversely affect the phenotype prediction.
- Risk of therapeutic failure or adverse reactions with gene substrates may be affected by genetic and nongenetic factors that are not detected by this test. The test result does not replace the need for therapeutic drug or clinical monitoring.
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Codeine and CYP2D6. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Ondansetron and Tropisetron based on CYP2D6 genotype. [Page Last Modified: Jan 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Phenytoin and CYP2C9 and HLA-B. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Selective Serotonin Reuptake Inhibitors and CYP2D6 and CYP2C19. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Tamoxifen based on CYP2D6 genotype. [Page Last Modified: Feb 2019; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Tricyclic Antidepressants and CYP2D6 and CYP2C19. [Page Last Modified: Oct 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guidelines. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Clopidogrel and CYP2C19. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Tacrolimus and CYP3A5. [Page Last Modified: Nov 2018; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Voriconazole and CYP2C19. [Page Last Modified: Feb 2019; Accessed: Feb 2019]
- Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for Pharmacogenetics-Guided Warfarin Dosing. [Page Last Modified: Apr 2019; Accessed: Apr 2019]
Last Update: July 2019
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