Carrier Screening for Genetic Diseases Policy Number: PG0442 ADVANTAGE | ELITE | HMO Last Review: 07/25/2019

INDIVIDUAL MARKETPLACE | PROMEDICA MEDICARE PLAN | PPO

GUIDELINES This policy does not certify benefits or authorization of benefits, which is designated by each individual policyholder contract. Paramount applies coding edits to all medical claims through coding logic software to evaluate the accuracy and adherence to accepted national standards. This guideline is solely for explaining correct procedure reporting and does not imply coverage and reimbursement.

SCOPE X Professional X Facility

DESCRIPTION Carrier screening is testing asymptomatic individuals to identify those who are heterozygous for serious or lethal single-gene disorders with the purpose of informing the risk of conceiving an affected child. Risk-based carrier screening is performed in individuals having an increased risk based on population carrier prevalence, and personal or family history. Conditions selected for screening can be based on ethnicities at high risk (e.g., Tay- Sachs disease in individuals of Ashkenazi Jewish descent) or may be pan-ethnic (e.g., screening for cystic fibrosis carriers). Ethnicity-based screening for some conditions has been offered for decades and, in some cases, has reduced the prevalence of diseases.

While methods for carrier screening of conditions individually may have been onerous in the past, contemporary molecular techniques including next-generation sequencing allow simultaneously identifying carriers of a wide range of disorders efficiently and inexpensively.

Expanded carrier screening (ECS) involves screening individuals or couples for disorders in many genes (up to 100s). The disorders included may also span a range of disease severity or phenotype. Arguments for ECS include potential issues in assessing ethnicity, ability to identify more potential conditions, efficiency, and cost. However, there are possible downsides of screening individuals at low risk such as the consequences of screening for rare single-gene disorders in which the likely phenotype may be uncertain (e.g., due to variable expressivity and incomplete penetrance). Additionally, there are circumstances in which the condition screened may not have as accurate results with an expanded screening panel compared to current recommendations for screening (i.e. Tay- Sachs disease, Hemoglobinopathies).The list of conditions included in ECS panels is not standardized. Although ECS panels would include conditions assessed in risk-based screening, ECS panels include many conditions not routinely evaluated and for which there are no existing professional guidelines. For information regarding multi- gene panel testing, please refer to Medical Policy PG0453.

POLICY Prior authorization is required for genetic testing unless otherwise noted in one of our policies.

Some genetic testing requires prior authorization or may be non-covered. A provider must refer to the Paramount prior authorization list and specific medical policy in reference to specific tests for coverage determinations. Refer to these policies regarding genetic testing for carrier screening (this list may not be all-inclusive):  PG0287 Cell-Free DNA Tests/Non-Invasive Prenatal Screening For Fetal Aneuploidy (81420, 81422, 81507, 0009M)  PG0296 Comparative Genomic Hybridization (CGH) (81228, 81229, S3870)  PG0355 Genetic Testing for Hereditary Thrombophilia (81240, 81241, 81291)

PG0442 – 12/28/2020  PG0360 Genetic Testing for Fragile X-Related Disorders (81243, 81244)  PG0387 Genetic Testing for Cystic Fibrosis (81220-81224)  PG0398 Genetic Testing for Spinal Muscular Atrophy (81329, 81336, 81337)

Direct-to-consumer (DTC) genetic testing is non-covered.

For information regarding Multi-Gene Panel Testing, please refer to Medical Policy PG0453.

Refer to CODING/BILLING INFORMATION below for coverage determination.

COVERAGE CRITERIA HMO, PPO, Individual Marketplace, Elite/ProMedica Medicare Plan, Advantage Pre-test genetic counseling (as well as post-test genetic counseling) is recommended when considering genetic testing related to carrier status. Documentation of pre-test genetic counseling is required for coverage of carrier screening.

Pre-test genetic counseling should address the following topics (ACMG, 2008):  A general description of the disorder(s) offered in the carrier screen  Discussion of variable expressivity and incomplete penetrance if applicable  Discussion of residual risk in light of a negative screening result  A description of what it means to be a “carrier”  Carrier screening is voluntary; Informed consent must be obtained.  Informed consent includes discussion of confidentiality, discrimination (i.e. discussion of the Genetic Information Non-Discrimination Act, and applicable state laws), potential psychosocial issues, and economic considerations.

Post-test genetic counseling should address the following topics with a positive carrier screening result:  Discussion of findings- what the individual is a carrier of, description of the condition, and discussion of risk to fetus or future pregnancies  Possible reproductive options  Implications for family members; encouragement to share information with family members

Post-test genetic counseling should address residual risk after a negative carrier screening test.

If obstetric care providers are uncomfortable providing genetic counseling related to carrier screening, referral to a certified genetics professional (such as a genetic counselor) is warranted.

Preconception or prenatal carrier testing for Cystic Fibrosis (CF) with a targeted mutation analysis (23-25 mutations) as recommended by the American College of Medical Genetics (ACMG) is considered medically necessary for a parent or prospective parent. Please see PG0387 for further details regarding genetic testing for Cystic Fibrosis.

Preconception or prenatal carrier testing for Spinal Muscular Atrophy (SMA) is considered medically necessary for a parent or prospective parent. Please see PG0398 for further details regarding genetic testing for Spinal Muscular Atrophy.

Preconception or prenatal carrier testing through a panel carrier test that includes the below conditions is considered medically necessary for a parent or prospective parent of Ashkenazi Jewish (also known as Eastern European/Central European Jewish) descent (defined as having at least one grandparent who is Ashkenazi Jewish).  Cystic Fibrosis  Familial Dysautonomia  Tay-Sachs disease  Fanconi anemia (Group C)

PG0442 – 12/28/2020  Niemann-Pick disease (Type A)  Bloom syndrome  Mucolipidosis IV  Gaucher disease (Type 1)  Familial hyperinsulinism  Glycogen storage disease (Type 1)  Joubert syndrome (type 2)  Maple syrup urine disease (type 1B)  Usher syndrome (Type 1F and 3)

For All Other Carrier Screening Tests

In order to determine the clinical utility of gene test(s), all of the following information must be submitted for review: 1. Name of the genetic test(s) or panel test 2. Name of the performing laboratory and/or genetic testing organization (more than one may be listed) 3. The exact gene(s) and/or mutations being tested 4. Relevant billing codes 5. Medical records related to the genetic test  History and physical exam  Conventional testing and outcomes  Conservative treatment provided, if any

Carrier testing for genetic diseases is considered medically necessary when ONE of the following criteria is met:  The individuals have a previously affected child with the genetic disease  One or both individuals have a first- or second-degree relative who is affected  One individual is known to be a carrier  One or both individuals are members of a population known to have an allele frequency of ≥1%  One or both individuals has had abnormal or inconclusive biochemical or hematologic screening for a genetic condition (such as Tay-Sachs disease [beta-hexosaminidase A enzyme activity] or Alpha- Thalassemia [complete blood count, electrophoresis, etc])

AND ALL of the following criteria are met:  The natural history of the disease is well understood and there is a reasonable likelihood that the disease is one with high morbidity and/or mortality in the homozygous or compound heterozygous state  Alternative biochemical or other clinical tests to definitively diagnose carrier status are not available, or, if available, provide an indeterminate result or are individually less efficacious than genetic testing  The genetic test has >90% detection rate to guide clinical decision making and residual risk is understood  An association of the marker with the disorder has been established  Individual has not previously received genetic testing for the disorder. Note: In general, genetic testing for a particular disorder should be performed once per lifetime; however, there are rare instances in which testing may be performed more than once in a lifetime (eg, previous testing methodology is inaccurate, a new discovery has added significant relevant mutations for a disease, significant changes in technology or treatments indicate that test results or outcomes may change as a result of repeat testing)  Results of genetic testing will directly impact and change clinical management or assist with reproductive planning of the individual being tested  Technical and clinical performance of the genetic test is supported by published peer-reviewed medical literature  Testing is of a voluntary nature for the member and informed consent has been obtained and documented

Paramount considers preimplantation genetic diagnosis not medically necessary for sex selection for nonmedical purposes.

Panels including multiple genes or multiple conditions, and in cases where a tiered approach/method is clinically

PG0442 – 12/28/2020 available, are considered medically necessary only for the number of genes or tests deemed medically necessary to establish a diagnosis.

Direct-to-consumer (DTC) genetic testing is experimental and investigational and therefore non-covered because there is insufficient evidence in the peer-reviewed medical literature of the effectiveness of these panels.

CODING/BILLING INFORMATION The appearance of a code in this section does not necessarily indicate coverage. Codes that are covered may have selection criteria that must be met. Payment for supplies may be included in payment for other services rendered. CPT CODES HMO, PPO, Elite/ProMedica Advantage Individual Medicare Plan Marketplace 81200 ASPA (aspartoacylase) (e.g., Prior Authorization Non-covered Prior Canavan disease) gene analysis, required Authorization common variants (e.g., E285A, required Y231X) 81205 BCKDHB (branched-chain keto acid Prior Authorization Non-covered Prior dehydrogenase E1, beta required Authorization polypeptide) (e.g., Maple syrup required urine disease) gene analysis, common variants (e.g., R183P, G278S, E422X) 81209 BLM (Bloom syndrome, RecQ Prior Authorization Non-covered Prior helicase-like) (e.g., Bloom required Authorization syndrome) gene analysis, required 2281del6ins7 variant 81220 CFTR (cystic fibrosis) gene Prior Authorization Prior Authorization Prior analysis; common variants (eg required required Authorization ACMG, ACOG guidelines) required 81242 FANCC (Fanconi anemia, Prior Authorization Non-covered Prior complementation group C) (e.g., required Authorization Fanconi anemia, type C) gene required analysis, common variant (e.g., IVS4+4A>T) 81250 G6PC (glucose-6-phosphatase, Prior Authorization Non-covered Prior catalytic subunit) (e.g., Glycogen required Authorization storage disease, Type 1a, von required Gierke disease) gene analysis, common variants (e.g., R83C, Q347X) 81251 GBA (glucosidase, beta, acid) (e.g., Prior Authorization Non-covered Prior Gaucher disease) gene analysis, required Authorization common variants (e.g., N370S, required 84GG, L444P, IVS2+1G>A) 81252 GJB2 (gap junction protein, beta 2, Prior Authorization Non-covered Prior 26kDa, connexin 26) (e.g., required Authorization nonsyndromic hearing loss) gene required analysis; full gene sequence (LCD L32288) 81253 GJB2 (gap junction protein, beta 2, Prior Authorization Non-covered Prior 26kDa; connexin 26) (e.g., required Authorization nonsyndromic hearing loss) gene required

PG0442 – 12/28/2020 analysis; known familial variants (LCD L32288) 81254 GJB6 (gap junction protein, beta 6, Prior Authorization Non-covered Prior 30kDa, connexin 30) (e.g., required Authorization nonsyndromic hearing loss) gene required analysis, common variants (e.g., 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)]) (LCD L32288) 81255 HEXA (hexosaminidase A [alpha Prior Authorization Non-covered Prior polypeptide]) (e.g., Tay-Sachs required Authorization disease) gene analysis, common required variants (e.g., 1278insTATC, 1421+1G>C, G269S) 81257 HBA1/HBA2 (alpha globin 1 and Prior Authoriztion Non-covered Prior alpha globin 2) (e.g., alpha required Authorization thalassemia, Hb Bart hydrops fetalis required syndrome, HbH disease), gene analysis; common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring) 81258 HBA1/HBA2 (alpha globin 1 and Prior Authorization Non-covered Prior alpha globin 2) (e.g., alpha required Authorization thalassemia, Hb Bart hydrops fetalis required syndrome, HbH disease), gene analysis; known familial variant (Effective 01/01/2018 new code) 81259 HBA1/HBA2 (alpha globin 1 and Prior Authorization Non-covered Prior alpha globin 2) (e.g., alpha required Authorization thalassemia, Hb Bart hydrops fetalis required syndrome, HbH disease), gene analysis; full gene sequence (Effective 01/01/2018 new code) 81260 IKBKAP (inhibitor of kappa light Prior Authorization Non-covered Prior polypeptide gene enhancer in B- required Authorization cells, kinase complex-associated required protein) (e.g., familial dysautonomia) gene analysis, common variants (e.g., 2507+6T>C, R696P) 81265 Comparative analysis using Short Prior Authorization Prior Authorization Prior Tandem Repeat (STR) markers; NOT required NOT required Authorization patient and comparative specimen NOT required (e.g., pre-transplant recipient and donor germline testing, post- transplant non-hematopoietic recipient germline [e.g., buccal swab or other germline tissue sample] and donor testing, twin zygosity testing, or maternal cell contamination of fetal cells) 81266 Comparative analysis using Short Prior Authorization Prior Authorization Prior Tandem Repeat (STR) markers; NOT required NOT required Authorization

PG0442 – 12/28/2020 each additional specimen (e.g., NOT required additional cord blood donor, additional fetal samples from different cultures, or additional zygosity in multiple birth pregnancies) (List separately in addition to code for primary procedure) 81269 HBA1/HBA2 (alpha globin 1 and Prior Authorization Non-covered Prior alpha globin 2) (eg, alpha required Authorization thalassemia, Hb Bart hydrops fetalis required syndrome, HbH disease), gene analysis; duplication/deletion variants (Effective 01/01/2018 new code) 81290 MCOLN1 (mucolipin 1) (e.g., Prior Authorization Non-covered Prior Mucolipidosis, type IV) gene required Authorization analysis, common variants (e.g., required IVS3-2A>G, del6.4kb) 81330 SMPD1(sphingomyelin Prior Authoriztion Non-covered Prior phosphodiesterase 1, acid required Authorization lysosomal) (e.g., Niemann-Pick required disease, Type A) gene analysis, common variants (e.g., R496L, L302P, fsP330) 81361 HBB (hemoglobin, subunit beta) Prior Authorization Non-covered Prior (eg, sickle cell anemia, beta required Authorization thalassemia hemoglobinopathy); required common variant(s) (eg, HbS, HbC, HbE) 81362 HBB (hemoglobin, subunit beta) Prior Authorization Non-covered Prior (eg, sickle cell anemia, beta required Authorization thalassemia hemoglobinopathy); required known familial variant(s) 81363 HBB (hemoglobin, subunit beta) Prior Authorization Non-covered Prior (eg, sickle cell anemia, beta required Authorization thalassemia hemoglobinopathy); required duplication/deletion variant(s) 81364 HBB (hemoglobin, subunit beta) Prior Authorization Non-covered Prior (eg, sickle cell anemia, beta required Authorization thalassemia hemoglobinopathy); full required gene sequence (Effective 01/01/2018 new code) 81400 Molecular pathology procedure, Prior Authorization Prior Authorization Prior Level 1 analysis)(e.g., identification required required Authorization of single germline variant [e.g., required SNP] by techniques such as restriction enzyme digestion or melt curve analysis) 81401 Molecular pathology procedure, Prior Authorization Prior Authorization Prior Level 2 (e.g., 2-10 SNPs, 1 required required Authorization methylated variant, or 1 somatic required variant [typically using nonsequencing target variant

PG0442 – 12/28/2020 analysis], or detection of a dynamic mutation disorder/triplet repeat) 81403 Molecular pathology procedure, Prior Authorization Prior Authorization Prior Level 4 (eg, analysis of single exon required required Authorization by DNA sequence analysis, required analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) 81404 Molecular pathology procedure, Prior Authorization Prior Authorization Prior Level 5 (eg, analysis of 2-5 exons required required Authorization by DNA sequence analysis, required mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) 81406 Molecular pathology procedure, Prior Authorization Prior Authorization Prior Level 7 (e.g., analysis of 11-25 required required Authorization exons by DNA sequence analysis, required mutation scanning or duplication/deletion variants of 26- 50 exons, cytogenomic array analysis for neoplasia) 81412 Ashkenazi Jewish associated Prior Authorization Non-covered Prior disorders (eg, Bloom syndrome, required Authorization Canavan disease, cystic fibrosis, required familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 Genetic testing for severe inherited 81443 Prior Authoriztion Non-covered Prior conditions (e.g., cystic fibrosis, required Authoriztion Ashkenazi Jewishassociated disorders [e.g., Bloom syndrome, required Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (e.g., ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH) 81479 Unlisted molecular pathology Prior Authorization Prior Authorization Prior procedure required required Authorization required HCPCS CODES HMO, PPO, Elite/ProMedica Advantage

PG0442 – 12/28/2020 Individual Medicare Plan Marketplace S3844 DNA analysis of the connexin 26 Non-covered Non-covered Non-covered gene (GJB2) for susceptibility to congenital, profound deafness S3845 Genetic testing for alpha- Non-covered Non-covered Non-covered thalassemia S3846 Genetic testing for hemoglobin E Non-covered Non-covered Non-covered beta-thalassemia S3849 Genetic testing for Niemann-Pick Non-covered Non-covered Non-covered diseases S3850 Genetic testing for sickle cell Non-covered Non-covered Non-covered anemia S3852 DNA analysis for APOE epsilon 4 Non-covered Non-covered Non-covered allele for susceptibility to Alzheimer's disease S3853 Genetic testing for myotonic Non-covered Non-covered Non-covered muscular dystrophy

REVISION HISTORY EXPLANATION ORIGINAL EFFECTIVE DATE: 08/23/2018 08/23/18: Direct-to-consumer (DTC) genetic testing is non-covered. Expanded carrier screening panels are non- covered. Policy created to reflect most current clinical evidence per The Technology Assessment Working Group (TAWG). 6/26/19: Policy created to reflect most current clinical evidence. Added several relevant CPT codes. All CPT codes related to carrier screening that is covered now require prior authorization. 07/25/19: Corrected procedure 81220 for the Elite Product line, was listed as non-covered and should be authorization required. Corrected medical policy reference from PG0451 to PG0453. 12/28/2020: Medical policy placed on the new Paramount Medical policy format

REFERENCES/RESOURCES Centers for Medicare and Medicaid Services, CMS Manual System and other CMS publications and services Ohio Department of Medicaid American Medical Association, Current Procedural Terminology (CPT®) and associated publications and services Centers for Medicare and Medicaid Services, Healthcare Common Procedure Coding System, HCPCS Release and Code Sets Industry Standard Review Hayes, Inc. The American College of Obstetricians and Gynecologists (ACOG), Committee Opinion 690, March 2017, Reaffirmed 2019, Carrier Screening in the Age of Genomic Medicine

The American College of Obstetricians and Gynecologists (ACOG), Committee Opinion 691, March 2017, Reaffirmed 2019, Carrier Screening for Genetic Conditions

American College of Medical Genetics (ACMG), January 2008, Carrier Screening in Individuals of Ashkenazi Jewish Descent

American College of Medical Genetics (ACMG), June 2013, ACMG Position Statement on Prenatal/Preconception Expanded Carrier Screening

American College of Medical Genetics (ACMG), November 2008, Carrier Screening for Spinal Muscular Atrophy

PG0442 – 12/28/2020 American College of Medical Genetics (ACMG), March/April 2001, Laboratory Standards and Guidelines for Population-Based Cystic Fibrosis Carrier Screening

Joint Statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine, Expanded Carrier Screening in Reproductive Medicine-Points to Consider, 2015

PG0442 – 12/28/2020