Please refer to CMS website for the most current applicable CMS Online Manual System (IOMs)/National Coverage Determination (NCD)/ Local Coverage Determination (LCD)/Local Coverage Article (LCA)/ Transmittals.

Genetic Testing for Diagnosis of Inherited Conditions

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MolDxX: Molecular Diagnostic Tests (MDT) ID Number L36807

Billing and Coding:

• MolDX: MECP2 Genetic Testing
• MolDX: Molecular Diagnostic Tests (MDT)

A57772 A55208

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Billing and Coding: MolDX:

• SMPD1 Genetic Testing
• Molecular Pathology Procedures | Billing and Coding: Molecular L35000 A56199 . eK National CT, IL, MA, ME, MN, NH, NY, RI, VT, WI
• Pathology Procedures
• Tests (MDT) Billing and Coding: MolDX: Aspartoacyclase 2 Deficiency A54253
• MolDxX: Molecular Diagnostic (ASPA) Testing Billing and Coding: MolDX: BCKDHB Gene Test Billing and Coding: MolDX: BLM Gene Analysis Billing and Coding: MolDXx: . Fragile X Billing and Coding: MolDX: GBA Genetic Testing L36021 AS54255 AS54256 A54264 —— AS54265 ————
• Billing and Coding: MolDX: HEXA Gene Analysis Billing and Coding: MolDXx: IKBKAP Genetic Testing Billing and Coding: MolDX: . L1CAM Gene Sequencing Guidelines Billing and Coding: MolDX: AS54268 A54270 — A54274 — J15- CGS Administrators, LLC KY, OH

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Billing and Coding:

• MolDX: MCOLN1 Genetic Testing Guidelines
• MolDX: MECP2 Genetic Testing
• MolDX: Molecular Diagnostic Tests (MDT) A54278 A56973
• MolDxX: Molecular Diagnostic L35160
• Tests (MDT)
• Billing and Coding: MolDX: Aspartoacyclase 2 Deficiency (ASPA) Testing A55088 CA, HI, NV, American Samoa, Guam, Northern Mariana Islands
• Billing and Coding: MolDX: A55099
• BCKDHB Gene Test
• Billing and Coding: MolDX: BLM | Gene Analysis A55113
• Billing and Coding: MolDX: A55241
• Fragile X
• Billing and Coding: MolDX: GBA__| Genetic A55243
• and MolDX: HEXA A55255

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• Billing and Coding: MolDX: MECP2 Genetic Testing A55285
• Billing and Coding: MolDX: SMPD1 Genetic Testing
• MolDX: Molecular Diagnostic Tests (MDT) A55627 L36256

Genetic Testing for Diagnosis of Inherited Conditions

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• Billing and Coding: MolDX: Aspartoacyclase 2 Deficiency (ASPA) Testing L35025 A53602 A53600

JE - Noridian

• Billing and Coding: MolDX: IKBKAP Genetic Testing A55612
• Billing and Coding: MolDX: L1CAM Gene Sequencing A55277
• Billing and Coding: MolDX: MCOLN1 Genetic Testing A55283
• Billing and Coding: Molecular Diagnostic Tests (MDT) A57526

JF - Noridian Healthcare Solutions, LLC

• Billing and Coding: MolDX: Aspartoacyclase 2 Deficiency (ASPA) Testing A55089
• BCKDHB Gene Test
• Billing and Coding: MolDX: BLM Gene Analysis A55114
• Billing and Coding: MolDX: Fragile X A55242
• Billing and Coding: MolDX: GBA Genetic Testing A55244
• Billing and Coding: MolDX: HEXA Gene Analysis A55256
• Billing and Coding: MolDX: IKBKAP Genetic Testing A55613
• Billing and Coding: MolDX: L1CAM Gene Sequencing A55278
• Billing and Coding: MolDX: MCOLN1 Genetic Testing A55284
• Billing and Coding: MolDX: MECP2 Genetic Testing A55286
• Billing and Coding: MolDX: SMPD1 Genetic Testing A55631

LCDLCA

Billing and Coding: MolDX: SMPD1 Genetic Testing MolDX: Molecular Diagnostic Tests (MDT) Billing and Coding: MolDX: Aspartoacyclase 2 Deficiency (ASPA) Testing L35025 A53602 A53600

Palmetto GBA | AL, GA, NC, SC, TN, VA, WV LCD JN - First Coast Service Options, Inc.

FL, PR, U.S. VI

Description

Genetic testing may be performed to analyze an individual’s deoxyribonucleic acid (DNA) to detect gene variants to assist in confirming a diagnosis in those who exhibit disease signs and symptoms and to aid with treatment decisions.

Examples of genetic conditions that may be evaluated by genetic testing include, but are not limited to, achondroplasia, alpha-1 antitrypsin deficiency, cardiofaciocutaneous syndrome, Celiac Genetic Testing for Diagnosis of Inherited Conditions Page: 7 of 38 disease, Charcot-Marie-Tooth disease, dystrophic epidermolysis bullosa, hereditary neuropathy with liability to pressure palsies (HNPP), muscular dystrophy, neurofibromatosis, Noonan syndrome, polycystic kidney disease (PKD) and spastic paraplegia.

Coverage Determination

Humana follows the CMS requirements that only allows coverage and payment for services that are reasonable and necessary for the diagnosis and treatment of illness or injury or to improve the functioning of a malformed body member except as specifically allowed by Medicare.

Genetic tests must demonstrate clinical utility, analytical and clinical validity and fulfill the CMS "reasonable and necessary" criteria. Analytic validity (test accurately identifies the gene variant), clinical validity (test identifies or predicts the clinically defined disorder) and clinical utility (test measurably improves clinical outcomes) of the genetic test is supported by generally accepted standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, specialty society recommendations, and views of physicians practicing in relevant clinical areas.

The test must be ordered by a physician who is treating the beneficiary and the results will be used in the management of a beneficiary’s specific medical problem.For jurisdictions with no Medicare guidance for a particular test, Humana will utilize the MolDX program and Technical Assessments for molecular assays as the standard to evaluate clinical utility, analytical and clinical validity in conjunction with adhering to Medicare’s reasonable and necessary requirement.In interpreting or supplementing the criteria above and in order to determine medical necessity consistently, Humana may consider the following criteria:

General Criteria for Genetic Testing for Diagnosis of Inherited Conditions

Apply General Criteria for Genetic Testing for Diagnosis of Inherited Conditions when disease- or gene- specific criteria are not available on this medical coverage policy.Genetic testing for diagnosis of inherited conditions will be considered medically reasonable and necessary when the following requirements are met:

• Analytic validity, clinical validity and clinical utility of the genetic test is supported by the MolDX program; AND
• Individual displays signs and symptoms of a hereditary disease
• Alternative laboratory or clinical tests to definitively diagnose the disorder/identify the condition are unavailable or results are clearly equivocal; AND
• Results of the genetic testing must directly impact treatment or management of the Medicare beneficiary

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Scientific literature reliably supports a gene-disease association

Criteria for Specific Inherited Conditions

Achondroplasia single gene testing (FGFR3) will be considered medically reasonable and necessary when the following requirements are met:

• 83,122,147,159,184,216
• Genetic testing is limited to the FGFR3 gene; AND
• Epiphyses are confirmed open by diagnostic imaging; AND
• Testing will impact management of the individual (eg, vosoritide [Voxzogo])

Alpha-1 antitrypsin deficiency single gene testing (SERPINA1) (81332) will be considered medically reasonable and necessary for the following indications:

• 16,80,123,137,138,165,187,215,221
• Genetic testing is limited to the SERPINA1 gene; AND
• Chronic obstructive pulmonary disease (COPD); OR
• Granulomatosis with polyangiitis; OR
• Necrotizing panniculitis; OR
• Unexplained bronchiectasis; OR
• Unexplained chronic liver disease

Celiac disease HLA-DQ2/HLA-DQ8 testing will be considered medically reasonable and necessary for the workup of an individual with an unclear diagnosis of celiac disease and gluten hypersensitivity usually related to ambiguous standard laboratory results and/or inconsistent biopsy results (eg, HLA-DQ2 by HLA- DQB1*02 and of DQ8 by HLA-DQB1*0302).

80

Dystrophic epidermolysis bullosa (DEB) single gene testing (COL7A1) will be considered medically reasonable and necessary when the following requirements are met:

• 117,146,191
• Genetic testing is limited to the COL7A1 gene; AND
• Individual to be tested exhibits clinical characteristics of dystrophic epidermolysis bullosa (DEB) (eg, fragility of the skin, blistering and erosions, dystrophic or absent nails).

Epilepsy genomic sequence analysis multigene panel (81419) will be considered medically reasonable and necessary for unexplained epilepsy when the following requirements are met:

• 68,210
• Analytic validity, clinical validity and clinical utility of the genetic test is supported by the MolDX program; AND
• Alternative laboratory or clinical tests to definitively diagnose the disorder/identify the condition are unavailable or results are clearly equivocal; AND
• Results of the genetic testing must directly impact treatment or management of the Medicare beneficiary

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Hereditary transthyretin amyloidosis single gene testing (TTR) will be considered medically reasonable and necessary when the following requirements are met:

• 1,2,99,124,133,145,149,158,196,229,238
• Genetic testing is limited to the TTR gene; AND
• Individual to be tested diagnosed with polyneuropathy and a comprehensive neurologic examination has ruled out other causes of sensorimotor/autonomic neuropathy (eg, chronic inflammatory demyelinating polyneuropathy); AND
• No history of liver transplant; AND
• Polyneuropathy disability (PND) scoring system indicates stage I, II, IIIa or IIIb; AND
• Testing will result in a change of management (eg, vutrisiran [Amvuttra], patisiran [Onpattro] or inotersen [Tegsedi])

Inherited retinal disorders single gene* (ABCA4, CNGA1, CRB1, EYS, PDE6A, PDE6B, PRPF31, PRPH2, RDH12, RHO, RP1, RP2, RPE65, RPRGR, USH2A) will be considered medically reasonable and necessary when the following requirements are met:

• 4,100,129,197
• Individual to be tested diagnosed with an inherited retinal disorder (eg, retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy); AND
• Exhibits progressive loss of photoreceptor function accompanied by vision lossFor multigene panels for inherited retinal disorders, please refer to Limitations.

Oculopharyngeal muscular dystrophy (OPMD) single gene testing (PABPN1) (81312) will be considered medically reasonable and necessary when the following requirements are met:

• 68,156,205,237
• Genetic testing is limited to the PABPN1 gene; AND
• Individual to be tested has dysphagia (defined as a swallowing time greater than 7 seconds when drinking 80mL of ice-cold water as documented by a swallow study); AND
• Previous corrective surgery for ptosis; OR
• Vertical separation of at least one palpebral fissure that measures less than 8mm at rest
• Testing Strategy for OPMD: PABPN1 gene sequence analysis or targeted analysis for GCN repeat number in exon 1.

Polycystic kidney disease (PKD) (autosomal dominant or autosomal recessive) gene testing (PKD1, PKD2, PKHD1) will be considered medically reasonable and necessary when the following requirements are met:

• 84,85,125,160,206,207,217
• Single gene analysis of PKD1, PKD2 or PKHD1 when the individual to be tested has equivocal or uninformative imaging results; OR
• Multigene panel that includes PKD1, PKD2, PKHD1 will be considered medically reasonable and necessary when the individual to be tested has equivocal or uninformative imaging results and the analytic validity, clinical validity and clinical utility of the genetic test is supported by the MolDX program.

The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms.

Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy.

Coverage Limitations

US Government Publishing Office. Electronic code of federal regulations: part 411 – 42 CFR § 411.15 - Particular services excluded from coverage

The following tests may not be considered a benefit (statutory exclusion):

• Gaucher disease (GBA)39,40,41,42
• Familial dysautonomia (IKBKAP)48,49,50,51,52
• L1 syndrome (L1CAM)53,54,55,56,57
• Maple syrup urine disease (BCKDHB)22,23,24,25,26,27
• Mucolipidosis type IV (MCOLN1)58,59,60,61,62
• Niemann-Pick disease (SMPD1)69,70,71,72,73
• Tests considered screening in the absence of clinical signs and symptoms of disease that are not specifically identified by the law;214 OR

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Tests that confirm a diagnosis or known information;214 OR

Tests to determine risk for developing a disease or condition;214 OR

Tests performed to measure the quality of a process;214 OR

Tests without diagnosis specific indications;214 OR

Tests identified as investigational by available literature and/or the literature supplied by the developerand are not a part of a clinical trial214

These treatments and services fall within the Medicare program’s statutory exclusion that prohibits payment for items and services that have not been demonstrated to be reasonable and necessary for the diagnosis and treatment of illness or injury (§1862(a)(1) of the Act).

Other Services/Items Statutory Exclusion

Other services/items fall within the Medicare program’s statutory exclusion at 1862(a)(12), which prohibits payment. The following items will not be considered medically reasonable and necessary:

• Any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same individual
• Deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis
• Genetic tests that have not demonstrated clinical utility, analytical and clinical validity via the MolDX Program
• Bloom disease (BLM) (81209)28,29,30,31,32
• Canavan disease (also known as asparoacyclase 2 deficiency [ASPA])17,18,19,20,21
• Charcot-Marie-Tooth for any of the following genes:
  • GJB180
  • MPZ80
  • PMP22 full gene sequencing (81325)68
  • PMP22 deletion/duplication analysis (81324)68
  • PMP22 known familial variant analysis (81326)68
• Corneal dystrophy (TGFB1) (81333)68
• Duchenne/Becker muscular dystrophy (DMD) (81161/0218U)68
• Fragile X syndrome (FMR1 [81243/81244] and AFF2 [81171/81172] genes)33,34,35,36,37
• Hereditary peripheral neuropathies genomic sequence analysis panel (81448)68
• Inherited retinal disorders (eg, retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy) genomic sequence analysis panel (81434)68
• Myotonic dystrophy type 1 - DMPK full gene sequence analysis (81187)68
• Myotonic dystrophy type 2 (CNBP) (81234/81239)68
• Neurofibromatosis type 1 single gene testing (NF1)80
• NF2-related schwannomatosis (formerly neurofibromatosis type 2) single gene testing (NF2)80
• Nonsyndromic hearing loss including the following:
  • Genomic sequence analysis panel (81430) and deletion/duplication analysis panel (81431)68
  • GJB2 (81252/81253)68
  • GJB6 (81254)68
• Noonan spectrum disorders including the following:
  • Genomic sequence analysis panel (81442)68
  • PTPN1180
  • SOS180
• Prader-Willi syndrome (UBE3A) (81331)80
• Rett syndrome (MECP2 [81302/81304/0234U])63,64,65,66,67
• Spinal and bulbar muscular atrophy (Kennedy’s Disease) (AR) (81204/81173/81174/0230U)80
• Spinal muscular atrophy (SMN1) (81336)80
• Tay-Sachs disease (HEXA)43,44,45,46,47
• X-linked intellectual disability (XLID) genomic sequence analysis panel (81470) and deletion/duplication analysis panel (81471)68

A review of the current medical literature shows that the evidence is insufficient to determine that these services are standard medical treatments. There remains an absence of randomized, blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of these services in clinical management.

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