CurrentBlue Cross Blue Shield - NebraskaPolicy ALPHA-1

MA Specialty Testing: Respiratory (Preauthorization Required)

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Defines medical necessity and preauthorization requirements for genetic and other specialty diagnostic tests for respiratory disorders (e.g., alpha-1 antitrypsin deficiency, cystic fibrosis, and other genetic lung disorders) for Blue Cross Blue Shield - Nebraska members.

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CurrentBlue Cross Blue Shield - NebraskaPolicy ALPHA-1

MA Specialty Testing: Respiratory (Preauthorization Required)

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Sign up for Blue Cross Blue Shield - Nebraska Policy ALPHA-1 alerts

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Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Respiratory (Preauthorization Required)

Policy CodePolicy ALPHA-1

Change TypeNo material change

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionRequest preauthorization when billing listed molecular pathology or CF/SERPINA1 testing codes.

SourceLink

3primary topic areas

preauth requiredauthorization status

CFTR-specificCFTR codes included

>20molecular CPTs listed

05-01-2026original effective date

Coverage Criteria for Specialty Respiratory Genetic Testing

Alpha-1 Antitrypsin Deficiency — SERPINA1 testing (covered when ALL of the following are met)

Covered when clinical features OR family history criteria are met

Clinical indications: Member has any of: chronic obstructive pulmonary disease (COPD), unexplained chronic liver disease, necrotizing panniculitis, granulomatosis with polyangiitis, or unexplained bronchiectasis.

From policy I.A.

Age and family history: Member is age 18 years or older AND has a sibling with a known SERPINA1 mutation (heterozygous or homozygous).

From policy I.B.

Cystic Fibrosis — CFTR sequencing/deletion-duplication (covered when ANY of the following are met)

Covered to establish or confirm CF diagnosis when specific diagnostic findings or clinical presentation are present

Diagnostic test results: Member has a positive (>= 60 mmol/L) OR inconclusive (30-59 mmol/L) sweat chloride test.sweat chloride thresholds as listed

From policy I.A and thresholds

Newborn screen: Member has a positive newborn screen for cystic fibrosis indicated by elevated immunoreactive trypsinogen.

From policy I.B

Clinical symptoms: Member has symptoms of cystic fibrosis from at least TWO different organ systems (sinus; lower respiratory; gastrointestinal/lumen; gastrointestinal/hepatobiliary; reproductive; or other CF-related symptoms).>=2 organ systems

From policy I.C and Cystic Fibrosis Foundation guidance

CFTR Intron 9 PolyT and TG Analysis (covered when ALL are met)

Indications: Member has a diagnosis of cystic fibrosis AND has an R117H variant in the CFTR gene.

From policy CFTR Intron 9 section

Other Covered Genetic Lung Disorders (covered when clinical features consistent with disorder)

Genetic testing may be considered reasonable and necessary to establish or confirm diagnosis to guide management for listed rare genetic lung disorders when clinical features consistent with the disorder are present

Disorders listed: Familial pulmonary fibrosis OR primary ciliary dyskinesia OR pulmonary alveolar proteinosis (PAP).

From policy I.A

This policy applies to genetic testing for inherited respiratory disorders, specifically SERPINA1 testing for alpha-1 antitrypsin deficiency and CFTR testing for cystic fibrosis. SERPINA1 testing (common variant analysis, sequencing, and/or deletion/duplication analysis) is considered reasonable and necessary when the member meets the clinical criteria (e.g., COPD, unexplained chronic liver disease, necrotizing panniculitis, granulomatosis with polyangiitis, or unexplained bronchiectasis) or age and family history requirements described in the policy. CFTR sequencing and/or deletion-duplication analysis is considered reasonable and necessary to establish or confirm cystic fibrosis when the member has a positive (≥ 60 mmol/L) or inconclusive (30–59 mmol/L) sweat chloride, a positive newborn screen for CF, or symptoms involving at least two different organ systems consistent with cystic fibrosis.

When requesting authorization or submitting a claim for respiratory molecular testing, providers must include both the applicable procedure code(s) and an appropriate diagnosis code. The policy notes that both a procedure and diagnosis are required for submission and that omission of the code pair may result in denial.

This medical policy is used to administer plan benefits but does not itself constitute authorization, certification, or a contract for benefits. Coverage and payment are determined by the terms and conditions of the member’s applicable benefit contract.

Testing for SERPINA1 (alpha-1 antitrypsin deficiency) and CFTR (cystic fibrosis) described in this policy is considered not reasonable and necessary for indications other than those specifically listed. Services outside the enumerated clinical scenarios in the policy are not supported for coverage under this guideline.

Coding Examples and Molecular Pathology Procedure Levels

SERPINA1 example CPTCPT

81332

SERPINA1 Common Variant Analysis or Sequencing and/or Deletion/Duplication Analysis (example listed)

SERPINA1 full gene example CPTCPT

81479

SERPINA1 Full Gene Sequencing and Deletion/Duplication (Invitae) (example listed)

CFTR example CPTsCPT

81223	Diagnostic CFTR Sequencing and/or Deletion/Duplication Analysis (example listed)
81222	Cystic Fibrosis Gene Deletion or Duplication (example listed)
81224	CFTR Intron 9 PolyT and TG Analysis (example listed)

Other covered lung disorder CPTsCPT

81400-81408

Other covered lung disorders (example range listed)

Example Covered CPT CodesCPTCovered

81222	CFTR GENE ANALYSIS DUPLICATION/DELETION VARIANTS
81223	CFTR GENE ANALYSIS FULL GENE SEQUENCE
81224	CFTR GENE ANALYSIS INTRON 8 POLY-T ANALYSIS
81400	MOLECULAR PATHOLOGY PROCEDURE LEVEL 1

Molecular Pathology Procedure LevelsCPTCovered

81401	MOLECULAR PATHOLOGY PROCEDURE LEVEL 2
81402	MOLECULAR PATHOLOGY PROCEDURE LEVEL 3
81403	MOLECULAR PATHOLOGY PROCEDURE LEVEL 4
81404	MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405	MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
81406	MOLECULAR PATHOLOGY PROCEDURE LEVEL 7
81407	MOLECULAR PATHOLOGY PROCEDURE LEVEL 8
81408	MOLECULAR PATHOLOGY PROCEDURE LEVEL 9

Covered CPT Codes (examples listed)CPTCovered

81408

MOLECULAR PATHOLOGY PROCEDURE LEVEL 9 (Full Description listed)

Unlisted molecular pathologyCPTCovered

81479

UNLISTED MOLECULAR PATHOLOGY PROCEDURE

inv-17: Sweat chloride — diagnostic thresholds

Positive (diagnostic)>= 60 mmol/L sweat chloride

Inconclusive (intermediate)30-59 mmol/L sweat chloride

Context for intermediate rangeIndividuals with intermediate sweat chloride (30-59 mmol/L) on 2 occasions should be considered for extended CFTR analysis or functional testing

Provider Actions, Preauthorization, and Billing Guidance

Prior Authorization

Preauthorization required for specialty respiratory testing

Preauthorization is required for specialty respiratory testing listed in this policy; providers must request prior authorization when billing the example CPTs shown (e.g., 81332, 81223, 81222, 81224, 81400–81408, 81479).

Request prior authorization through BCBSNE processes before performing or submitting claims for these tests.
Reference table lists example CPTs that may be subject to prior authorization.

Prior Authorization

Prior authorization required for listed CPT codes

Preauthorization specifically applies to the molecular pathology and CFTR procedure codes listed (for example 81222, 81223, 81224 and 81400–81408); obtain authorization using the exact CPT code for the test to be performed.

Use the specific CPT code (e.g., 81222, 81223, 81224, 81400–81408) on the authorization request.
Do not substitute a different CPT without prior approval.

Background and Scope

This policy defines the scope of coverage for genetic and specialty diagnostic testing used to establish or confirm diagnoses of inherited or uncommon respiratory disorders. It includes criteria for alpha-1 antitrypsin deficiency (SERPINA1 testing), cystic fibrosis (CFTR sequencing, deletion/duplication, and intron 9 polyT/TG analysis), and selected rare genetic lung disorders where testing may guide diagnosis and management. The policy references specialty society guidance and provides thresholds and clinical scenarios that determine when testing is considered reasonable and necessary.

Definitions and Key Terms

inv-31: SERPINA1 testing (AATD) definition

DefinitionSERPINA1 common variant analysis or sequencing and/or deletion/duplication analysis

PurposeTo establish a diagnosis of alpha-1 antitrypsin (AAT) deficiency when clinical criteria or family history are present

Not medically necessaryConsidered not reasonable and necessary for indications other than those specified in the policy

inv-32: CFTR testing (Cystic Fibrosis) definition

DefinitionCFTR sequencing and/or deletion/duplication analysis and CFTR intron 9 polyT/TG analysis

PurposeTo establish or confirm a diagnosis of cystic fibrosis when sweat chloride, newborn screen, or multi‑system clinical features indicate possible CF

Policy Summary

PayerBlue Cross Blue Shield - Nebraska

PolicyMA Specialty Testing: Respiratory (Preauthorization Required)

Policy CodePolicy ALPHA-1

Change TypeNo material change

Effective DateMay 1, 2026

Next Review DateJan 1, 2027

Key ActionRequest preauthorization when billing listed molecular pathology or CF/SERPINA1 testing codes.

SourceLink

On This Page

Prior Authorization

Preauthorization required for molecular pathology procedure codes

Molecular pathology procedure codes including Level 8, Level 9 and the unlisted molecular pathology code are included in the policy and require preauthorization when billed (examples: 81407, 81408, 81479).

Submit prior authorization for molecular pathology procedure levels appropriate to the assay (Level 8/9 when applicable).
Include 81479 if using an unlisted molecular pathology procedure and obtain authorization.

Documentation Required

Provide both procedure and diagnosis codes on requests

Include both the specific procedure CPT and an appropriate diagnosis code on the authorization request and claim; absence of the required code pairing may result in denial.

Ensure the procedure and diagnosis code pair is present—the policy notes “Both a procedure and diagnosis are required. Code pair was previously added.”
Verify the diagnosis matches the coverage criteria before submission.

Note

Use reference table for administrative guidance (but confirm medical necessity)

When submitting authorization requests, use the exact CPT code(s) for the test performed and reference the policy’s example test table; inclusion in the table does not itself guarantee coverage.

Use the reference table to identify example tests and CPTs but confirm medical necessity per criteria.
Do not rely on the table alone—submit clinical documentation supporting the requested test.

Denial Risk

Benefit contract governs coverage (coverage disclaimer)

Medical policies do not guarantee benefits—coverage is governed by the member’s applicable benefit contract; if the service is not covered by the member’s plan, claims may be denied even if the policy criteria are met.

Confirm the member’s benefit contract terms and conditions before ordering or submitting claims.
Policies are used to administer benefits but do not constitute authorization or a contract for coverage.

Billing Rule

Reference table examples are not guarantees of coverage

Inclusion of a test or CPT in the policy’s reference table is an example only and is not a guarantee of coverage; providers must still meet medical necessity criteria and obtain any required preauthorization.

Treat the reference table as illustrative—coverage depends on meeting the policy criteria and benefit terms.
Obtain prior authorization where required and submit supporting documentation.

Documentation Required

Use the policy-listed CPT codes on authorizations and claims

List the specific CPT codes shown in the policy (e.g., 81222, 81223, 81224, 81400) on both the authorization request and the claim to ensure correct processing.

Include exact CPT(s) for the service requested on the prior authorization form.
Use the same CPT(s) on the claim submission to avoid processing issues.

Billing Rule

Submit appropriate molecular pathology CPTs (Level 8/9 or unlisted)

Submit molecular pathology procedure codes appropriate to the test complexity—this policy lists Level 8 and Level 9 examples and the unlisted molecular pathology code (81479); choose the CPT that reflects the procedure performed.

If the test meets Level 8 or Level 9 complexity, submit the corresponding 81407–81408 code as listed.
For assays not described by a specific code, submit CPT 81479 (unlisted) with supporting documentation and obtain authorization.

Denial Risk

Apply NCD/LCD precedence first

If a National Coverage Determination (NCD) or Local Coverage Determination (LCD) exists for the service, it will be applied before this policy; absence of CMS guidance means this policy will be utilized.

Check for applicable NCDs or LCDs prior to relying on this policy for coverage decisions.
An applicable NCD/LCD takes precedence over this commercial policy.

Billing Rule

Ensure procedure and diagnosis code pairing on requests and claims

Both a procedure code and a diagnosis code are required on submissions; the policy explicitly states “Both a procedure and diagnosis are required. Code pair was previously added.”

Do not submit claims or authorizations missing either the procedure CPT or a supporting diagnosis code.
Ensure diagnosis coding supports the medical necessity criteria in the policy.

Note

Confirm member benefit contract terms govern coverage

Policies are tools to administer plan benefits and do not replace the member’s benefit contract; coverage determinations and payment are ultimately governed by the terms and conditions of the applicable benefit contract.

Confirm member eligibility and benefit coverage prior to ordering tests.
A medical policy does not constitute authorization, certification, or a contract for benefits.

Not medically necessaryConsidered not reasonable and necessary for indications other than those specified in the policy

inv-33: 81222 — CFTR gene analysis duplication/deletion variants

CPT code81222

Short descriptionCFTR gene analysis — duplication/deletion variants

UseUsed for testing for CFTR duplication/deletion variants as part of CFTR analysis

inv-34: 81223 — CFTR gene analysis full gene sequence

CPT code81223

Short descriptionCFTR gene analysis — full gene sequence

UseUsed for comprehensive CFTR sequencing to detect sequence-level variants across the gene

inv-35: 81224 — CFTR intron 8 poly-T analysis

CPT code81224

Short descriptionCFTR gene analysis — intron 8 (intron 9 polyT/TG) poly‑T analysis

IndicationUsed for CFTR intron 9 polyT and TG analysis (e.g., when R117H variant present or male infertility evaluation)

inv-36: Level 8 molecular pathology definition

LevelMolecular pathology procedure, Level 8

Typical complexityAnalysis of ~26–50 exons by DNA sequence analysis, mutation scanning, or duplication/deletion variants of >50 exons; may include sequence analysis of multiple genes on one platform

ExamplesLevel 8 used for full gene sequence testing across moderately large genes (examples listed in policy)

inv-37: Level 9 molecular pathology definition

LevelMolecular pathology procedure, Level 9

Typical complexityAnalysis of >50 exons in a single gene by DNA sequence analysis (highest single‑gene complexity)

ExamplesLevel 9 applied to very large genes requiring extensive sequencing (examples listed in policy)