Genetic Testing for Cytochrome P450 and VKORC1 Polymorphisms
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Defines medical policy coverage for pharmacogenetic testing of cytochrome P450 enzymes and VKORC1 for Providence Health Plan members, specifying indications considered medically necessary or not and listing disallowed multi-gene panels.
No material clinical or coverage changes in this revision.
Coverage Criteria
inv-02: Not medically necessary
Not medically necessary conditions and test types
Explicit list of common non-covered indications
Multi-gene panels excluded
VKORC1 universally not covered
Named example panels are explicitly not covered
inv-03: Covered gene–drug indications
Covered situations where testing may be necessary
Each listed gene–drug pair is identified in the policy as a situation with sufficient evidence to consider testing.
Specific named commercial multi-gene pharmacogenomic panels are explicitly not covered under this policy. Examples listed in the policy include EffectiveRX Neuropsychiatric Panel (GENETWORx), GeneSight Psychotropic (Assurex Health), OneOme RightMed Comprehensive and RightMed Mental Health Gene Reports, Genelex Polypharmacy panels, Tempus nP Assay, UCSF Pharmacogenomics Panel, and multiple other proprietary neuropsychiatric, pain, and polypharmacy pharmacogenomic tests named in the exclusion list.
Multigene panel tests marketed to guide medication selection for psychiatric disorders or for acute or chronic pain are not supported by the evidence cited in this policy. Systematic reviews of tests such as GeneSight Psychotropic and IDgenetix report high risk of bias, short follow-up, and lack of significant results for primary outcomes; therefore these multigene panels and similar broad pharmacogenetic panels are considered not medically necessary for guiding medication selection in psychiatry or pain.
When an unlisted code is submitted for a service that is a non-covered item under this policy, the claim will be denied as not covered. For potentially covered services billed with unlisted molecular assay codes, prior authorization is recommended to avoid post-service denial.
The policy states that VKORC1 genotyping is considered not medically necessary for the treatment of any indication. In addition, multi-gene CYP450 panels are considered not medically necessary, and CYP450 genotyping for indications that do not meet the specific covered criteria in Section I (for example testing for opioids, SSRIs, antipsychotics, meloxicam, H. pylori, tamoxifen, or warfarin) is also not medically necessary.
For VKORC1 genotyping and for CYP gene genotyping outside the specific gene–drug pairs identified as covered in this policy, the evidence is insufficient to show improved clinical outcomes. The policy therefore finds insufficient evidence to support routine genotype testing of VKORC1 or most other CYP genes for medication selection or dosing, and such testing may be denied when submitted for unsupported indications.
Revision history notes a change in denial classification: prior versions recorded investigational denials for certain tests; the policy history documents a change from an 'investigational' denial type to 'not medically necessary' for applicable items as part of prior updates.
Covered Indications (Specific Gene–Drug Pairs)
inv-31: CYP2C9 genotyping for adults with relapsing forms of multiple sclerosis being considered for siponimod
Used to determine candidacy for siponimod per policy I.A
inv-32: CYP2C19 genotyping for patients being considered for clopidogrel for acute coronary syndrome, recent MI, recent stroke, or established peripheral arterial disease
Any one of the four indications suffices to meet criteria
inv-33: CYP2D6 genotyping for Gaucher disease type I patients being considered for eliglustat or for Huntington disease patients being considered for tetrabenazine
Either indication sufficient
inv-34: CYP27A1 genotyping for patients with cerebrotendinous xanthomatosis being considered for chenodiol
Single-condition requirement
inv-35: CYP2C9 testing to inform siponimod (Mayzent) use for relapsing forms of multiple sclerosis in adults
CYP2C9 testing to inform siponimod (Mayzent) use for relapsing forms of multiple sclerosis in adults
Testing tied to siponimod prescribing pathway
inv-36: CYP2C19 testing to inform clopidogrel (Plavix) use for FDA-outlined conditions (acute coronary syndrome, recent MI, recent stroke, or established peripheral arterial disease)
CYP2C19 testing to inform clopidogrel (Plavix) use for FDA-outlined conditions (acute coronary syndrome, recent MI, recent stroke, or established peripheral arterial disease)
Meets policy I.B when any one condition is present
inv-37: CYP2D6 testing to inform tetrabenazine (Xenazine) use in Huntington's chorea
CYP2D6 testing to inform tetrabenazine (Xenazine) use in Huntington's chorea
Meets policy I.C.2
inv-38: CYP2D6 testing to inform eliglustat (Cerdelga) use in Gaucher disease type 1
CYP2D6 testing to inform eliglustat (Cerdelga) use in Gaucher disease type 1
Meets policy I.C.1
inv-39: CYP27A1 testing to inform chenodiol (Chenodal) use in cerebrotendinous xanthomatosis
CYP27A1 testing to inform chenodiol (Chenodal) use in cerebrotendinous xanthomatosis
Meets policy I.D
Not Covered
The policy explicitly lists several categories of services that are not covered, including VKORC1 genotyping for any indication, multi-gene CYP450 panels, and a number of named commercial pharmacogenomic panels (for example, EffectiveRX Neuropsychiatric Panel, GeneSight Psychotropic, OneOme RightMed, Genelex Polypharmacy, Tempus nP Assay, and UCSF Pharmacogenomics Panel). These tests are identified in the policy exclusion list and are considered not medically necessary.
Multigene panels intended to guide psychiatric medication selection (for example GeneSight Psychotropic and IDgenetix) and broad pharmacogenetic panels for pain or other indications lack robust evidence of clinical benefit according to the policy's evidence review; such panels are therefore listed as not covered.
Per the policy coding notes, any service billed with an unlisted molecular procedure code that corresponds to a non-covered service addressed by this policy will be denied as not covered. Providers are advised that unlisted codes are reviewed for medical necessity, correct coding, and pricing at claim adjudication.
Billing and Coding
| 0029U | Proprietary/targeted pharmacogenetic sequence analysis (listed in billing section) |
| 0030U | Proprietary/targeted pharmacogenetic sequence analysis (listed in billing section) |
| 0031U | Proprietary/targeted pharmacogenetic sequence analysis (listed in billing section) |
| 0070U | CYP2D6 gene analysis, common and select rare variants (allele list included) |
| 0071U | CYP2D6 gene analysis, full gene sequence (list separately in addition to code for primary procedure) |
| 0072U | CYP2D6 targeted sequence analysis (eg, CYP2D6-2D7 hybrid gene) (list separately) |
| 0073U | Additional CYP2D6-related targeted analysis (listed) |
| 0029U | PLA/Proprietary codes referenced in policy text |
| 0030U | PLA/Proprietary codes referenced in policy text |
| 0031U | PLA/Proprietary codes referenced in policy text |
| 0070U | PLA/Proprietary code referenced |
| 0071U | PLA/Proprietary code referenced |
| 0072U | PLA/Proprietary code referenced |
| 0073U | PLA/Proprietary code referenced |
| 0074U | PLA/Proprietary code referenced |
| 0075U | PLA/Proprietary code referenced |
| 0076U | PLA/Proprietary code referenced |
Provider Actions and Billing Guidance
Commercial product applicability
This policy applies to Commercial product members; follow Company prior authorization processes and plan benefit rules when submitting requests for coverage.
Adhere to billing guidance for U-code pharmacogenetic tests
Certain pharmacogenetic targeted sequence analysis tests are identified by proprietary HCPCS U-codes in the billing section; providers must follow payer billing guidance and Company prior authorization processes for those U-codes when applicable.
Obtain prior authorization when using unlisted molecular assay codes
Prior authorization is recommended when submitting unlisted codes (e.g., 81479, 81599) for services that may be covered to avoid post-service denial; if an unlisted code is submitted for a non-covered service it will be denied as not covered.
Verify coverage and authorize when uncertain
Confirm coverage criteria and documentation before ordering testing; when coverage is uncertain, obtain prior authorization to document medical necessity per Company processes.
Step therapy not specified
No step therapy rules are specified in this policy for CYP450 or VKORC1 testing.
Provide supportive documentation of medical necessity
When ordering tests, ensure documentation demonstrates that the patient meets the policy's specific medical necessity criteria (e.g., indication and that the patient is being considered for the listed medication).
- Documentation should support the specific gene–drug indication listed in the policy (for example, intent to use clopidogrel, siponimod, eliglustat, tetrabenazine, or chenodiol).
- Coverage determinations are guided by the policy and the applicable coverage agreement.
Include coding details and CYP2D6 allele/copy-number information
Billing and coding submissions should reference the specific targeted sequence analysis and proprietary U-codes and, when applicable, list CYP2D6 allele and copy-number details included in the test.
- Include the specific HCPCS/CPT/PLA/U-code submitted (examples: 0029U, 0070U, 0071U, 81226) and, for CYP2D6 testing, the allele(s) and copy-number/duplication/deletion analysis results as applicable.
- Reference any listed allele nomenclature when applicable (policy enumerates extensive CYP2D6 alleles).
Unlisted code review and claim-level documentation
All unlisted codes are reviewed at the claim level for medical necessity, correct coding, and pricing; provider contracts, member benefits, eligibility, and utilization audits may affect reimbursement.
- If an unlisted code is submitted for a non-covered service it will be denied as not covered.
- Prior authorization is recommended for unlisted codes used for potentially covered services to avoid post-service denial.
Denial risk if coverage criteria not met
Claims for CYP450 genotyping will be denied when the specific coverage criteria in Section I are not met, including testing related to opioids, SSRIs, antipsychotics, meloxicam, H. pylori, tamoxifen, and warfarin, and for multi-gene CYP450 panels and VKORC1 testing which are not medically necessary.
- Do not submit claims for excluded indications or multi-gene panels—these are considered not medically necessary and are subject to denial.
Insufficient-evidence denial risk for VKORC1 and many CYP tests
Testing for VKORC1 genotyping and most other CYP gene genotyping outside the specified gene–drug pairs is considered to have insufficient evidence of improved outcomes and may be denied.
- Avoid ordering VKORC1 genotyping for any indication, as it is considered not medically necessary per the policy.
Denial risk for unlisted code submissions
If an unlisted code is submitted for a service specifically excluded by this policy it will be denied as not covered; for potentially covered services billed with unlisted codes, prior authorization is recommended to reduce post-service denial risk.
Background
Pharmacogenetics studies how inherited or acquired genetic variants influence medication response and drug metabolism. The policy highlights Cytochrome P450 (CYP450) enzymes — notably CYP2D6, CYP2C19, and CYP2C9 — as major drug-metabolizing enzymes. While genotyping of these genes may inform drug selection or dosing in a limited set of well-defined gene–drug pairs, the overall clinical utility varies by gene and indication and is supported only for specific situations described in the coverage criteria.
Definitions
Revision History
Denial type changed from 'investigational' to 'not medically necessary' in policy revision notes.
Annual update that added non-covered criteria to the policy.
Annual review noted with no changes to policy criteria or code configuration.
Q2 2026 code set update reflected in revision history (effective date 2026-07-01).
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