Code Description CPT
81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence
81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring) (effective 1/1/18)
81258 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant (effective 1/1/18)
81259 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence (effective 1/1/18)
81269 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants (effective 1/1/18)
81412 Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, 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
81479 Unlisted molecular pathology procedure
What are MoPath Codes?
MoPath codes are labels for molecular diagnostics tests that enable payers (i.e., Medicare, Medicaid, private insurance companies) to properly identify and bill for services. In 2012, the AMA CPT estab-lished a new set of analyte-specific MoPath codes to replace the methodology-based codes (CPT 83890-83914; 88384-88386) that previously allowed labs to bill different coding combinations (also known as “code stacks”) for tests evaluating the same analyte. These “stacking” codes were retired as of January 1, 2013. Labs are now required to report tests using the analyte-specific MoPath codes.
The MoPath codes are categorized into Tier 1 and Tier 2 codes:
• Tier 1 codes represent the majority of commonly performed single-analyte molecular tests.
• Tier 2 codes represent procedures that are generally performed in lower volumes than Tier 1 procedures (e.g., when the incidence of the disease being tested is rare), and correspond to nine ascending levels of technical resources and interpretive work performed by the physician or other qualified healthcare professional
In general, CF genetic testing is widely covered for both carrier screening and confirmatory diagnostic testing (Figures 1 and 2). Private payers generally separate coverage guidelines for CF carrier screening versus confirmatory diagnostic testing. For both indica-tions, the majority of payers have either issued positive coverage policies or no policies at all. The absence of a coverage policy does not necessarily indicate non-coverage, but implies that the procedure may be covered if medical necessity can be justified.
Based on private payer coverage guidelines, CF carrier screening is generally covered for individuals who meet any of the following criteria:
• Couples seeking prenatal care
• Couples who are planning a pregnancy
• Persons with a family history of CF
• Persons with a 1st degree relative identified as a CF carrier
• Reproductive partners of persons with CF Additionally, CF diagnostic testing is typically covered for individuals
who meet any of the following criteria:
• Individual who exhibits symptoms of CF but has a negative sweat test
• Infant with meconium ileus or other symptoms indicative of CF who is too young to produce inadequate volumes of sweat for a sweat chloride test
• Male infertility from either of the following:
– Congenital bilateral absence of vas deferens (CBAVD)
– Azoospermia or severe oligospermia (i.e., < 5 million sperm/milliliter) with palpable vas deferens The majority of state Medicaid agencies do not have policies specifi-cally addressing coverage for CF genetic testing (carrier screening or diagnostic testing), but instead have general coverage policies for laboratory services performed by CLIA-approved labs.
For 2013, the Centers for Medicare & Medicaid Services (CMS) assigned the local Medicare Administrative Contractors (MACs) the responsibility of setting regional fee schedule amounts for the new MoPath code set (including payment rates for CF testing) via gapfilling.Gapfilling is used when a comparable test does not exist. CMS instructs local MACs to establish payment rates in the first year based on charges and routine discounts to charges, resources required, and other payers’ payment rates. For reimbursement in the second year and beyond, CMS calculates a national payment rate by using the median of the local MAC fee schedules.On September 30, 2013, CMS released the 2014 national Medicare fee schedule amounts for the MoPath codes, which were based on the final gapfill rates determined by each MAC
. However, the national fee schedule did not include any payment rates for the cystic fibrosis testing codes. Since payment rates will vary by payer (both private and public), laboratories are encouraged to contact individual payers directly to clarify the fee schedule amounts for these codes in 2014.
Preconception Screening for Carrier Status of Genetic Diseases
Genetic tests are laboratory tests that measure changes in human DNA, chromosomes, genes or gene products (proteins). Blood, skin, cheek swabs, and amniotic fluid are some common samples that can be tested. Genetic testing for carrier status is done on people planning a pregnancy. The goal is to see if they have a potential disease that could be passed on to their offspring. For certain disorders, a carrier state can exist where a person has no symptoms of the disease, but has the potential to pass the disease on to their children because they carry a gene for the disease. Often it takes at least two copies of the gene for the disease to cause symptoms. Usually carrier testing is done before conception when individuals are planning a pregnancy, but it may also be done in the early stages of pregnancy.
Policy Coverage Criteria
This policy applies only if there is not a separate policy that outlines specific criteria for carrier testing. If a separate policy exists, then criteria for medical necessity in that policy supersedes the guidelines in this policy (see Related Policies).
Note: Usually carrier testing is done before conception when individuals are planning a pregnancy, but it may also be done in the early stages of pregnancy.
Test Type Medical Necessity Expanded Carrier
Expanded Carrier Screening Panels
Expanded carrier screening panels which test for mutations on many different genes are considered not medically necessary. Based on the individual tested, a subset of tests within the panel may be covered when the policy criteria are met.
The names of expanded carrier panels, and their individual mutation components, are rapidly evolving. Examples of panels addressed in this policy include but are not limited to: * Counsyl™ (Counsyl) * GoodStart Select™ (GoodStart Genetics) * Inherigen™ (GenPath) * InheriGen Plus * Inheritest™ (LabCorp) * Natera One™ Disease Panel (Natera) Genetic Disease Medical Necessity The General Population Cystic fibrosis (CPT 81220) Covered for all individuals with a panel that tests the most common genes
Note: Carrier testing for cystic fibrosis using CPT 81223 “CFTR (eg, cystic fibrosis) gene analysis; full gene sequence” is considered not medically necessary for carrier testing.
Genetic Disease Medical Necessity Spinal muscular atrophy (CPT 81400, 81401)
Covered for all individuals
Genetic Disease Medical Necessity Specific Groups or Populations
The following genetic testing may also be considered medically necessary due to an increased frequency of certain disorders in groups or populations
Ashkenazi Jewish founder mutations:
* Bloom syndrome * Canavan disease * Cystic fibrosis * Familial dysautonomia * Fanconi anemia (group C) * Gaucher disease * Mucolipidosis IV * Niemann-Pick (type A)
* Tay-Sachs disease
FMR1 variants (including Fragile-X syndrome)
Ashkenazi Jewish founder mutations may be considered medically necessary when the individual meets one of the following criteria: * Ashkenazi Jewish ancestry consisting of a minimum of one
Jewish grandparent * If the Jewish partner has a positive carrier test result, the other
partner (regardless of ethnic background) should be screened only for that identified mutation
Genetic testing for Ashkenazi Jewish founder mutation is considered not medically necessary for all other uses.
Genetic testing for FMR1 variants may be considered medically necessary when any of the following criteria are met: * Parent of either sex with intellectual disability, developmental delay, or autism spectrum disorder * Parent with a family history of fragile X syndrome or a family history of undiagnosed intellectual disability * Prenatal testing of fetuses of mothers who are known carriers to determine whether the fetus inherited the normal or mutant FMR1 gene
* Affected individuals or first- and second- degree relatives of affected individuals who have had a positive cytogenetic fragile X test (less accurate historic test) result who are seeking further counseling related to the risk of carrier status
Genetic testing for FMR1 variants (including Fragile-X syndrome) is considered not medically necessary for all other
Genetic Disease Medical Necessity uses. Alpha-thalassemia
preconception (carrier) testing
Preconception (carrier) testing for alpha-thalassemia in prospective parents may be considered medically necessary when all of the following criteria are met: * At least one parent is of a high-risk ethnic group, such as
Southeast Asian, African or Mediterranean ancestry * At least one parent has had abnormal biochemical testing
which may include ANY of the following: o Anemia o Microcytosis (a low MCV – small blood cells) o Hypochromia (a low MCH or MCHC – red blood cells with
less hemoglobin) o Abnormal hemoglobin electrophoresis
Genetic testing for hemoglobinopathies, except for alphathalassemia, is considered not medically necessary.
Genetic Disease Medical Necessity Other Inherited Disorders
Carrier testing of specific disorder
May be considered medically necessary when ONE of the following criteria are present: * One or both parents have a first- or second-degree relative*
who has the disorder * One parent is or both parents are a known carrier of the
Note: 1st-degree relatives are parents, siblings, and children. 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.
AND all of the following criteria must also be met: * The natural history of the disease is understood and the
disease is likely to result in severe health problems * Other biochemical or clinical tests to diagnose carrier status are
Genetic Disease Medical Necessity Coding not available, or are less accurate than genetic testing * The genetic test has adequate sensitivity and specificity to guide clinical decision making o The American College of Medical Genetics and Genomics (ACMG) recommends testing for specific mutations, which will result in carrier detection rate of 95% or higher for most disorders.
* A clear association of the genetic change with the disorder has been established Genetic testing for other specific disorders is considered not medically necessary when the criteria above are not met.
If there is no family history of, risk based or ethnic predilection for a disease, carrier screening is not recommended when the carrier rate is less than 1% in the general population.
ACMG has defined expanded panels as those that use next-generation sequencing to screen for variants in many genes, as opposed to gene-by-gene screening (eg, ethnic-specific screening or pan-ethnic testing for cystic fibrosis).
Expanded panels may include the diseases that are present with increased frequency in specific populations, but typically include testing for a wide range of diseases for which the patient is not at risk of being a carrier.
Carrier screening should only be performed in adults.
For individuals who are at risk due to an established family history of fragile X syndrome, DNA testing alone is sufficient. If the diagnosis of the affected relative was based on previous cytogenetic testing for fragile X syndrome, at least one affected relative should have DNA testing.
Prenatal testing of a fetus should be offered when the mother is a known carrier to determine whether the fetus inherited the normal or mutant FMR1 gene. Ideally DNA testing should be performed on cultured amniocytes obtained by amniocentesis after 15 weeks’ gestation. DNA testing can be performed on chorionic villi obtained by chorionic villus sampling at 10 to 12 weeks’ gestation, but results must be interpreted with caution because the methylation status of the FMR1 gene is often not yet established in chorionic villi at the time of sampling. follow-up amniocentesis may be necessary to resolve an ambiguous result.
Definition of Terms
1st-, 2nd-, or 3rd-degree relative: For the purpose of familial assessment, 1st-, 2nd-, or 3rddegree relatives are blood relatives on the same side of the family (maternal or paternal). The maternal and paternal sides of the family should be considered independently for familial patterns of inherited disorders.
* 1st-degree relatives are parents, siblings, and children.
* 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.
* 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins
Carrier testing: Carrier genetic testing is performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children.
A carrier of a genetic disorder has one abnormal allele for a disorder. Carriers of an autosomal recessive mutation are typically unaffected. Offspring who inherit the mutation from both parents usually manifest the disorder. When associated with an autosomal dominant or an Xlinked dominant disorder, the individual may be affected with the disorder or be at high risk of developing the disorder later in life. Women with an X-linked recessive mutation are usually unaffected. Males receiving a chromosome with an X-linked recessive mutation usually manifest the disorder.
Compound heterozygous: The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair.
Expressivity/expression: The degree to which a penetrant gene is expressed within an individual.
Genetic testing: A test that analyzes chromosomes, DNA, RNA, genes, or gene products to detect inherited (germline) or non-inherited (somatic) genetic variants related to disease or health
Homozygous: Having the same alleles at a particular gene locus on homologous chromosomes (chromosome pairs).
Penetrance: The proportion of individuals with a mutation that causes a particular disorder who exhibit clinical symptoms of that disorder.
Residual risk: The risk that an individual is a carrier of a particular disease, but genetic testing for carrier status of the disease is negative (eg, if the individual has a disease-causing mutation that wasn’t included in the test assay).
Testing sequence: Testing sequence of carrier testing for genetic diseases is generally done on the mother or affected partner first, and if positive, then the other parent is tested.
Genetics Nomenclature Update
Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). HGVS nomenclature is recommended by HGVS, the Human Variome Project, and the HUman Genome Organization (HUGO).
The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from ACMG, AMP, and the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Variant Classification Definition
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology. providing a diagnosis eliminates the need for further diagnostic workup. A chain of evidence supports improved outcomes following FMR1 variant testing.. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have a personal or family history of FXS who are seeking reproductive counseling, the evidence includes studies evaluating the clinical validity of FMR1 variant testing and the effect on reproductive decision making. Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, fetuses of known carrier mothers, or affected individuals or their relatives who have had a positive cytogenetic fragile X test result who are seeking further counseling related to the risk of carrier status among themselves or their relatives. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.