CONCERT GENETIC TESTING: HEMATOLOGIC CONDITIONS (NONCANCEROUS)
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Defines medical necessity and investigational indications for genetic and variant testing used to diagnose inherited, non-malignant hematologic disorders (e.g., thrombophilia, hemoglobinopathies, hemophilia, G6PD, von Willebrand). Applies to providers ordering genetic testing for covered members.
No material clinical or coverage changes in this revision.
Coverage Criteria for Genetic Testing — Noncancerous Hematologic Conditions
KNOWN FAMILIAL VARIANT ANALYSIS FOR HEMATOLOGIC CONDITIONS (NON-CANCEROUS)
Targeted mutation analysis for a known familial variant is medically necessary when ALL of the following are met:
Targeted mutation analysis CPT examples: 81403, 81258, 81362; targeted mutation analysis is considered investigational for all other indications.
INHERITED THROMBOPHILIA
F5 (81241) and F2 (81240) variant analysis to confirm or establish a diagnosis of inherited thrombophilia is medically necessary when ANY of the following are met:
CPT examples: 81241 (F5), 81240 (F2). See policy text for additional pregnancy- and family-history–related criteria.
HEMOGLOBINOPATHIES
HBA1/HBA2 and/or HBB variant analysis to confirm or establish a diagnosis of a hemoglobinopathy is medically necessary when ANY of the following are met:
CPT examples: 81257, 81259, 81269, S3845, S3850, 81361, 81363, 81364, S3846. Molecular analysis is generally reserved for cases where basic hematology and hemoglobin analysis cannot provide a conclusive diagnosis.
HEMOPHILIA
F8 and/or F9 variant analysis to confirm or establish a diagnosis of hemophilia A or B is medically necessary when ANY of the listed clinical bleeding features are present:
CPT examples: 81403, 81406, 81407, 81238, 81479.
G6PD VARIANT ANALYSIS
G6PD variant analysis
Diagnosis of G6PD deficiency can be achieved by quantitative spectrophotometric analysis or a rapid fluorescent spot test detecting NADPH generation; genetic testing is not recommended for routine diagnosis.
Covered: specified noncancerous hematologic conditions
Genetic testing to establish or confirm diagnosis for certain rare noncancerous hematologic conditions is considered medically necessary when specified clinical features are present.
Medically necessary genetic testing for listed conditions
- Conditions list: Atypical Hemolytic-Uremic Syndrome (aHUS); Complete Plasminogen Activator Inhibitor 1 Deficiency (PAI-1); Diamond-Blackfan Anemia (DBA); Hereditary Spherocytosis; Factor VII Deficiency; Factor X Deficiency; Factor XI Deficiency (Hemophilia C); Factor XII Deficiency; Factor XIII Deficiency.
F5 (Factor V Leiden) and F2 (prothrombin) variant analysis is investigational for indications outside the specified clinical and family criteria. The policy explicitly lists fetal loss and adverse pregnancy outcomes (for example, placental abruption, fetal growth restriction, or preeclampsia) among indications for which F5/F2 testing is considered investigational. Additionally, G6PD variant analysis is identified as investigational for establishing or confirming a diagnosis of G6PD deficiency because diagnosis can be achieved by standard functional assays (spectrophotometric or fluorescent spot tests).
Variant analyses for G6PD (CPT 81247–81249), GP1BA/VWF (CPTs including 81401, 81403, 81404, 81405, 81406, 81408, 81479), and F8/F9 are considered investigational when used to confirm or establish diagnoses in situations where standard laboratory testing can establish the diagnosis. The policy states these tests may be subject to denial when ordered for diagnostic confirmation without meeting investigational exception criteria.
Guideline sources cited in the policy note that genetic testing is not part of routine laboratory evaluations for certain disorders. For G6PD deficiency, the recommended diagnostic tests are quantitative spectrophotometric analysis or a rapid fluorescent spot test detecting NADPH generation, with genetic testing not included among standard initial tests. For von Willebrand disease (VWD), guideline laboratory recommendations to aid diagnosis likewise do not include genetic testing.
Targeted familial variant (known-familial) testing is investigational when the member does not have a close relative with a documented pathogenic or likely pathogenic variant. Separately, F5/F2 testing (for inherited thrombophilia) and G6PD variant analysis are identified as investigational for many other indications specified in policy (for example, F5/F2 testing for fetal loss or adverse pregnancy outcomes).
Genetic testing for G6PD deficiency and for von Willebrand disease is generally not supported to establish or confirm diagnosis when standard laboratory or biochemical tests can provide the diagnosis. The policy emphasizes that diagnosis of G6PD deficiency is typically achieved by quantitative spectrophotometric analysis or a rapid fluorescent spot test, and VWD diagnosis relies on standard VWD laboratory testing rather than genetic analysis.
Medically Necessary (Covered) Indications
EXTRA
Covered indications and related examples (see individual sections for detailed criteria and CPT examples).
Referenced CPT and Supplemental Codes
| 81401 | GP1BA and VWF variant analysis (as listed) |
| 81403 | GP1BA and VWF variant analysis / F8 variant analysis (as listed) |
| 81404 | GP1BA and VWF variant analysis (as listed) |
| 81405 | GP1BA and VWF variant analysis (as listed) |
| 81406 | GP1BA and VWF variant analysis / VWF sequencing analysis (as listed) |
| 81408 | VWF sequencing analysis (as listed) |
| 81479 | Unlisted molecular pathology procedure (used for some variant analyses) |
Provider Actions, Documentation & Prior Authorization
Check prior authorization for referenced CPT codes
Certain CPT codes referenced in this policy (examples include 81240, 81241, 81247, 81257, 81259, 81269, 81361, 81363, 81364, 81403, 81406, 81407, 81479) may require prior authorization per plan coding/coverage rules. Providers should verify applicable prior authorization requirements with the member’s plan and reference current coding guidance before ordering or submitting claims.
- Verify member benefit and prior authorization requirements before ordering genetic testing.
- Reference the most up-to-date professional coding guidance and plan-specific authorization rules.
Investigational variant analyses present prior authorization/denial risk
Variant analysis tests identified as investigational in the policy (examples: G6PD CPTs 81247–81249; GP1BA/VWF CPTs 81401, 81403–81406, 81408; selected F8/F9 CPTs such as 81407, 81238, 81479) may be subject to denial or require prior authorization if submitted to confirm/establish a diagnosis. Providers should confirm coverage before ordering.
- Investigational-listed CPTs may not be covered to confirm/establish diagnoses when standard laboratory testing can establish the diagnosis.
- Prior authorization or pre-authorization review may be required; confirm with plan.
Verify prior authorization and benefit terms before ordering
Prior authorization may be required per the Health Plan's administrative policies and coverage documents; providers must verify benefit terms and prior authorization procedures for the member before ordering genetic testing.
- This policy is a guide to medical necessity but does not guarantee payment; follow plan-specific administrative policies.
- Confirm prior authorization requirements with the member’s plan and submit supporting documentation as required.
Include specific clinical indication and rationale on test requests
When ordering tests to establish genetic causes for hematologic conditions, include the specific clinical indication and relevant diagnostic findings in the request to support medical necessity.
- Specify the suspected disorder and clinical features consistent with disorder (e.g., resources such as GeneReviews, OMIM may be referenced).
- Include rationale linking testing to management to assist benefit determination.
Use molecular testing for hemoglobinopathies only after inconclusive hematology screening
Reserve molecular analyses for hemoglobinopathies for cases where standard hematology and hemoglobin analysis cannot provide a conclusive diagnosis; perform stepwise testing with hematologic screening first.
- Start with hematologic screening (MCV, MCH, CBC, hemoglobin electrophoresis, DCIP) and proceed to molecular testing only if results are positive or inconclusive.
- DNA analysis may be indispensable for genetic counseling, risk calculation, or prenatal/preimplantation diagnosis, but is not routinely first-line.
Ensure clinical documentation supports familial or diagnostic criteria
Provide complete clinical documentation demonstrating either a close relative with a known pathogenic/likely pathogenic variant for known-familial testing, or the specific clinical features/criteria listed in the policy for diagnostic testing (thrombophilia, hemoglobinopathy, hemophilia, or other listed conditions).
- For known-familial targeted mutation analysis, document the close relative and the known pathogenic/likely pathogenic variant.
- For diagnostic single-gene testing, document the clinical features that meet the policy criteria (e.g., first unprovoked VTE <50 y, recurrent VTE, hemarthrosis, positive/inconclusive hemoglobin screening).
Document disorder-specific clinical features and authoritative references
When genetic testing is requested to establish or confirm a diagnosis for listed rare hematologic conditions, document clinical features consistent with the disorder and reference authoritative resources (e.g., GeneReviews, OMIM) as applicable.
- Cite clinical features and, when appropriate, reference GeneReviews or other scholarly sources to justify testing.
- Ensure documentation links testing to management decisions for the member.
Follow contract and coverage document terms (policy is guidance only)
Follow the member’s contract and coverage documents; this policy guides medical necessity determinations but does not replace plan terms, and does not guarantee payment or coverage.
- Coverage decisions are subject to the terms, conditions, exclusions, and limitations of the member’s coverage documents.
- Verify state/federal requirements and any Health Plan-level administrative procedures that may affect coverage.
Known-familial targeted testing requires documented affected relative
Targeted mutation analysis for a known familial variant is considered investigational (not covered) when the member does not have a close relative with a known pathogenic or likely pathogenic variant; such submissions are at risk for denial.
- Known-familial targeted testing is medically necessary only when a close relative with a known pathogenic or likely pathogenic variant is documented.
- Requests for targeted familial testing without documented affected relative and variant are considered investigational.
F5/F2 and G6PD variant analyses may be investigational and denied if criteria not met
F5/F2 (Factor V Leiden and prothrombin) and G6PD variant analyses are considered investigational for many indications outside the policy’s listed criteria and are at risk for denial if used to confirm diagnoses when not meeting those criteria.
- F5/F2 testing is medically necessary only when the member meets listed clinical/family criteria (e.g., first unprovoked VTE <50 years, unusual site VTE, recurrent VTE); otherwise it is investigational.
- G6PD variant analysis (81247–81249) to confirm diagnosis is considered investigational because diagnosis can be achieved by functional assays.
Specific CPTs for G6PD, GP1BA/VWF, and F8/F9 pose high investigational/denial risk
Requests for G6PD variant analysis (CPT 81247, 81248, 81249), GP1BA and/or VWF variant analysis (CPTs 81401, 81403, 81404, 81405, 81406, 81408, 81479), and listed F8/F9 CPTs may be considered investigational and are subject to denial when submitted to confirm/establish diagnosis without meeting investigational exception criteria.
- G6PD and VWF/GP1BA variant analyses are considered investigational because diagnosis can be achieved by standard biochemical testing.
- F8/F9 variant analysis is medically necessary only when the member meets listed clinical bleeding features; otherwise it may be investigational.
Consider genetic counseling for familial variant testing
Consider referral for genetic counseling when ordering familial variant testing or when identifying familial pathogenic variants will influence testing of at-risk relatives and genetic risk calculation.
- Genetic counseling is referenced as useful for interpreting familial pathogenic variants and for family-based risk assessment.
- Although not mandated, counseling should be considered to support patient decision-making and interpretation.
No explicit ordering restrictions — document diagnostic/family criteria on orders
There are no explicit ordering-provider restrictions stated in this policy excerpt, but clinical documentation must demonstrate features consistent with the diagnostic indication when requesting testing.
- Ensure orders include the clinical features or family history that meet policy criteria to reduce risk of denial.
- Reference disorder-specific criteria and diagnostics in the request to support medical necessity.
Investigational and Not Covered Indications
Targeted mutation analysis for a known familial variant is considered not covered (investigational) unless the member has a close relative with a documented pathogenic or likely pathogenic variant. The policy specifies that known-familial targeted testing is medically necessary only when the member has a close relative with a known pathogenic/likely pathogenic variant; all other indications are investigational.
Variant analyses for G6PD, GP1BA/VWF, and F8/F9 are designated as not covered (investigational) when they are requested to confirm or establish diagnoses in contexts where standard laboratory testing (functional or biochemical assays) would be adequate to make the diagnosis.
Guideline statements cited in the policy indicate that recommended laboratory evaluations for G6PD deficiency and von Willebrand disease do not include genetic testing. These guideline recommendations support the policy position that genetic testing is not routinely indicated for initial diagnosis of these conditions.
Eligibility Requirements and Preconditions for Coverage
Known-familial targeted mutation analysis requires that the member have a close relative with a known pathogenic or likely pathogenic variant as documented in the clinical record. For thrombophilia testing (F5/F2), the policy also references specific clinical and family history criteria (for example, first unprovoked VTE younger than 50 years, VTE at unusual sites, recurrent VTE, or defined family history patterns) that must be met for testing to be considered medically necessary.
Eligibility for known familial variant testing is contingent on documentation that a close relative carries a pathogenic or likely pathogenic variant. For diagnostic testing (for example, hemophilia F8/F9 variant analysis), clinical features consistent with the disorder—such as hemarthrosis, deep-muscle hematomas, intracranial bleeding without major trauma, or prolonged bleeding after procedures—must be present to support medical necessity.
Background and Definitions
Genetic testing for noncancerous hematologic conditions can confirm diagnoses that influence management and may avoid additional diagnostic procedures. The policy covers situations where genetic testing is used to establish or confirm diagnoses for conditions such as inherited thrombophilias (F5/F2), hemoglobinopathies (HBA1/HBA2/HBB), hemophilia (F8/F9), and other rare hematologic disorders, while also delineating circumstances where genetic testing is investigational because standard laboratory tests suffice.
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