Humana Genetic Testing for Cardiac Conditions Form

Description

Cardiovascular Disease Genetic Markers Cardiovascular disease (CVD) risk testing is performed to help determine an individual’s risk of having a cardiovascular event such as a heart attack or stroke. The most common test used to determine CVD risk is the lipid profile, which measures cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C) and low- density lipoprotein cholesterol (LDL-C).

Panels beyond the basic lipid profile are commercially available and may include analysis of genetic markers for CVD risk including single nucleotide polymorphism (SNPs) genotyping and often pharmacogenomics tests. SNP genotype testing has been proposed to identify an individual at risk for atrial fibrillation (AF), coronary artery disease and early myocardial infarction (MI). Examples include but may not be limited to:

• 4q25 genotype testing (eg, 4q25-AF Risk Genotype Test, Cardio IQ 4q25-AF Risk Genotype Test) (Refer to Coverage Limitations section)
• 9p21 genotype testing (eg, Cardio IQ 9p21 Genotype Test) (Refer to Coverage Limitations section)
• LPA Intron-25 genotype testing (eg, Cardio IQ LPA Intron-25 Genotype Test, LPA-Intron 25 Genotype Test) (Refer to Coverage Limitations section)
• ST2 (growth stimulation expressed gene 2) (eg, Cardio IQ ST2) (Refer to Coverage Limitations section)

CVD risk panels may also include genetic tests to determine an individual’s susceptibility for hypercoagulation or thrombosis, which has been proposed as a risk factor for CVD. Testing may include factor II (ie, F2 gene), factor V (ie, F5 gene) or plasminogen activator inhibitor (PAI-1). (Refer to Coverage Limitations section)

Health and wellness SNP genotyping tests are also commercially available to analyze genes associated with various wellness factors, such as diet, exercise and metabolism, to purportedly guide an individual to personalized lifestyle choices to improve overall health and wellbeing. These tests may also be marketed to improve CVD risk by choosing a diet or exercise regimen based on an individual’s genetic makeup. Examples of these tests include but may not be limited to: Cardiac Healthy Weight DNA Insight, Healthy Woman DNA Insight. (Refer to Coverage Limitations section)

Inherited Cardiomyopathies and Channelopathies

Cardiomyopathy is a chronic disease of the myocardium (heart muscle). The heart muscle becomes enlarged, thick or rigid, resulting in a failure to pump blood effectively, which can lead to arrhythmias (irregular heartbeats) and possible heart failure. Cardiomyopathy can be acquired or inherited. Hypertrophic cardiomyopathy (HCM) is one of the main types of cardiomyopathy.

Cardiac ion channelopathies are a group of diseases that develop due to defects in ion channels and can be caused by either genetic or acquired factors. Inherited cardiac channelopathies include, but are not limited to, Brugada syndrome (BrS).

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS). Genetic testing may be used to detect variants believed to be linked to inherited cardiomyopathies and channelopathies to assist with diagnosis, determine prognosis and identify susceptibility in at-risk, unaffected family members.

A variety of multigene panel tests, with or without next-generation sequencing (NGS) technology, that simultaneously analyze many genes at one time are currently commercially available. Targeted multigene panels examine only those genes associated with a given disease.

Multicondition multigene panels are also available to analyze a broader range of genes associated with a group of diseases (eg, inherited channelopathies). In this example the panel may target genes for all inherited channelopathies including BrS, CPVT and LQTS. (Refer to Coverage Limitations section)

Finally, what can be termed as comprehensive multigene panels offer analysis of an even broader range of genes and include those associated with both inherited cardiomyopathies and channelopathies. (Refer to Coverage Limitations section)

Examples of multicondition and comprehensive multigene panels include, but may not be limited to:

• Arrhythmia Panel
• AtheroGxOne
• Cardiomyopathies Del/Dup Panel
• Cardiomyopathy and Arrhythmia Panel
• Cardiomyopathy Panel
• CardioNext
• CMNext
• Combined Cardiac Panel
• Comprehensive Cardiomyopathy Multi-Gene Panel
• DCMNext
• GeneSeq: Cardio Familial Arrhythmia Panel
• GeneSeq: Cardio Familial Cardiomyopathy Profile
• Genomic Unity Cardiac Ion Channelopathies Analysis (0237U)

Genetic Testing for Cardiac Conditions

Effective Date: 08/24/2023

Revision Date: 08/24/2023

Review Date: 08/24/2023

Policy Number: HUM-0516-023 Page: 4 of 26

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic (autosomal dominant) disorder. Gene variants can inhibit the liver from metabolizing excess low density lipoprotein cholesterol (LDL-C), resulting in lifelong exposure to elevated LDL-C levels which contributes to premature atherosclerotic cardiovascular disease.

There are two forms of FH including heterozygous FH (HeFH) (single gene variant received from one parent) and homozygous FH (HoFH) (more than one variant received from one or both parents). HeFH is the most common form and is found in approximately 1:250 individuals. HoFH is rare, occurring in approximately 1:350,000 individuals, but can have an earlier onset with more severe outcomes.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing
• Retrieved archival tissue
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure

Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Coverage Determination

Any state mandates for genetic testing for cardiac conditions take precedence over this medical coverage policy.

Genetic testing may be excluded by certificate. Please consult the member's individual certificate regarding Plan coverage.

Apply General Criteria for Genetic and Pharmacogenomics Tests when disease- or gene-specific criteria are not available on a medical coverage policy. For information regarding General Criteria for Genetic and Pharmacogenomics Tests, please refer to Genetic Testing Medical Coverage Policy.

Catecholaminergic Polymorphic Ventricular Tachycardia (CALM1, CALM2, CALM3, CASQ2, KCNJ2, RYR2, TECRL and TRDN Genes)

Genetic Testing for Cardiac Conditions Effective Date: 08/24/2023 Revision Date: 08/24/2023 Review Date: 08/24/2023 Policy Number: HUM-0516-023 Page: 6 of 26

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Humana members may be eligible under the Plan for genetic testing for catecholaminergic polymorphic ventricular tachycardia (CPVT) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested exhibits clinical features suggestive of CPVT including unexplained exercise- or catecholamine-induced polymorphic ventricular arrhythmias and syncope during physical activity or acute emotion occurring in a structurally normal heart; OR
• CPVT Testing Strategy (Affected): perform single gene testing of CALM1, CALM2, CALM3, CASQ2, KCNJ2, RYR2, TECRL or TRDN genes or targeted multigene analysis (sequencing and/or deletion/duplication) of CALM1, CALM2, CALM3, CASQ2, KCNJ2, RYR2, TECRL and TRDN genes.
• Individual to be tested is unaffected and has an affected first-degree relative in whom a pathogenic or likely pathogenic CPVT variant has been identified
• Testing Strategy: test for known familial variant (KFV)

Familial Hypercholesterolemia (APOB, LDLR, LDLRAP1 [ARH] and PCSK9 Genes)

Humana members may be eligible under the Plan for genetic testing for familial hypercholesterolemia (FH) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Acquired and secondary causes of hypercholesterolemia (eg, diet and medication-induced hypercholesterolemia, endocrine, hepatic and renal disease) have been excluded by standard diagnostic evaluation; AND
• Individual to be tested has a persistent LDL-C level* greater than 190 mg/dL (18 years of age or older) or 160 mg/dL (17 years of age or younger); OR

Genetic Testing for Cardiac Conditions Effective Date: 08/24/2023 Revision Date: 08/24/2023 Review Date: 08/24/2023 Policy Number: HUM-0516-023 Page: 7 of 26

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Individual to be tested has diagnosis of premature atherosclerotic cardiovascular disease (before age 55 in males; before age 60 in females); OR

• Individual to be tested has an affected first- or second-degree relative with one of the following:
• Diagnosis of premature atherosclerotic cardiovascular disease (54 years of age or younger in males, 59 years of age or younger in females); OR
• Diagnosis of FH functional variant(s)

Testing Strategy: perform single gene testing of APOB, LDLR, LDLRAP1 or PCSK9 genes or targeted multigene analysis (sequencing and/or deletion/duplication) of APOB, LDLR, LDLRAP1 and PCSK9 genes. If the individual to be tested has an affected first- or second-degree relative with a diagnosis of FH functional variant(s), test for KFV. *Two or more measurements, including assessment after intensive lifestyle modification.²¹

Hypertrophic Cardiomyopathy – Nonsyndromic (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2 and TPMI Genes)

Humana members may be eligible under the Plan for genetic testing for hypertrophic cardiomyopathy (HCM) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has an affected first-degree relative in whom a pathogenic or likely pathogenic HCM variant has been identified; OR

Testing Strategy: test for KFV

• Individual to be tested has been diagnosed with left ventricular hypertrophy (LVH) using noninvasive cardiac imaging (eg, electrocardiogram [ECG], echocardiography and/or cardiac magnetic resonance imaging [MRI]) and no identifiable cause (eg, valvular disease, hypertension, infiltrative or neuromuscular disorder) has been identified

Testing Strategy: perform targeted multigene analysis for pathogenic variants of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2 and TPMI genes

Long QT Syndrome (KCNH2, KCNQ1 and SCN5A Genes)

Humana members may be eligible under the Plan for genetic testing for long QT syndrome (LQTS) when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has prolonged QT interval on ECG in whom an acquired cause of QT interval prolongation has been ruled out (eg, bradycardia, electrolyte imbalances, heart failure or medications); OR

Testing Strategy for LTQS (Affected):

1. Testing begins with sequence analysis of KCNH2, KCNQ1 and SCN5A genes
2. Deletion/duplication analysis may be performed next if no pathogenic variant is identified

• Individual to be tested is unaffected and has an affected first-degree relative in whom a pathogenic or likely pathogenic LQTS variant has been identified

Testing Strategy: test for KFV

Coverage Limitations

Humana members may NOT be eligible under the Plan for genetic testing for cardiac conditions for any indications or tests other than those listed above including, but may not be limited to:

• Cardiovascular disease (CVD) risk markers, alone or within panels including, but may not be limited to:

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• 4q25 genotype testing (eg, 4q25-AF Risk Genotype, Cardio IQ 4q25-AF Risk Genotype)
• 9p21 genotype testing (eg, 9p21 Genotype)
• Apolipoprotein E (Apo E) genotype testing
• CARDIO inCode-Score (0401U)
• Hypercoagulation, prothrombin or thrombophilia genetic testing including, but not limited to:
  • Factor II (thrombin) (F2 gene)
  • Factor V Leiden (F5 gene)
  • Plasminogen activator inhibitor (PAI-1)
• LPA Intron-25 genotype testing (eg, Cardio IQ Intron-25 Genotype, LPA Intron-25 Genotype)
• ST2 (growth stimulation expressed gene 2) (eg, Cardio IQ ST2 [83006]) testing
• Comprehensive or multicondition multigene panels, with or without NGS, including but may not be limited to:
  • Arrhythmia Panel
  • AtheroGxOne
  • Cardiomyopathies Del/Dup Panel
  • Cardiomyopathy and Arrhythmia Panel
  • Cardiomyopathy Panel
  • CardioNext
  • CMNext
  • Combined Cardiac Panel
  • Comprehensive Cardiomyopathy Multi-Gene Panel
  • DCMNext
  • GeneSeq: Cardio-Familial Arrhythmia Panel
  • GeneSeq: Cardio Familial Cardiomyopathy Profile
  • Genomic Unity Cardiac Ion Channelopathies Analysis
• HCMNext
• Invitae Arrhythmia and Cardiomyopathy Comprehensive Panel
• Invitae Arrhythmia Comprehensive Panel
• Invitae Arrhythmogenic Cardiomyopathy Panel
• Invitae Cardiomyopathy Comprehensive Panel
• Invitae Hypertrophic Cardiomyopathy Panel
• LongQTNext
• Pan Cardiomyopathy Panel
• RhythmNext
• Health and wellness single nucleotide polymorphism (SNP) genotyping tests (eg, Cardiac Healthy Weight DNA Insight, Healthy Woman DNA Insight)

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for genetic testing for cardiac conditions for ANY genes, indications or tests other than those listed above including:

• Brugada syndrome
• Individual to be tested has an affected first-, second- or third-degree relative with a negative genetic testing result for the associated condition
• KFV detection analysis using either of the following methods:
  • Multigene panel that includes the KFV
  • Sequencing, deletion/duplication analysis or large genomic rearrangement analysis (conducted individually, as comprehensive testing or sequentially) without KFV results of a first, second- or third-degree relative
• Deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis

These are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition.

Humana members may NOT be eligible under the Plan for multigene panels unless ALL genes in the panel meet disease- or gene-specific criteria (Refer to Coverage Determination section or Limitations section for single genes in a panel).

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Additional information about inherited cardiac conditions may be found from the following websites:

Background

• American Heart Association
• National Library of Medicine

Medical Alternatives

Alternatives to genetic testing for Brugada syndrome include, but may not be limited to, the following:

• Clinical exam and ECG, with or without provocation with sodium channel blocking drugs

Alternatives to genetic testing for CPVT include, but may not be limited to, the following:

• Avoidance of vigorous physical activity and exposure to stress
• Exercise stress testing and electrocardiographic (eg, Holter) monitoring in an at-risk individual

Alternatives to genetic testing for CVD risk include, but may not be limited to, the following:

• Traditional risk factor analysis, including age, high-density lipoprotein cholesterol, total cholesterol, smoking and systolic blood pressure

Alternatives to diagnostic genetic testing for HCM include, but may not be limited to, the following:

• Clinical exam, ECG and/or echocardiography

Alternatives to multigene panels include, but may not be limited to, the following:

• Targeted gene testing for specific hereditary cardiac conditions based on personal and family history

Physician consultation is advised to make an informed decision based on an individual’s health needs.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.