CurrentCapital BluecrossPolicy MP 2.251

GENETIC TESTING FOR ALPHA1- ANTITRYPSIN DEFICIENCY

Policy MP 2.251 defines medical necessity criteria for genetic testing for alpha1-antitrypsin (AAT) deficiency, applicable to certain Capital Blue Cross products, and lists coding and background guidance. Effective date 2025-09-01.

Policy Summary

PayerCapital Bluecross

PolicyGENETIC TESTING FOR ALPHA1- ANTITRYPSIN DEFICIENCY

Policy CodePolicy MP 2.251

Change TypeNo material clinical change (administrative and reference updates)

Effective DateSep 1, 2025

Next Review Date

Key ActionProviders must document clinical factors or a first-degree relative with AAT deficiency and include serum AAT concentration results when ordering genetic testing.

POLICY UPDATE CHANGES

04/06/2020 Policy statement changed to 'either'/'or' vs 'both'/'and'.

02/19/2024 Updated statement, guidelines, and background regulatory status; no change in intent.

02/10/2025 Consensus Review. No change to policy statement. References updated. Coding reviewed.

07/22/2025 Administrative Update removed Benefit Variations Section and updated Disclaimer.

2Covered Indication Pathways

1Investigational/Not covered pathway(s)

2Key procedure codes listed

Coverage Summary

Scope summary: Policy MP 2.251 defines medical necessity criteria for genetic testing for alpha1-antitrypsin (AAT) deficiency and applies to certain Capital Blue Cross products; effective date 9/1/2025 with last review noted 7/22/2025.

Coverage stance: Mixed — genetic testing for AATD is considered medically necessary when either (1) an individual is suspected of having AATD because of specified clinical factors or a high-risk first-degree relative, or (2) the individual has a serum AAT level in the range of severe deficiency; testing is investigational in all other situations.

High-level note: Genetic testing is medically necessary in the specified situations above to confirm diagnosis or guide management, and is investigational outside those criteria.

Key thresholds and quick facts

Effective date9/1/2025

Last review07/22/2025

Policy numberMP 2.251

SubjectGenetic testing for alpha1-antitrypsin deficiency

Serum alpha-1 antitrypsin level thresholdLess than 11 μmol generally associated with increased risk; severe phenotype examples include ZZ: 2.5–7 μmol (20–45 mg/dL); Znull: <2.5 μmol (<20 mg/dL)

Serum AAT percent of normal thresholdA serum AAT concentration <15%–20% of normal is highly suggestive of a homozygous pathogenic variant

Medical-Necessity Criteria

Medically necessary

Genetic testing for alpha1-antitrypsin deficiency may be considered medically necessary when either of the following conditions are met:

ANY of the following

Individual is suspected of having alpha1-antitrypsin deficiency because of clinical factors and/or because the individual may be at high risk of having alpha1-antitrypsin deficiency due to a first-degree relative with AAT deficiency (see Policy Guidelines).
Individual has a serum alpha-1 antitrypsin level in the range of severe deficiency (see Policy Guidelines).

Investigational / Not medically necessary

Genetic testing for alpha1-antitrypsin deficiency is considered investigational in all other situations.

Policy Guidelines & Definitions

Policy Guidelines — Clinical suspicion

Clinical factors relevant for suspicion of AATD (based on 2016 Alpha-1 Foundation guidelines):

Clinical factors (ANY of the following)

Individuals with chronic obstructive pulmonary disease (COPD).
Individuals with asthma and airflow obstruction not completely reversible with bronchodilators.
Individuals with otherwise unexplained liver disease.
Individuals with necrotizing panniculitis.
Individuals with anti-proteinase 3-positive vasculitis (cytoplasmic ANCA-positive vasculitis).
Individuals with bronchiectasis without evident etiology.

Family history: First-degree relative (parent, child, sibling) with AAT deficiency increases high-risk status for testing.

Policy Guidelines — Serum level threshold guidance

Serum level interpretation and phenotype ranges:

A level less than 11 μmol (or corresponding mg/dL ranges) is generally considered associated with increased risk of clinical disease although cutoff may vary by test.<11 μmol

Representative serum ranges by phenotype

MM: 20-48 μmol; 150-350 mg/dL.
MZ: 17-33 μmol; 90-210 mg/dL.
SS: 15-33 μmol; 100-200 mg/dL.
SZ: 8-16 μmol; 75-120 mg/dL.

Background: Alpha1-antitrypsin deficiency (AATD) is a codominant genetic disorder caused by variants in the SERPINA1 gene; common alleles include M, S, and Z, with ZZ and certain null alleles associated with the most severe reductions in serum AAT and highest risk of lung disease.

Diagnostic approaches: Available tests include serum AAT quantitation (to detect low total AAT levels), phenotype testing (isoelectric focusing to identify circulating AAT protein types), and genotype testing (nucleic acid–based assays or PCR that commonly detect S and Z alleles). Typical laboratory approaches include initial serum quantitation followed by phenotype or genotype testing if levels are low or clinical suspicion persists; discordant results between genotype and phenotype prompt phenotype testing.

Policy linkage: Policy Guidelines reference serum thresholds (a level less than 11 μmol generally associated with increased risk and representative phenotype ranges such as ZZ: 2.5–7 μmol (20–45 mg/dL)) and refer to ACMG-AMP variant classification nomenclature and recommendations for reporting and interpretation; genetic counseling is recommended when testing is considered.

First-degree relative: defined as a parent, child, or sibling and a first-degree relative with AAT deficiency places an individual at higher risk for testing.

Pathogenic variant classification (ACMG-AMP): standard terminology for variant interpretation includes pathogenic, likely pathogenic, uncertain significance, likely benign, and benign as recommended by ACMG-AMP and described in the Policy Guidelines.

Provider Actions

Documentation Required

Document clinical suspicion or family history

Document the clinical factors that prompted suspicion for alpha1-antitrypsin deficiency or a first-degree relative with AAT deficiency. Examples of clinical factors include COPD, asthma with non–fully reversible airflow obstruction, unexplained liver disease, necrotizing panniculitis, ANCA (anti-proteinase 3)-positive vasculitis, or bronchiectasis without an evident etiology. Also document family history: a first-degree relative is defined as a parent, child, or sibling.

Chronic obstructive pulmonary disease (COPD)
Asthma with airflow obstruction not completely reversible with bronchodilators
Otherwise unexplained liver disease
Necrotizing panniculitis
Anti-proteinase 3–positive (cytoplasmic ANCA) vasculitis
Bronchiectasis without evident etiology
Family history: first-degree relative (parent, child, sibling) with AAT deficiency

Documentation Required

Report serum AAT level

Include the measured serum alpha-1 antitrypsin concentration when ordering genetic testing to demonstrate whether the level falls within the severe deficiency range referenced in policy (see serum thresholds guidance).

Example threshold: level less than 11 μmol is generally associated with increased risk of clinical disease
Representative severe ranges: ZZ 2.5–7 μmol (20–45 mg/dL); Znull <2.5 μmol (<20 mg/dL)
A serum AAT concentration <15%–20% of normal is highly suggestive of a homozygous pathogenic variant

Billing Rule

Use listed procedure codes

When genetic testing is medically necessary, report the testing with the procedure codes listed in the policy and include the appropriate diagnosis code for alpha1-antitrypsin deficiency as applicable.

G0452
81332
Diagnosis code: E88.01

Revision History

04/06/2020revised

Policy statement changed to 'either'/'or' vs 'both'/'and' (logical phrasing of criteria).

02/19/2024clarified

Updated statement, guidelines, and background regulatory status; no change in intent. References reviewed and updated; coding unchanged.

02/10/2025clarified

Consensus review with no change to policy statement; references updated and coding reviewed.

07/22/2025removedLatest

Administrative update: removed Benefit Variations section and updated Disclaimer (administrative only; no clinical policy change).

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