Coverage Policy Manual
Policy #: 2005003
Category: Laboratory
Initiated: January 2005
Last Review: July 2022
  Genetic Test: Cytochrome p450 Genotype Guided Treatment Strategy

Description:
The cytochrome p450 (CYP450) family is involved in the metabolism of a significant proportion of currently administered drugs, and genetic variants in cytochrome p450 are associated with altered metabolism of many drugs. Genetic testing for cytochrome p450 variants may assist in selecting and dosing drugs that are impacted by these genetic variants.
 
Background
Drug efficacy and toxicity vary substantially across 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.
 
Various 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 (polymorphisms) 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 is the study of 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 polymorphisms (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 effects, and decrease medical costs.
 
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, β-blockers, antiarrhythmics, antidepressants, morphine derivatives), including most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton pump inhibitors, diazepam, propranolol, imipramine, and amitriptyline.
 
Some CYP450 enzyme genes 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 enzyme variants constitute one important group of drug-gene interactions influencing the variability of 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 (IMs), who have one active and one inactive enzyme gene allele, may experience to a lesser degree some of the consequences of poor metabolizers. 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.
 
Ultrarapid metabolizers 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 effects and PMs may not respond.
 
However, it is very important to realize that many drugs are metabolized to varying degrees by more than one enzyme, either within or outside of the CYP450 superfamily. In addition, interaction between different metabolizing genes, interaction of genes and environment, and interactions among different non-genetic 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 inter-individual differences in metabolism and consequent efficacy or toxicity.
 
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 (TDM) for drugs with a very narrow therapeutic range and/or potential serious adverse effects outside that range. However, TDM 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 (e.g., in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.
 
The clinical utility of CYP450 genotyping, i.e., the likelihood that genotyping will significantly improve drug choice/dosing and consequent patient outcomes, is favored when the drug under consideration has a narrow therapeutic dose range (window), 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. Yet, the potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed the process of achieving a therapeutic dose and avoiding significant adverse events.
 
Regulatory Status   
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Diagnostic genotyping tests for certain CYP450 enzymes are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
 
Selected Testing Kits for CYP450 Genotyping Cleared for Marketing by the Food and Drug Administration
 
  • xTAG Cyp2c19 Kit V3, manufactured by Luminex Molecular Diagnostics, was approved in 2013
  • Spartan Rx Cyp2c19 Test System, manufactured by Spartan Bioscience, was approved in 2013
  • Verigene Cyp2c19 Nucleic Acid Test (2c19), manufactured by Nanosphere, was approved in 2012
  • Infiniti Cyp2c19 Assay, manufactured by Autogenomics, was approved in  2010
  • xTAG Cyp2d6 Kit V3, Model I030c0300 (96)
  • Invader Ugt1a1 Molecular Assay, manufactured by Third Wave Technologies, was approved in 2005
  • Roche AmpliChip Cyp450 Test, manufactured by Roche Molecular Systems, was approved in 2005
 
Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Genelex Corp.), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4, and CYP3A5. Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Assurex Health) and PersonaGene Genetic Panels (AIBioTech).
 
Pathway genomics offers a similar panel, Pain Management DNA Insight™.
 
Sky Toxicology offers SkyPGx a comprehensive pharmacogenetic panel which includes cytochrome genotyping. The test is marketed to identify a patient’s ability to metabolize a various prescription and non-prescription medications.
 
Food and Drug Administration Labeling on CYP450Genotyping
The FDA maintains online compendia of pharmacogenetic associations online under 3 categories: 1. pharmacogenetic associations for which the data support therapeutic management recommendations; 2. pharmacogenetic associations for which the data indicate a potential impact on safety or response and 3. pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only. (FDA, 2022)
 
The FDA has included pharmacogenomics information in the physician prescribing information (drug labels) of multiple drugs. In most cases, this information is general and lacks specific directives for clinical decision making. In the following examples, the FDA has given clear and specific directives on either use of a specific dose (eg, eliglustat, tetrabenazine) or when a drug may not be used at all (eg, codeine).
 
Eliglustat
The FDA has approved eliglustat for treatment of adults with Gaucher disease type 1 who are CYP2D6 EMs, intermediate metabolizers, or PMs as detected by an FDA-cleared test. Further, the label acknowledges the limitation of use among UMs because they may not achieve adequate concentrations and a specific dosage was not recommended for patients with indeterminate CYP2D6 metabolizer status. Further, the label states that the dosing strategy should be 84 mg orally, twice daily for CYP2D6 EMs or intermediate metabolizers and 84 mg orally, once daily for CYP2D6 PMs. The FDA has included a black box to warn about the reduced effectiveness in PMs and to advise healthcare professionals to consider alternative dosing or to use of other medications in patients identified as potential PMs. (Cerdelga, 2021)
 
Tetrabenazine
The FDA has approved tetrabenazine for the treatment of chorea associated with Huntington disease. According to the label, patients requiring doses above 50 mg per day should be genotyped for the drug-metabolizing enzyme CYP2D6 to determine if the patient is a PM or EM. For patients categorized as PMs using an FDA-approved test, the maximum daily dose should not exceed 50 mg, with a maximum single dose of 25 mg. (Xenazine, 2019)
 
Codeine
The FDA does not recommend genotyping before prescribing codeine. The FDA has contraindicated codeine for treating pain or cough in children under 12 years of age and codeine is not recommended for use in adolescents ages 12 to 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease. There is an additional warning to mothers not to breastfeed when taking codeine. (FDA, 2017)
 
Siponimod
The FDA has approved siponimod for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. The recommended maintenance dosage is 2 mg. The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. Siponimod is contraindicated in patients with a CYP2C9*3/*3 genotype. (Mayzent, 2019)
 
 
Coding
 
Effective in 2012, there is specific CPT coding for this testing:
 
81225: CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)
 
81226: CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *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) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6)
 
There are also Tier 2 CPT codes that include cytochrome P450 testing:
 
81401: Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) includes –
 
CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
 
CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
 
81402: Molecular pathology procedure, Level 3 (e.g., >10 SNPs, 2-10 methylated variants, or 2-10 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 –
 
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., congenital adrenal hyperplasia, 21-hydroxylase deficiency), common variants (e.g., IVS2-13G, P30L, I172N, exon 6 mutation cluster [I235N, V236E, M238K], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30- kb deletion variant)
 
81404: Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) includes –
 
CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (e.g., primary congenital glaucoma), full gene sequence
 
81405: Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) includes –
 
CYP11B1 (cytochrome P450, family 11, subfamily B, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
 
CYP17A1 (cytochrome P450, family 17, subfamily A, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
 
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., steroid 21-hydroxylase isoform, congenital adrenal hyperplasia), full gene sequence
 
Related Polices
Separate policies have been developed to address genetic testing of CYP450 enzymes for Tamoxifen and Warfarin Treatment:  
 
Policy 2009003-Genetic Test: Tamoxifen Treatment (CYP2D6).
 
Policy 2007015-Genetic Test: Warfarin Dose/Response

Policy/
Coverage:
Effective July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals:
 
    • With Gaucher disease being considered for treatment with eliglustat; OR
    • With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.
 
CYP2C9 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals:
 
    • With relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, being considered for treatment with siponimod.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • selection or dosing of clopidogrel
    • selection or dosage of codeine
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • selection or dosing of clopidogrel
    • selection or dosage of codeine
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
 
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (e.g., the Genecept Assay). Genetic testing for mental health conditions is discussed in coverage policy 2013046.
 
Effective Prior to July 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
 
        • With Gaucher disease being considered for treatment with eliglustat; OR
        • With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
        • Selection or dosing of clopidogrel
        • deciding whether to prescribe codeine for nursing mothers
        • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
        • dosing of immunosuppressant for organ transplantation
        • selection or dose of beta blockers (e.g., metoprolol)
        • dosing and management of antituberculosis medications
        • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (eg, the Genecept Assay). Genetic testing for mental health conditions is discussed in coverage policy 2013046.
 
 
EFFECTIVE PRIOR TO JULY 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
 
    • With Gaucher disease being considered for treatment with eliglustat; OR
    • With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • Selection or dosing of clopidogrel
    • selection or dosing of selective serotonin reuptake inhibitors (SSRI)
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE DECEMBER 2013 – FEBRUARY 2016
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • Selection or dosing of clopidogrel
    • selection or dosing of selective serotonin reuptake inhibitors (SSRI)
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
Effective October 2013 to November 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:  
 
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norephinephrine reuptake inhibitors
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
 
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Note: CYP450 genotyping for Tamoxifen, Warfarin, Clopidogrel and drugs used to treat depression are handled in separate policies.
 
Effective October 2012 – August 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:
 
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
 
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Note: CYP450 genotyping for Tamoxifen, Warfarin, and clopidogrel are handled in separate policies.
 
Effective, May 2010
CYP450 phenotyping for CYP2C19 *2 and *3 alleles meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) in order to identify those who are poor metabolizers of the drug (patients with CYP2C19*2/2,*3/3, and *2/3 genotypes) and who are therefore likely to exhibit poor response to the drug.
 
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication does not meet member benefit certificate primary coverage criteria because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management.  
 
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication is considered investigational.   Investigational services are excluded in the member benefit certificate
 
Effective, January 2005 through April 2010
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is not covered because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management.  Therefore this testing does not meet Primary Coverage Criteria of effectiveness.
 
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational.   Investigational services are excluded in the member benefit certificate

Rationale:
The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes in compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.
 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
 
P450 genotype-guided TREATMENT strategy
 
Clinical Context and Therapy Purpose
The purpose of a P450 genotype-guided strategy is to tailor selection and dosing of drugs based on gene composition for drug metabolism. In theory, this should lead to early selection and optimal dosing of the most effective drugs, while minimizing treatment failures or toxicities.
 
The question addressed in this evidence review is: Does P450 genotype-guided strategy change patient management in a way that improves net health outcome?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant populations of interest are patients being considered for treatment with clopidogrel, eliglustat, tetrabenazine, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, antipsychotic drugs, codeine, efavirenz and other antiretroviral therapies for HIV infection, immunosuppressants for organ transplantation, β-blockers (eg, metoprolol), and antitubercular medications.
 
Interventions
Commercial tests for individual genes or gene panels are available and are listed in the Regulatory Status section. Only those panels that include CYP450 genes are listed in that section.
 
Comparators
The following practice is currently being used: standard clinical management without genetic testing.
 
Timing
Outcomes in the first 3 months are relevant because the interest is in whether P450 genotype-guided strategy reduces adverse events or avoids treatment failure.
 
Setting
Consultations about the choice of the drug generally occur in an outpatient setting, and a variety of specialists may be involved including primary care providers (HIV, β-blockers, tuberculosis and cough medications), cardiologists (clopidogrel), psychiatrists (antidepressants, antipsychotics), neurologists (Huntington disease), and endocrinologists (Gaucher disease).
 
Clopidogrel
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) is the standard of care for the prevention of subsequent atherothrombotic events such as stent thrombosis or recurrent acute coronary syndrome in patients who undergo a percutaneous intervention or who have an acute coronary syndrome.
 
Clopidogrel is a prodrug that is converted to its active form by several CYP450 enzymes (particularly CYP2C19). Individuals with genetic variants that inactivate the CYP2C19 enzyme are associated with lack of response to clopidogrel. There are several variants of CYP2C19 but the 2 most frequent variants associated with loss of function alleles are CYP2C19*2 and CYP2C19*3. It is hypothesized that such individuals may benefit from other drugs such as prasugrel or ticagrelor or a higher dose of clopidogrel. Approximately 30% of whites and blacks and 65% of Asians carry a nonfunctional CYP2C19 gene variant (Scott, 2013). While CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite, the variability in clinical response seen with clopidogrel may also result from other factors such as variable absorption, accelerated platelet turnover, reduced CYP3A metabolic activity, increased adenosine diphosphate exposure, or upregulation of P2Y12 pathways, drug-drug interactions, comorbidities (eg, diabetes, obesity), and medication adherence.
 
Multiple observational studies in patients undergoing percutaneous coronary intervention (PCI) have reported associations between the presence of loss of function alleles and lower levels of active clopidogrel metabolites, high platelet reactivity, and increased risk of adverse cardiovascular events. However, evidence of publication bias has been reported in these studies where smaller studies have reported larger benefits than larger studies which have reported no effect or smaller effect (Holmes, 2011). Wang et al reported post hoc analysis of the CHANCE trial conducted in China; it randomized patients with a transient ischemic attack or minor stroke to clopidogrel plus aspirin or aspirin alone. In a subgroup analysis of patients who did not have the loss of function alleles, clopidogrel plus aspirin vs aspirin alone was associated with statistical significant reduction in the risk of stroke (6.7% vs 12.4%; hazard ratio, 0.51; 95% confidence interval, 0.35 to 0.75) but not among those who carried loss of function alleles (9.4% vs 10.8%; hazard ratio, 0.93; 95% confidence interval, 0.69 to 1.26) (Wang, 2016). Results of this analysis have contributed to the formulation of the hypothesis of a differential effect of clopidogrel in patients with and without loss of function alleles.
 
Trials are important to validate such hypotheses. However, only a few trials of genotype-directed dosing or drug choice have been conducted. It is important to note that these trials use “high on-treatment platelet reactivity” as the outcome measure. Patients who exhibit “high on-treatment platelet reactivity” are referred to as being nonresponsive, hyporesponsive, or resistant to clopidogrel in the published literature.
 
Roberts et al reported on the results of RCT that allocated patients undergoing PCI for acute coronary syndrome or stable angina to genotype-guided management to select for treatment with prasugrel (carriers) or clopidogrel (noncarriers) or to standard treatment with clopidogrel (Roberts, 2012). Among those who received prasugrel and clopidogrel based on genotyping test, 0% and 10%, respectively, exhibited high on-treatment reactivity while 17% patients who received standard treatment with clopidogrel without any genotypes testing exhibited high on-treatment reactivity. This difference was not statistically significant. So et al reported on the results of an RCT that randomized ST-elevation myocardial infarction patients who were carriers of CYP2C19*2, ABCB1 TT, and CYP2C19*17 alleles to prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg/d for 6 days and subsequently 75 mg/d) (So, 2016). Results showed that (1) carriers did not respond to augmented clopidogrel as well as they did to prasugrel (24% patients with high platelet reactivity vs 0%) and (2) among noncarriers, physician-directed clopidogrel was effective for most patients (95% did not have high platelet reactivity).
 
The studies were, in general, well-designed and -conducted, the major limitation being the use of platelet activity, which is an intermediate outcome measure, and lack of reporting on health endpoints over a longer follow-up.
 
Platelet reactivity during treatment is an intermediate end point that has been shown to have a limited value in guiding therapeutic decisions based on results of the large ARTIC RCT (Collet, 2012; Montalsecot, 2014). Briefly, the ARCTIC trial randomized 2440 patients scheduled for coronary stenting to platelet-function monitoring or no monitoring. Platelet-function testing was performed in the monitored group both before and 14 to 30 days after PCI. Multiple therapeutic changes, including an additional loading dose of clopidogrel (at a dose 600 mg) or a loading dose of prasugrel (at a dose of 60 mg) before the procedure, followed by a daily maintenance dose of clopidogrel 150 mg or prasugrel 10 mg, were made according to a predefined protocol. There was no difference in the rate of the primary composite end point (death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization) at 1 year between the monitoring (34.6%) and no monitoring groups (31.1%). In the absence of results from well-performed randomized trials designed to evaluate this issue, performing routine genetic testing or ex vivo tests of platelet reactivity to predict CYP2C19 metabolic state and identify PMs has not been shown to improve health clinical outcomes. TAILOR-PCI (NCT01742117) is a large ongoing RCT that will randomize 5270 patients undergoing PCI to clopidogrel without prospective genotyping guidance or a prospective CYP2C19 genotype-based antiplatelet therapy approach (ticagrelor 90 mg bid in CYP2C19*2 or CYP2C19*3 reduced function allele patients, clopidogrel 75 mg once daily in non-CYP2C19*2 or -CYP2C19*3 patients). The trial is expected to be completed in March 2020.
 
Section Summary: Clopidogrel
Two RCTs have evaluated the role of genetic testing for CYP2C19 for selecting appropriate antiplatelet treatment and/or amplified dosing of clopidogrel using an intermediate outcome measure of platelet reactivity to predict CYP2C19 metabolic state. One RCT has shown there was no statistical difference in patients with “on-treatment high platelet reactivity” who received genotype-guided management or standard treatment with clopidogrel. The second RCT showed that carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, while physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap.
 
Selection and Dosing of Other Drugs
 
Antiretroviral Agents
Efavirenz is a widely used non-nucleoside reverse transcriptase inhibitor component of highly active antiretroviral therapy for patients with HIV infection. However, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with its use. Forty percent to 70% of patients have reported adverse central nervous system events. While most resolve in the first few weeks of treatment, about 6% of patients discontinue efavirenz due to adverse events (King, 2008). Efavirenz is primarily metabolized by the CYP2B6 enzyme, and inactivating variants such as CYP2B6*6 are associated with higher efavirenz exposure, although plasma levels appear not to correlate with adverse events. On the other hand, CYP2B6 PMs have markedly reduced adverse events while maintaining viral immunosuppression at substantially lower doses (Torno, 2008; Gatanaga, 2007). An increased early discontinuation rate with efavirenz has been reported in retrospective cohort studies evaluating multiple CYP450 variants including CYP2B6 (Wyen, 2011; Lubomirov, 2011). CYP2B6 G516T and T983C single nucleotide variants were reported by Ciccacci et al to be associated with susceptibility to Stevens-Johnson syndrome in a case-control study of 27 patients who received nevirapine-containing antiretroviral treatment (Ciccacci, 2013). The current evidence documenting the usefulness of CYP450 variant genotyping to prospectively guide antiretroviral medications and assess its impact on clinical outcomes is lacking.
 
Immunosuppressants for Therapy for Organ Transplantation
Tacrolimus is the mainstay immunosuppressant drug and multiple studies have shown that individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus, possibly delaying achievement of target blood concentrations compared with those who are CYP3A5 nonexpressers (PMs) in whom drug levels may be elevated and possibly result in nephrotoxicity. The current evidence demonstrating the impact of CYP3A5 genotyping to guide tacrolimus dosing and its impact on clinical outcomes is a limited RCT by Thervet et al (Thervet, 2010). This RCT compared the impact of CYP3A5 genotype-informed dosing with standard dosing strategies on tacrolimus drug levels. The trial was not powered to assess any clinical outcomes such as graft function or survival, which otherwise were similar between groups.
 
b-Blockers
Several reports have indicated that lipophilic b-blockers (eg, metoprolol), used in treating hypertension, may exhibit impaired elimination in patients with CYP2D6 variants (Bijl, 2009; Yuan, 2008). The current evidence documenting the usefulness of CYP2D6 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
 
Antitubercular Medications
A number of studies, summarized in a systematic review by Wang et al, have reported an association between CYP2E1 status and the risk of liver toxicity from antitubercular medications (Wang, 2016). The current evidence documenting the usefulness of CYP2E1 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
 
Section Summary: Selection and Dosing of Other Drugs
In general, most published CYP450 pharmacogenomic studies for highly active antiretroviral agents, b-blockers, and antitubercular medications are retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered, and hypothesis generating. Prospective intervention studies, including RCTs documenting clinical usefulness of CYP450 genotyping to improve existing clinical decision-making to guide dose or drug selection, which will then translate into improvement in patient outcomes, were not identified.
 
Summary of Evidence
 
Clopidogrel
For individuals with a need for antiplatelet therapy who are undergoing or being considered for clopidogrel therapy who receive a CYP2C19-guided treatment strategy, the evidence incudes 2 RCTs. Relevant outcomes are overall survival, medication use, and treatment-related morbidity. The 2 RCTs evaluated the impact of CYP2C19 genotyping using an intermediate outcome measure (platelet reactivity). One RCT showed no statistical difference between patients with on-treatment high platelet reactivity between genotype-guided management or standard treatment with clopidogrel. The second RCT showed carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, and physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Other Drugs
For individuals who are undergoing or being considered for treatment with highly active antiretroviral agents, immunosuppressant therapy for organ transplantation, b-blockers, or antitubercular medications who receive a CYP2C19-guided treatment strategy, the evidence includes retrospective studies. Relevant outcomes are medication use and treatment-related morbidity. In general, most published CYP450 pharmacogenomic studies for these drugs consist of retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered and hypothesis generating. Prospective intervention studies, including RCTs documenting the clinical usefulness of CYP450 genotyping to improve existing clinical decision making to guide dose or drug selection, which may then translate into improvement in patient outcomes, were not identified. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Supplemental Information
 
Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
 
In response to requests, input was received from 4 physician specialty societies and 4 academic medical centers while this policy was under review in 2012. Opinions on use of genotype testing of patients being considered for clopidogrel treatment were mixed, with 5 suggesting the test be considered investigational and 3 suggesting it be considered medically necessary.
 
Practice Guidelines and Position Statements
A consensus statement by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) on genetic testing for the selection and dosing of clopidogrel was published in 2010 (Holmes, 2010). The recommendations for practice included the following statements:
 
    1. “Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. Careful clinical judgment is required to assess the importance of the variability in response to clopidogrel for an individual patient and its associated risk to the patient…
    2. Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes in registry experiences and clinical trials.
    3. The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined....
    4. Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. The selection of the specific test, as well as the issue of reimbursement, is both important additional considerations.
    5. The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time….
    6. There are several possible therapeutic options for patients who experience an adverse event while taking clopidogrel in the absence of any concern about medication compliance.”
 
2019 Update
A literature search was conducted through June 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Claassens et al reported on the results of the CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment (POPular Genetics) trial (Claassens, 2019). In this non-inferiority trial, patients with acute coronary syndrome were randomly assigned to receive standard treatment (prasugrel or ticagrelor) or genotype-guided treatment (clopidogrel in those without CYP2C19 loss of-function variants; standard treatment otherwise). Results of the primary combined endpoint met the P value for non-inferiority. Thus, one can conclude that a genotype guided strategy led to outcomes that were at least as good as, if not better than, outcomes with the standard approach of prescribing prasugrel or ticagrelor to all patients. However, the trial results do not inform whether using genotype based strategy for prescribing clopidogrel results in any incremental net health benefit versus standard treatment with clopidogrel. Furthermore, there was no difference in the incidence of PLATO major bleeding between the genotype-guided group and the standard-treatment group (2.3% in both groups; hazard ratio, 0.97; 95% CI, 0.58 to 1.63). The statistical significant difference observed in the primary bleeding outcome was primarily driven by PLATO minor bleeding events in the genotype-guided group versus standard-treatment group (7.6% vs. 10.5%; HR=0.72; 95% CI, 0.55 to 0.94).
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Pereira et al reported the results of the open-label randomized TAILOR-PCI trial (NCT01742117) of 5,302 patients undergoing PCI for acute coronary syndromes or stable coronary artery disease (Pereira, 2020). The genotype-guided group underwent point-of-care genotyping for detection of CYP2C19 carriers and were prescribed ticagrelor (prasugrel was recommended as an alternative for patients who did not tolerate ticagrelor) and noncarriers were prescribed clopidogrel. Patients randomized to the conventional group were prescribed clopidogrel and underwent genotyping after 12 months. Among 5,302 patients randomized (median age, 62 years; 25% women), 94% completed the trial. Of 1,849 CYP2C19 carriers, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months) occurred in 35 of 903 CYP2C19 carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (HR=0.66; 95% CI 0.43 to 1.02; p = 0.06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR= 1.22; 95% CI: 0.60 to 2.51; p = 0.58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR= 0.84; 95% CI: 0.65 to 1.07; p = 0.16). The trial failed to meet the pre-specified endpoint and the authors contend that the trial was underpowered to detect an effect size less than the 50% relative risk after a revised sample calculation. Despite the occurrence of 89 ischemic events observed in this trial, which exceeded the 76 events anticipated to provide adequate power, the observed RR reduction was 34% instead of the estimated 50%, hence a borderline p value of 0.056 was observed. Further, the authors also comment that the potential benefit of genotype-guided oral P2Y12 inhibitor therapy may be important early after PCI rather than 12 months after PCI. A post-hoc analysis of the data from the trial showed that a nearly 80% reduction in the rate of adverse events occurred in the first three months of treatment among patients who received genetically guided therapy compared with those who did not.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
0031UCYP1A2 (cytochrome P450 family 1, subfamily A, member 2) (eg, drug metabolism) gene analysis, common variants (ie, *1F, *1K, *6, *7)
81225CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)
81226CYP2D6 (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)
81227CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
81230CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, *2, *22)
81231CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *7)
81401Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, *2, *3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G>A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G>A, 1138G>C, 1620C>A, 1620C>G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G>A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A>G, m.1494C>T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81402Molecular pathology procedure, Level 3 (eg, >10 SNPs, 2-10 methylated variants, or 2-10 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]) Chromosome 1p-/19q- (eg, glial tumors), deletion analysis Chromosome 18q- (eg, D18S55, D18S58, D18S61, D18S64, and D18S69) (eg, colon cancer), allelic imbalance assessment (ie, loss of heterozygosity) COL1A1/PDGFB (t(17;22)) (eg, dermatofibrosarcoma protuberans), translocation analysis, multiple breakpoints, qualitative, and quantitative, if performed CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (eg, congenital adrenal hyperplasia, 21-hydroxylase deficiency), common variants (eg, IVS2-13G, P30L, I172N, exon 6 mutation cluster [I235N, V236E, M238K], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30-kb deletion variant) ESR1/PGR (receptor 1/progesterone receptor) ratio (eg, breast cancer) MEFV (Mediterranean fever) (eg, familial Mediterranean fever), common variants (eg, E148Q, P369S, F479L, M680I, I692del, M694V, M694I, K695R, V726A, A744S, R761H) TRD@ (T cell antigen receptor, delta) (eg, leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population Uniparental disomy (UPD) (eg, Russell-Silver syndrome, Prader-Willi/Angelman syndrome), short tandem repeat (STR) analysis
81404Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
81405Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)

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