Coding Code Description CPT
0028U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, copy number variants, common variants with reflex to targeted sequence analysis (new code effective 1/1/18)
0029U Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (ie, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823) (new code effective 1/1/18)
0031U CYP1A2 (cytochrome P450 family 1, subfamily A, member 2)(eg, drug metabolism) gene analysis, common variants (ie, *1F, *1K, *6, *7) (new code effective 1/1/18)
0069U Oncology (colorectal), microrna, rt-pcr expression profiling of mir-31-3p, formalin-
0070U fixed paraffin-embedded tissue, algorithm reported as an expression score
CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, common and select rare variants (ie, *2, *3, *4, *4N, *5, *6, *7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *29, *35, *36, *41, *57, *61, *63, *68, *83, *xN)
0071U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, full gene sequence (List separately in addition to code for primary procedure)
0072U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D6-2D7 hybrid gene) (List separately in addition to code for primary procedure)
0073U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D7-2D6 hybrid gene) (List separately in addition to code for primary procedure)
0074U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, non-duplicated gene when duplication/multiplication is trans) (List separately in addition to code for primary procedure)
0075U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 5’ gene duplication/multiplication) (List separately in addition to code for primary procedure)
0076U CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 3’ gene duplication/ multiplication) (List separately in addition to code for primary procedure)
81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug
81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
81230 CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, *2, *22) (new code effective 1/1/18)
81231 CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *7) (new code effective 1/1/18)
81402 Molecular pathology procedure, Level 3 (eg, >10 SNPs, 2-10 methylated variants, or 210 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) includes:
Cytochrome P450 Genotype-Guided Treatment Strategy
Metabolism is the term for how the body processes substances. Just as the body processes (metabolizes) foods, it also metabolizes medications. One gene in particular, cytochrome P450 (also called CYP450), is known to be involved in processing a large number of drugs. Certain changes, called mutations, may affect how well or poorly a drug is metabolized. Medical studies have shown that genetic testing for certain CYP450 gene mutations is helpful in determining how a person would metabolize some drugs. For example, drugs like clopidogrel for heart disease, eliglustat for Gaucher disease, and tetrabenazine for Huntington disease. However, reliable and large studies have not yet shown that this type of genetic testing is useful for other drugs. This policy describes when CYP450 genetic testing is covered.
Policy Coverage Criteria
Test Medical Necessity
CYP450 genotyping (including CYP2C19 and CYP2D6 genes)
CYP450 genotyping for the CYP2C19 gene may be considered medically necessary for the following indication: * To aid in the choice of clopidogrel (Plavix®) versus alternative
anti-platelet agents OR * To determine optimal dosing for clopidogrel CYP2D6 genotyping to determine drug metabolizer status may be considered medically necessary for the following indications: * Patient with Gaucher disease considering treatment with
eliglustat (Cerdelga™) OR * Patient with Huntington disease considering treatment with
tetrabenazine (Xenazine®) in a dosage greater than 50 mg per day
CYP450 genotyping (including CYP2C19 and CYP2D6 genes)
CYP450 genotyping (including CYP2C19 and CYP2D6 genes)to determine drug choice or dose for all other drugs not listed in the Medical Necessity section above is considered investigational, unless noted otherwise in a separate policy (see Related Medical Policies). The use of genetic testing panels that include multiple CYP450 variants/mutations/polymorphisms is considered investigational.
Note: Multigene testing panels that include CYP450 and other non CYP450 genes are addressed in other policies. (See Related Medical Policies) This policy only addresses individual genetic tests for CYP450 (including CYP2C19, and CYP2D6 genes).
Definition of Terms
Cytochrome P450: This refers to a family of 60 different enzymes involved in drug and toxin metabolism.
Genotype testing: This is a type of testing used to determine the DNA sequence in genes.
Metabolize: This is a term that refers to breaking down a molecule into smaller units. If a drug is metabolized, it is no longer clinically active.
Polymorphisms: This is a genetic variation between individuals resulting in differences in form or gene expression, in this case differing activity of various enzymes.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause Mendelian disorders.
Previous Updated Definition
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
The cytochrome P450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in cytochrome P450 are associated with altered metabolism of many drugs. Testing for cytochrome P450 variants may assist in selecting and dosing drugs affected by these genetic variants.
Background Drug Efficacy and Toxicity
Drug efficacy and toxicity vary substantially between individuals. Because drugs and doses are typically adjusted, if needed, by trial-and-error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.
Multiple factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions.
Inherited (germline) DNA sequence variation in genes coding for drug-metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the activity of those molecules and thus on the efficacy or toxicity of a drug.
Pharmacogenomics studies how an individual’s genetic inheritance affects the body’s response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA variants (genotyping) in genes related to the metabolic pathway (pharmacokinetics) or signal transduction pathway (pharmacodynamics) of the drug. Potentially, test results could be used to optimize drug choice and/or dose for more effective therapy, avoid serious adverse events, and decrease medical costs.
Cytochrome P450 System
The cytochrome P450 (CYP450) family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. CYP2D6 metabolizes approximately 25% of all clinically used medications (eg, dextromethorphan, ß-blockers, antiarrhythmics, antidepressants, morphine derivatives), including most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton pump inhibitors, diazepam, propranolol, imipramine, amitriptyline, and clopidogrel.
Some CYP450 enzymes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzymes constitute an important group of drug-gene interactions influencing the variability of the effect of some CYP450-metabolized drugs.
Individuals with 2 copies (alleles) of the most common (wild-type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule are termed extensive metabolizers (EMs; normal). Poor metabolizers (PMs) lack active enzyme gene alleles, and intermediate metabolizers, who have 1 active and 1 inactive enzyme gene allele, may experience to a lesser degree some of the consequences of PMs. Ultrarapid metabolizers (UMs) are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.
UMs administered an active drug may not reach therapeutic concentrations at usual recommended doses of active drugs, while PMs may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, UMs may suffer adverse events, and PMs may not respond.
Many drugs are metabolized to varying degrees by more than 1 enzyme, either within or outside of the CYP450 superfamily. Also, the interaction between different metabolizing genes, the interaction between genes and environment, and interactions among different nongenetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain interindividual differences in metabolism and consequent efficacy or toxicity.
Determining Genetic Variability In Drug Response
Genetically determined variability in drug response has been traditionally addressed using a trial-and-error approach to prescribing and dosing, along with therapeutic drug monitoring for drugs with a very narrow therapeutic range and/or potentially serious adverse events outside that range. However, therapeutic drug monitoring is not available for all drugs of interest, and a cautious trial-and-error approach can lengthen the time to achieving an effective dose.
CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (eg, in urine). However, testing and interpretation are timeconsuming and inconvenient; as a result, phenotyping is seldom performed.
The clinical utility of CYP450 genotyping (ie, the likelihood that genotyping will significantly improve drug choice, dosing, and patient outcomes) may be favored when the drug under consideration has a narrow therapeutic dose range, when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics, and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. The potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed up the process of achieving a therapeutic dose and avoiding significant adverse events.FDA has required the package insert for clopidogrel carry a black box warning concerning possible worse outcomes with clopidogrel treatment in patients with genetic variants. The FDA warning suggests changes in doses or changes in drug.