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Effective Date: 07/01/2018 Title: Pharmacogenetics Testing
Revision Date: Document: BI581:00
CPT Code(s): G9143, S0265, 81225-81227, 81230-81232, 81283, 81291, 81335, 81346, 81350, 81355, 81373, 81376, 81380-81382, 81479, 96040, 0028U, 0030U, 0033U-0034U
Public Statement

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

1)    Pharmacogenetics is the study of variability in drug response due to genetic factors.

2)    Many pharmacogenetics test are considered experimental and investigational because their clinical utility has not been proven.

3)    All pharmacogenetics testing requires prior authorization.

Medical Statement

QualChoice follows MCG guidelines on Pharmacogenetics Testing. Please refer to appropriate MCG guidelines or DNA Direct for details.

1)    The following tests are considered experimental and investigational due to inconclusive or non-supportive evidence, and therefore are not covered:

a)    Cytochrome P450 – 3A4/3A5 Genotyping; MCG ACG: A-0775 (AC) Hepatic cytochrome P450 enzymes play a significant role in drug metabolism. Cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) are responsible for the metabolism of many endogenous substrates of the many commonly used medications, including immunosuppressives (e.g., tacrolimus), opioid analgesics (e.g., fentanyl, methadone),antibiotics (e.g., erythromycin, clarithromycin), psychotropics (e.g., clozapine, quetiapine), statins (e.g., simvastatin), and tyrosine kinase inhibitors (e.g., sunitinib);

b)    Psychotropic Medication Pharmacogenetics – CYP450 Polymorphisms and AmpliChip Panel; MCG ACG: A-0692 (AC). Cytochrome P450 enzymes, primarily CYP2D6 (11) and CYP2C19, (12) are involved in the metabolism of tricyclic antidepressants, SSRIs, and antipsychotics; more than one CYP450 enzyme may be involved in the metabolism of a given psychotropic medication;

c)    Psychotropic Medication Pharmacogenetics – ABCB1, BDNF, COMT, DRD, FKBP5, HTR, MC4R, SLC6A4, SPTA1, and TPH1 Genes; MCG ACG: A-0859 (AC);

d)    Psychotropic Medication Pharmacogenetics – Gene Panels; MCG ACG: A-0861 (AC);

e)    Psychotropic Medication Pharmacogenetics – HLA Typing; MCG ACG: A-0862 (AC);

f)     GeneSight panel or any other pharmacogenomics testing panel for Major Depressive Disorder (CPT 81599, 81479 and 84999)-- DNA Direct.

g)    Azathioprine and 6-Mercaptopurine Pharmacogenetics – TPMT Gene; MCG ACG: A-0628 (AC);

h)   Clopidogrel Pharmacogenetics – CYP2C19 Gene; MCG ACG: A-0631 (AC);

i)     Irinotecan Pharmacogenetics – UGT1A1 Gene; MCG ACG: A-0624 (AC);

j)      Tamoxifen Pharmacogenetics – CYP2D6 Gene; MCG ACG: A-0647 (AC) (NCCN and DNA Direct also do not support this);

k)    Carbamazepine Pharmacogenetics – HLA Testing; MCG ACG: A-0649 (AC);

l)     Hepatitis C Medication Pharmacogenetics – IFNL3 and IFNL4 Genes; MCG: A-0783 (AC);

m)  Citalopram Pharmacogenetics – GRIK4 Gene; MCG ACG: A-0820 (AC);

n)   Naltrexone Pharmacogenetics – OPRM1 Gene; MCG ACG: A-0845 (AC);

o)    ADHD Medication Pharmacogenetics – ADRA2A, COMT, CYP2B6, and CYP2D6 Genes for Atomoxetine (Strattera); MCG ACG: A-0764 (AC).

2)    The following pharmacogenetics tests require prior-authorization:

a)    Warfarin Pharmacogenetics – CYP2C9, CYP4F2, and VKORC1 Gene testing may be indicated for members who meet the following criteria:

                          i.    Age 18 years and older;

                         ii.    Venous thromboembolism prophylaxis with warfarin planned for elective hip or knee arthroplasty;

                       iii.    No history of bleeding disorder or thrombophilia.

b)    5-Fluorouracil Pharmacogenetics – DPYD, MTHFR, and TYMS Gene testing requires that the member is considering or is currently on therapy with any 5-FU containing drug including:

                          i.    i5-fluorouracil (Fluorouracil®, Adrucil®);

                         ii.    Capecitabine (Xeloda®);

                       iii.    Fluorouracil topical formulations (Carac®, Efudex®, Fluoroplex®).

Codes Used in This BI:

G9143    Warfarin responsiveness testing by genetic tech using any method, any # of specimen(s)

S0265    Genetic counseling, under physician supv, ea 15 mn

81225    CYP2C19, gene analysis, common variants

81226    CYP2D6, gene analysis, common variants

81227    CYP2C9, gene analysis, common variants

81230    CYP3A4, gene analysis, common variants

81231    CYP3A5, gene analysis, common variants

81232    DPYD, gene analysis, common variant(s)

81283    IFNL3, gene analysis, rs12979860 variant

81291    MTHFR gene analysis, common variants

81335    TPMT, gene analysis, common variants

81346    TYMS, gene analysis, common variant(s)

81350    UGT1A1, gene analysis, gene analysis, common variants

81355    VKORC1, gene analysis, common variant(s)

81373    HLA Class I typing, low resolution; one locus, ea

81376    HLA Class II typing, low resolution; one locus, ea

81380    HLA Class I typing, high resolution; one locus, ea

81381    HLA Class I typing, high resolution; one allele or allele group, ea

81382    HLA Class II typing, high resolution; one locus, ea

81479    Unlisted molecular pathology procedure

96040    Medical genetics & genetic counseling services, ea 30 mn face-to-face w/patient/family

0028U   CYP2D6, gene analy, copy # variants, common variants w/reflex to targeted seq anal  

              (code deleted 1/1/19)             

0030U   Drug metabolism, targeted seq anal

0033U   HTR2A, HTR2C gene analysis, common variants

0034U   TPMT, NUDT15 gene analysis, common variants


Any pharmacogenetic test that meets the above prior-authorization criteria is covered once per member’s life time.


For psychotropic medication multigene panels, evidence is insufficient, conflicting, or poor and demonstrates an incomplete assessment of net benefit vs harm; additional research is recommended. (RG B) The clinical utility of pharmacogenetic testing for psychiatric disorders has not been demonstrated in large randomized clinical trials.(4)(23)(24) (EG 2) A systematic review and meta-analysis suggested that although studies found that SLC6A4, HTR1A, HTR2A, TPH1, and BDNF genes may play a role in antidepressant response, there were methodological problems with the studies that may have biased the findings.(25) (EG 1) A meta-analysis of data from 3 prospective studies involving 2256 participants (Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Genome-Based Therapeutic Drugs for Depression (GENDEP), and Munich Antidepressant Response Signature Project (MARS)) did not find any common genetic variation that reliably predicted antidepressant treatment outcome.(26) (EG 1) A meta-analysis of 3 prospective studies, only one of which was a randomized double-blind study, involving 258 patients with depression who had failed treatment with at least one antidepressant reported a significantly increased likelihood of achieving a clinical response to antidepressants in patients for whom the results of a commercially available multigene panel test (GeneSight) were provided to treating providers, as compared with patients who were treated using standard care (i.e., unguided by results of pharmacogenetic testing).(27) (EG 1) A study involving 166 patients with major depressive disorder randomized to antidepressants vs counseling reported no effect of polymorphisms in COMT, HTR, and SLC6A4 genes on treatment response or remission rates in either group.(10) (EG 1) A naturalistic unblinded prospective study evaluating pharmacogenetic-guided therapy utilizing a commercially available multigene panel test (Genecept) in 685 patients with anxiety or mood disorders reported that 87% of patients showed clinically measurable improvement as measured by the Clinical Global Impressions - Improvement scale. Significant decreases in anxiety, depression, and medication side effects, and increases in quality of life, were reported by patients. The direct impact of pharmacogenetic testing could not be evaluated due to the lack of a control group.(28) (EG 2) A prospective randomized trial of 237 patients with various psychiatric diagnoses (e.g., depression, anxiety, ADHD, psychosis) reported a significant decrease in adverse drug events over a 3-month follow-up period in patients receiving pharmacogenetic-guided therapy utilizing a commercially available multigene panel test (NeuroIDgenetix) as compared with a control group receiving standard treatment; treatment efficacy was similar in both groups.(29) (EG 1) An analysis of 24 candidate genes involving a subset (431 patients) of the GENDEP cohort found no genetic association with antidepressant adrenergic, cholinergic, and histaminergic side effects.

A potential link between HTR2C single nucleotide polymorphisms and serotoninergic side effects could not be confirmed in a replication dataset. A systematic review and meta-analysis of CYP450 polymorphisms in the management of adults with schizophrenia identified no studies that evaluated the clinical utility of CYP (predominantly CYP2D6) genotyping and concluded that routine pharmacogenetic testing prior to initiation of antipsychotic medications was not warranted. Review articles assert that although dosing recommendations for various metabolizer types (poor, intermediate, extensive, and ultra-rapid) have emerged in the published literature, there are no generally accepted guidelines or evidence-based dosing adjustments. A systematic review of pharmacogenetic testing to predict antipsychotic-induced weight gain concluded that the available association studies are conflicting due largely to methodological variation and small sample sizes. Additional studies focused on clinical utility were recommended. A review article of antipsychotic-induced weight gain identified several genetic markers that have been consistently replicated in independent samples, including DRD2 and HTR2C, but studies have been limited by methodological variability (e.g., in study design, type of antipsychotic used, concomitant medications) that will need to be addressed prior to development of valid and clinically useful predictive tests.

Clopidogrel is a prodrug that undergoes transformation to its active metabolite by hepatic cytochrome P450 (CYP) isoenzymes, primarily CYP2C19. Impaired Clopidogrel responsiveness, due to decreased formation of the active metabolite, has been associated with increased risk for cardiovascular events, stent thrombosis, and death. Significant interindividual variability exists in Clopidogrel responsiveness, and polymorphisms in the CYP2C19 gene contribute to approximately 12% of (but are not solely responsible for) this variability, other contributing factors include other genetic variants (e.g., ABCB1), obesity, diabetes, smoking, and concomitant medications (e.g., omeprazole, esomeprazole, ketoconazole).

Individuals carrying 1 or 2 variant loss-of-function alleles (i.e., CYP2C19*2, CYP2C19*3) have lower levels of clopidogrel`s active metabolite and are at increased risk for cardiovascular events. Ethnic differences exist in CYP2C19 allele distribution. The frequency of CYP2C19*2 is estimated to be 30% in Asian populations vs 15% in Caucasian and African American populations, whereas the frequency of CYP2C19*3 is estimated to be 6% to 10% in Asian populations and rare in Caucasian and African American populations. Existing studies suggest that individuals with at least one CYP2C19 variant allele are at increased risk for stent thrombosis. However, an analysis of genotyped individuals from previous randomized double-blind placebo-controlled trials comparing Clopidogrel with placebo revealed that CYP2C19 loss-of-function variants do not alter the safety and efficacy of Clopidogrel. The authors of this study concluded that loss-of-function allele carrier status should not preclude Clopidogrel therapy at currently recommended doses in patients with acute coronary syndromes being managed conservatively (i.e., without stenting). Systematic reviews and meta-analyses have detected a lower risk of cardiovascular outcomes and an increased risk of bleeding in individuals carrying 1 or 2 copies of the variant allele of the CYP2C19 gene (i.e., CYP2C19*17) associated with increased metabolism (gain-of-function allele) of Clopidogrel; however, the presence of this variant does not appear to confer a protective effect on the occurrence of ischemic events following coronary stent placement. Commercially available CYP2C19 genotyping tests vary in the number of polymorphisms tested. CYP2C19 genotyping may also be included in broader pharmacogenetic panels. Point-of-care genetic tests for the rapid identification of CYP2C19 carrier status have been developed.

The IFNL4 (interferon, lambda-4) gene is a frameshift variant of the IFNL3 gene. The rs12979860 polymorphism of IFNL3 lies within the first intron of IFNL4. The TT allele of IFNL4 (ss469415590, also known as rs368234815) is associated with spontaneous hepatitis C virus clearance. Donor IFNL4 TT/TT genotype is associated with early post-transplant fibrosis and decreased post-transplant survival. The delta G allele is more strongly associated with an unfavorable response to treatment of chronic hepatitis C virus with pegylated interferon and ribavirin than the T allele of IFNL3 rs12979860 in individuals of African ancestry. Findings of meta-analyses evaluating the association between the IFNL4 rs368234815 polymorphism and sustained virological response in patients with chronic hepatitis C virus are conflicting. A meta-analysis of 10 studies involving 4765 patients concluded that the IFNL4 rs368234815 TT/TT genotype was an important predictor of sustained viral response, independent of hepatitis C virus genotype, ethnicity, or treatment regimen. Another meta-analysis of 6 studies (4 of which were included in both meta-analyses) involving 2304 patients found an association between IFNL4 rs368234815 TT/TT genotype and sustained virological response in patients with chronic hepatitis C virus treated with pegylated interferon plus ribavirin, but the effect was limited to Caucasian patients with hepatitis C virus genotypes 1 and 4

Azathioprine and 6-mercaptopurine are prodrugs that undergo extensive metabolism by several enzymes, including thiopurine S-methyltransferase (TPMT).TPMT activity is correlated with variations in sensitivity and toxicity to thiopurine drugs. Patients homozygous for polymorphisms that reduce TPMT activity (poor metabolizers) are more likely to present with severe myelosuppression and toxicity. Conversely, high TPMT activity may be associated with a poor response to treatment. For TPMT gene testing, evidence is insufficient, conflicting, or poor and demonstrates an incomplete assessment of net benefit vs harm; additional research is recommended. TPMT mutations appear to account for less than 1/3 of observed thiopurine-related toxicity, and 73% of patients with severe bone marrow suppression do not carry a TPMT mutation; this suggests a multifactorial etiology for myelosuppression, including other gene variants.


1.     Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmacogenomics and Personalized Medicine 2016; 9:97-106. DOI: 10.2147/PGPM.S86013.

2.     Wang D, Sadee W. The Making of a CYP3A Biomarker Panel for Guiding Drug Therapy. Journal of personalized medicine 2012; 2(4):175-91.

3.     Booth RA, et al. Assessment of thiopurine s-methyltransferase activity in patients prescribed thiopurines: a systematic review. Annals of Internal Medicine 2011; 154(12):814-23.

4.     Moon W, Loftus EV. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 2016; 43(8):863-83.

5.     Mega JL, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. New England Journal of Medicine 2009; 360(4):354-62.

6.     Sorich MJ, Polasek TM, Wiese MD. Challenges and limitations in the interpretation of systematic reviews: making sense of clopidogrel and CYP2C19 pharmacogenetics. Clinical Pharmacology and Therapeutics 2013; 94(3):376-82.

7.     Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a systematic review. Journal of the American Medical Association 2014; 312(6):631-40.

8.     Indolfi G, Azzari C, Resti M. Polymorphisms in the IFNL3/IL28B gene and hepatitis C: from adults to children. World Journal of Gastroenterology 2014; 20(28):9245-52.

Application to Products
This policy applies to all health plans administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet. Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) for those plans insured by QualChoice. In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC, the SPD or EOC, as applicable, will prevail. State and federal mandates will be followed as they apply.
Changes: QualChoice reserves the right to alter, amend, change or supplement benefit interpretations as needed.
This policy has recently been updated. Please use the index above or enter policy title in search bar for the latest version.