Cytochrome P450 Genotyping

Content Review: September 2021 Last Update:
  • Assesses genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, 2C cluster variant (rs12777823), 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.
  • Assesses genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, 2C cluster variant (rs12777823), 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 may include comprehensive medication guidance based on the genotypes detected and access to GeneDose Live, a cloud-based medication management and risk mitigation tool

The cytochrome P450 (CYP) isozymes 2B6, 2C19, 2C8, 2C9, 2D6, 3A4, and 3A5 are involved in the metabolism of many drugs. Variants in the genes that code for these enzymes may influence pharmacokinetics of the respective medications, and therefore may predict or explain nonstandard dose requirements, therapeutic failure, or adverse reactions.

Disease Overview

Treatment Issues

Genetics

Genes

CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2C rs12777823, 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, not all variants on a chromosome/allele are interrogated and assumptions about phase are made, as shown below. More details about nomenclature, allele frequencies and phenotype predictions are available at PharmVar  or PharmGKB. 

Gene (Transcript)

Alleles

Predicted Allele Function
CYP2B6 (NM_000767) CYP2B6*4: rs2279343, c.785A>G Increased function
CYP2B6*6: rs3745274, c.516G>T; rs2279343, c.785A>G

Decreased function
CYP2B6*7: rs3745274, c.516G>T; rs2279343, c.785A>G; rs3211371, c.1459C>T Decreased function
CYP2B6*9: rs3745274, c.516G>T Decreased function
CYP2B6*18: rs28399499, c.983T>C No function
CYP2B6*22: rs34223104, c.-82T>C Increased function
CYP2B6*36: rs34223104, c.-82T>C; rs3745274, c.516G>T; rs2279343, c.785A>G Decreased 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*4A: rs28399504, c.1A>G

No function
CYP2C19*4B: rs28399504, c.1A>G, rs12248560, c.-806C>T 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*17: rs12248560, c.-806C>T

Increased function

CYP2C19*35: rs12769205, c.332-23A>G

No function
CYP2C8 (NM_000770)

CYP2C8*2: rs11572103, c.805A>T

Decreased function

CYP2C8*3: rs10509681, c.1196A>G

Decreased function

CYP2C8*4: rs1058930, c.792C>G

Decreased function
CYP2C cluster (NC_000010) CYP2C rs12777823, g.96405502 G>A Unclassifieda
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
CYP2C9*12: rs9332239, c.1465C>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*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*40: rs28371706, g.1023C>T; rs72549356, c.1863_1864ins TTTCGCCCCTTTCGCCCC; rs16947, g.2850C>T; rs1135840, g.4180G>C No function

CYP2D6*41: rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g.4180G>C

Decreased function
CYP2D6*42: rs16947, g.2850C>T; rs72549346, g.3260_3261insGT; rs1135840, g.4180G>C No function

CYP2D6*49: rs1065852, g.100C>T; rs1135822, g.1611T>A; rs1135840, g.4180G>C

Decreased function

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

Normal function

CYP3A4*15: rs4986907, c.485G>A

Decreased function

CYP3A4*22: rs35599367, c.522-191C>T

Decreased function
CYP3A5 (NM_000777)

CYP3A5*3: rs776746, c.219-237A>G

No function

CYP3A5*6: rs10264272, c.624G>A

No function

CYP3A5*7: rs41303343, c.1035dup

No function

aThe CYP2C cluster variant is associated with a decreased warfarin dose requirement in some people of African descent.

Results

  • Genetic variant(s) detected: alleles detected are reported. The combination of alleles detected or diplotype 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.
  • Functional variants without clinical indication or impact on clinical management may not be reported.

Limitations

  • Only the targeted genetic variants will be detected by 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.
  • The test result does not replace the need for therapeutic drug or clinical monitoring.

References

  1. PharmVar

    Pharmacogene Variation Consortium. PharmVar. Updated Nov 2020; accessed Dec 2020.

Related Information
Germline Pharmacogenetics - PGx