Cytochrome P450 Genotyping

  • Assesses 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 may include comprehensive medication guidance based on the genotypes detected and access to GeneDose Live, a cloud-based medication management and risk mitigation tool.
Related Tests

Assesses genetic risk of abnormal drug metabolism for CYP2C19 substrates. May aid in drug selection and dose planning.

Assesses genetic risk of abnormal drug metabolism for CYP2C8 and/or CYP2C9 substrates. May aid in drug selection and dose planning.

Assesses genetic risk of abnormal drug metabolism for CYP2D6 substrates. Includes detection of common copy number variations and gene hybrids. To better predict metabolic phenotype, testing to further characterize gene duplication(s) may be performed. May aid in drug selection and dose planning.

Assesses 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, 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

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, 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

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*9: rs2256871, c.752A>G Functional

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*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*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*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 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.

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 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.

References

  1. PharmVar

    Pharmacogene Variation Consortium. PharmVar. [Updated: Nov 2020; Accessed: Dec 2020]