CPT 81401, 81405, 81408, 81410, 81411 - Genetic Testing for Marfan Syndrome

Coding  Code Description CPT

81401 MED12 (mediator complex subunit 12)(eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S)

81405 ACTA2 (actin, alpha 2, smooth muscle, aorta) (eg, thoracic aortic aneurysms and aortic dissections), full gene sequence TGFBR1 (transforming growth factor, beta receptor 1) (eg, Marfan syndrome), full gene sequence

81408 FBN1 (fibrillin 1) (eg, Marfan syndrome), full gene sequence 
MYH11 (myosin, heavy chain 11, smooth muscle) (eg, thoracic aortic aneurysms and aortic dissections), full gene sequence

81410 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, EhlersDanlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK

81411 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1

Genetic Testing for Marfan Syndrome, Thoracic Aortic Aneurysms and Dissections, and Related Disorders


Connective tissue is one kind of tissue that is found in the body. It connects and provides support to other tissues such as muscles, nerves, and the skin. For example, fat, bone and cartilage are types of connective tissues. Some problems with connective tissue can be inherited. This policy describes when it may be medically necessary to do genetic testing to look for inherited connective tissue disorders. 

Note:   The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered. 
Policy Coverage Criteria 

Testing Medical Necessity

Individual genetic testing for the diagnosis of Marfan
Individual genetic testing for the diagnosis of Marfan syndrome, other syndromes associated with thoracic aortic

Testing Medical Necessity

syndrome aneurysms and dissections, and related disorders, and panels comprised entirely of focused genetic testing limited to the following genes*FBN1 and MYH11 and ACTA2, TGFBR1, and TGFBR2 may be considered medically necessary when: * Signs and symptoms of a connective tissue disorder are Individual, targeted familial variant testing for Marfan syndrome

present, but a definitive diagnosis cannot be made using established clinical diagnostic criteria.
Individual, targeted familial variant testing for Marfan syndrome, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders, for assessing future risk of disease in an asymptomatic individual, may be considered medically necessary when there is a known pathogenic variant in the family. (See Additional Information section below)
Testing Investigational
Genetic testing panels for Marfan syndrome

Additional Information

Genetic testing panels for Marfan syndrome, other syndromes associated with thoracic aortic aneurysms and dissections, and related disorders that are not limited to focused genetic testing that do not meet the criteria for limited focused gene variant testing described above are considered investigational. (See Additional Information section below)

* Tissues that surround organs, blood vessels, and bones are called connective tissue. Changes to certain genes may cause problems with connective tissue. Specific genes can be tested to diagnose connective tissue problems. 

* Syndromes associated with thoracic aortic aneurysms may have established clinical criteria with major and minor criteria, eg, Marfan syndrome (Ghent criteria) and Ehlers-Danlos syndrome type IV, or may be associated with characteristic clinical findings. While most of these syndromes can be diagnosed based on clinical findings, these syndromes may be associated with variability in clinical presentation and may show overlapping features with each other, and with other disorders. The use of genetic testing to establish a diagnosis in a patient with a suspected connective tissue disorder is most useful in those patients who do not meet sufficient clinical diagnostic criteria at the time of initial examination, in patients who have an atypical phenotype and other connective tissue disorders cannot be ruled out, and in individuals who belong to a family in which a pathogenic variant is known (presymptomatic diagnosis).

* Genetic testing has conventionally been used when a definitive diagnosis of one of these syndromes cannot be made. More recently, panels using next-generation sequencing (NGS), which test for multiple genes simultaneously, have been developed for the syndromes associated with thoracic aortic aneurysms and dissections, and other conditions that may have overlapping phenotypes. Although the laboratory-reported sensitivity is high for some of the conditions on the panel, the analytic validity of these panels is unknown, and detection rates of variants of uncertain significance are unknown.

* However, there may be certain clinical scenarios in which focused panel testing may be appropriate to include a narrow list of differential diagnoses of thoracic aortic aneurysms and dissection based on clinical findings.

Panel Testing

Specific CPT codes for genetic panel tests associated with aortic dysfunction or dilation syndromes (81410 and 81411) are described in the coding table above with the genes included in each test.

Related Information 

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 2). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to 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 3 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 2. 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

ACMG-AMP Standards and Guidelines for Variant Classification

Previous  Definition

Pathogenic Disease-causing change in the DNA sequence
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
American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Question: Claims processing for CPT Codes 81401-82408 when ICD-9s have been identified for coverage. The structure of these codes raises some practical considerations for claims submission and processing. The molecular pathology codes have a number of subparts, identified by specific genes. This means there could be a number of genes reported with the same CPT code. Each of those genes could have related ICD-9 codes. It would require reporting of the specific gene to be able to link the code with a diagnosis. In this draft coverage policy, 4 of the codes [81401, 81403, 81405, and 81406] have been associated with testing for Lynch Syndrome and would be covered for specific diagnosis codes. However, there are many genes under those same codes and other conditions that would be covered, e.g. lymphoma, leukemia which
are covered conditions (NCD §190.3).

Will claims for other gene testing reported under the same codes be denied because they do not have the ICD-9 for Lynch Syndrome? How are we to report testing for other genes and conditions reported under the same CPT code, so that they are not all inappropriately denied?

Response: These CPT codes are not gene specific and can be used for multiple tests. The higher level CPT codes are noted in the LCD to let providers know they are covered for the conditions listed in the policy. All other conditions are subject to the test being reasonable and medically necessary. We will request additional documentation for conditions or diseases that are not listed in the LCD for 81401, 81403, 81405 and 81406

Documentation Guidelines

Documentation must be adequate to verify that coverage guidelines listed above have been met. Thus, the medical record must contain documentation that the testing is expected to influence treatment of the condition toward which the testing is directed. The laboratory or billing provider must have on file the physician requisition which sets forth the diagnosis or condition that warrants the test(s). Examples of documentation requirements of the ordering physician/nonphysician practitioner (NPP) include, but are not limited to, history and physical or exam findings that support the decision making, problems/diagnoses, relevant data (e.g., lab testing, imaging results).

Documentation requirements of the performing laboratory (when requested) include, but are not limited to, lab accreditation, test requisition, test record/procedures, reports (preliminary and final), and quality control record. Documentation requirements for lab developed tests/protocols (when requested) include diagnostic test/assay, lab/manufacturer, names of comparable assays/services (if relevant), description of assay, analytical validity evidence, clinical validity evidence, and clinical utility.

Providers are required to code to specificity however, if an unlisted CPT code is used the documentation must clearly identify the unique procedure performed. When multiple procedure codes are submitted on a claim (unique and/or unlisted) the documentation supporting each code should be easily identifiable. If on review the contractor cannot link a billed code to the documentation, these services will be denied based on Title XVIII of the Social Security Act,

When the documentation does not meet the criteria for the service rendered or the documentation does not establish the medical necessity for the services, such services will be denied as not reasonable and necessary under Section 1862(a)(1)(A) of the Social Security Act.

Many applications of the molecular pathology procedures are not covered services given lack of benefit category (preventive service) and/or failure to reach the reasonable and necessary threshold for coverage (based on quality of clinical evidence and strength of recommendation). Furthermore, payment of claims in the past (based on stacking codes) or in the future (based on the new code series) is not a statement of coverage since the service was not audited for compliance with program requirements and documentation supporting the reasonable and necessary testing for the beneficiary. Certain tests and procedures may be subject to prepayment medical review (records requested) and paid claims must be supportable, if selected, for post payment audit by the MAC or other contractors. Tests for diseases or conditions that manifest severe signs or symptoms in newborns and in early childhood or that result in early death (e.g., Canavan disease) could be subject to automatic denials since these tests are not usually relevant to a Medicare beneficiary.

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