ModifiedCentenePolicy N/A

Genetic Testing: Eye Disorders (Clinical Coverage Criteria)

Defines medical necessity and investigational indications for genetic testing related to inherited eye disorders (e.g., macular degeneration, RPE65-associated retinal dystrophy, glaucoma, known familial variants) for members of Centene-affiliated health plans.

Policy Summary

PayerCentene

PolicyGenetic Testing: Eye Disorders (Clinical Coverage Criteria)

Policy CodePolicy N/A

Change TypeCoding and editorial revisions (V1.2024)

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization and document diagnosis and familial variant or Luxturna candidacy when ordering genetic testing (include proof of close relative variant for targeted testing and evidence of consideration for voretigene neparvovec for RPE65 testing).

SourceLink

POLICY UPDATE CHANGES

For RPE65-Associated Retinal Dystrophy/Leber Congenital Amaurosis: added CPT code 81479 to II.

Updated title to reflect V1.2024 version and updated overview, coding, reference-table, background and references.

Replaced 'coverage criteria' terminology with 'criteria' throughout the policy.

~500genes identified that contribute to inherited eye diseases

~1/3proportion of human diseases that may affect the eyes

RPE65 biallelicgene requirement for Luxturna eligibility

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Criteria for Medical Necessity and Investigational Determinations

Known Familial Variant Analysis

Targeted mutation analysis for a known familial variant (81403) is considered medically necessary when ALL of the following are met:

Known familial variant criteria: A. The member/enrollee has a close relative with a known pathogenic or likely pathogenic variant causing the condition.

Close relatives include first-, second-, or third-degree blood relatives.

Known familial variant criteria: B. The requested test is targeted mutation analysis for that known familial variant (CPT 81403).

Targeted mutation analysis for indications other than a close relative with a known pathogenic/likely pathogenic variant is investigational.

RPE65 Sequencing / Panel Analysis

Genetic testing via RPE65 sequencing/deletion-duplication analysis or a multigene panel that includes RPE65 is considered medically necessary when ALL of the following are met:

RPE65 testing for therapy consideration: A. The member/enrollee has a diagnosis of a retinal dystrophy or Leber congenital amaurosis.

Documentation should include clinical diagnosis of retinal dystrophy/Leber congenital amaurosis.

RPE65 testing for therapy consideration: B. The member/enrollee is being considered for treatment with voretigene neparvovec (Luxturna).

Detection of pathogenic or likely pathogenic variants in both copies of RPE65 (biallelic) is required; when two variants are found, documentation of trans configuration is required.

Macular Degeneration

Genetic testing for macular degeneration is considered:

Macular Degeneration: Genetic testing for macular degeneration (e.g., CPT codes 81404, 81406, 81408, 81479, 81599, 0205U) is considered investigational.

Testing should be performed only in CLIA-certified laboratories if ordered; direct-to-consumer AMD genetic testing is not recommended and routine genotyping to change management is not supported by current evidence.

Glaucoma

Genetic testing for glaucoma is considered:

Glaucoma: Genetic testing for glaucoma (e.g., CPT codes 81404, 81406, 81407, 81408, 81479) is considered investigational.

Very few genes are implicated in rare congenital forms; routine genetic testing for late-onset primary open-angle glaucoma is discouraged pending evidence of clinical utility.

Diagnosis-confirming testing for specific inherited eye disorders

Genetic testing to establish or confirm diagnosis is considered medically necessary when ALL of the following are met:

Clinical features consistent with disorder: The member/enrollee demonstrates clinical features consistent with a listed Mendelian eye disorder (examples include Duane syndrome; familial exudative vitreoretinopathy; retinitis pigmentosa; aniridia; X-linked congenital retinoschisis; presenile cataracts).

List is not comprehensive; other disorders will be evaluated per the General Approach to Genetic and Molecular Testing policy.

Clinical and coverage criteria

Coverage and clinical-use guidance summarized from referenced society and regulatory statements:

RPE65 testing for voretigene neparvovec candidacy: Genetic testing is required to detect pathogenic or likely pathogenic variants in RPE65; pathogenic/likely pathogenic variants must be present in both copies of RPE65 to establish biallelic disease. When two variants are detected, additional documentation of trans configuration is required.biallelic pathogenic or likely pathogenic variants with documented trans configuration

FDA approval for voretigene neparvovec applies to confirmed biallelic RPE65 mutation-associated retinal dystrophy in patients with sufficient viable retinal cells.

AMD genetic testing guidance: AMD genetic testing may provide information about progression risk but current evidence does not support altering clinical management or using genotyping to guide anti-VEGF therapy; testing should be performed only in CLIA-certified laboratories and direct-to-consumer tests are discouraged.N/A

ASRS recommends confining AMD genotyping to research until prospective studies demonstrate benefit.

Targeted mutation analysis (CPT code 81403) is considered investigational when used for indications other than confirming a known familial pathogenic or likely pathogenic variant. The policy requires that this test be used only when the member has a close relative with a known pathogenic or likely pathogenic variant; testing outside that scenario does not meet medical necessity criteria and may be denied.

Direct-to-consumer (DTC) genetic testing for age-related macular degeneration is discouraged because DTC tests often do not meet Clinical Laboratory Improvement Amendments (CLIA) standards and have high variability in results. The AAO also recommends avoiding DTC testing and advises that genotyping for genetically complex disorders such as AMD and late-onset primary open-angle glaucoma be confined to research until prospective trials demonstrate clinical benefit.

Genetic testing for macular degeneration (codes including 81404, 81406, 81408, 81479, 81599, 0205U) and genetic testing for glaucoma (codes including 81404, 81406, 81407, 81408, 81479) are explicitly considered investigational by this policy and are not supported as medically necessary indications.

Using AMD genetic testing to alter clinical management—such as increasing surveillance frequency, changing treatment plans, or predicting anti-VEGF response—is not supported by current evidence and is therefore discouraged. The AAO and ASRS guidance note that while AMD genotyping may provide information on progression risk, there is insufficient evidence that management changes based on genotyping improve visual outcomes; genotyping for this purpose should be limited to CLIA-certified laboratories and to research settings until prospective studies show benefit.

Relevant Billing and Diagnosis Codes

Referenced CPT/Proprietary Codesmixed

81403	Targeted mutation analysis for a known familial variant
81404	CPT listed (multigene panel / sequencing)
81406	CPT listed (sequencing)
81407	CPT listed (sequencing)
81408	CPT listed (panel/sequencing)
81479	Unlisted molecular pathology procedure
81599	Unlisted diagnostic procedure
0205U	Proprietary laboratory analysis (Vita Risk)

Referenced ICD-10 Codes (examples)ICD-10

H35.30	Macular degeneration, unspecified
H35.3110	Nonexudative macular degeneration, right eye, unspecified
H35.3194	Nonexudative macular degeneration, other eye, specified
H35.50	Hereditary retinal dystrophy
H40	Glaucoma
Z13.5	Encounter for screening for eye and ear disorders

Referenced CPT codes (added in revision)CPT

81479

unlisted molecular pathology procedure

Genetic test phase documentation — RPE65 variants

RequirementWhen two pathogenic or likely pathogenic RPE65 variants are detected, additional documentation that the variants are in trans configuration is required.

ReasonNext-generation and Sanger sequencing typically cannot resolve phase (trans vs. cis) when two RPE65 variants are found; documentation of trans configuration establishes biallelic disease.

Acceptable evidenceFamily segregation testing or other methods that demonstrate trans configuration may be used to document phase.

Prior Authorization, Documentation, and Ordering Guidance

Prior Authorization

Prior Authorization Required

Prior authorization is required when the policy's clinical criteria apply for genetic testing related to inherited eye disorders or when specified CPT/HCPCS codes are billed. Providers should obtain PA prior to testing to avoid claim denials.

Prior authorization required when criteria apply
Affected codes: 81403; 81404–81408; 81479; 81599; 0205U

Documentation Required

RPE65 Testing Requirement for Gene Therapy Eligibility

Genetic testing to document pathogenic or likely pathogenic variants in RPE65 is required to establish eligibility for voretigene neparvovec (Luxturna). Testing must demonstrate biallelic (both copies) pathogenic or likely pathogenic RPE65 variants and, when two variants are identified, documentation that they are in trans (opposite chromosomes) is necessary. Testing should be performed in CLIA/CAP-approved laboratories using appropriate methods (e.g., sequencing, deletion/duplication analysis) and may include multigene panels that contain RPE65.

Clinical Background and Scope

Many inherited eye diseases are genetically heterogeneous; approximately 500 genes have been linked to inherited eye disorders. Age-related macular degeneration (AMD) is a multifactorial condition with both genetic and environmental contributors and is a leading cause of irreversible vision loss in older adults. Because variant interpretation and clinical implications vary, specialty guidance (AAO, ASRS) emphasizes using CLIA-approved laboratories, providing genetic counseling, and limiting routine genotyping for complex disorders to research until evidence demonstrates clinical utility.

Key Definitions Used in This Policy

Close relatives (definition)

DefinitionClose relatives include first-, second-, and third-degree blood relatives on the same side of the family.

First-degreeParents, siblings, and children.

Second-degreeGrandparents, aunts/uncles, nieces/nephews, grandchildren, and half-siblings.

Third-degreeGreat grandparents, great aunts/uncles, great grandchildren, and first cousins.

RPE65 and biallelic requirement

Gene functionRPE65 encodes an ~65-kD retinal pigment epithelium protein that functions as a retinal isomerase responsible for regeneration of 11-cis-retinol in the visual cycle.

Document Changes and Version History

2023-10-01semi-annual review

Semi-annual review with updates to title (V1.2024), overview, coding, reference table, background, and references; terminology 'coverage criteria' replaced with 'criteria' throughout; various policy reference table edits and clarifications added.

2023-10-01coding update

Added CPT code 81479 (unlisted molecular pathology procedure) to RPE65‑Associated Retinal Dystrophy/Leber Congenital Amaurosis coding section.

2023-03-23policy development/approvalLatest