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A.2.04.103
Age-related macular degeneration is a complex disease involving both genetic and environmental influences. Testing for variants at certain genetic loci has been proposed to predict the risk of developing advanced age-related macular degeneration. Age-related macular degeneration is divided into the dry form, associated with slowly progressive vision loss, and the wet form, which may be associated with rapidly progressive and severe vision loss. The risks of age-related macular degeneration and of developing the wet form are associated with genetic and nongenetic (eg, age, smoking) factors.
Macular degeneration, the leading cause of severe vision loss in people older than age 60 years, occurs when the central portion of the retina (the macula) deteriorates. Because the disease develops as a person ages, it is often referred to as age-related macular degeneration. In 2019, approximately 19.8 million Americans 40 years of age and older were living with age-related macular degeneration. Sex- and age-standardized rates of age-related macular degeneration were lower for non-Hispanic Black people (7.0%) than for other racial and ethnic groups (13.3%).
There are two major types of age-related macular degeneration, known as the dry form and the wet form. The dry form is much more common, accounting for 85% to 90% of all cases of age-related macular degeneration, and it is characterized by the buildup of yellow deposits called drusen in the retina and slowly progressive vision loss. The condition typically affects vision in both eyes, although vision loss often occurs in one eye before the other. Age-related macular degeneration is generally thought to progress along a continuum from dry age-related macular degeneration to neovascular wet age-related macular degeneration, with approximately 10% to 15% of all age-related macular degeneration patients eventually developing the wet form. Occasionally patients with no prior signs of dry age-related macular degeneration present with wet age-related macular degeneration as the first manifestation of the condition.
The wet form of age-related macular degeneration, sometimes referred to as "vision-threatening" or "late stage" age-related macular degeneration, is characterized by the growth of abnormal blood vessels from the choroid underneath the macula, and is associated with severe vision loss that can rapidly worsen. The abnormal vessels leak blood and fluid into the retina, which damages the macula, leading to permanent loss of central vision.
Major risk factors for age-related macular degeneration include older age, cigarette smoking, cardiovascular diseases, nutritional factors, and certain genetic markers. Age appears to be the most important risk factor because the chance of developing the condition increases significantly as a person gets older. Smoking is another established risk factor. Other factors that may increase the risk of age-related macular degeneration include high blood pressure, heart disease, a high-fat diet, or a diet low in certain nutrients (eg, antioxidants, zinc), and obesity. Observational data (N=17,174) from the European EYE-RISK Consortium suggest that the odds of age-related macular degeneration increases by at least 2 times in patients with both genetic risk and predisposing lifestyle factors (eg, smoking and low dietary intake of vegetables, fruit, and fish).
Clinical Diagnosis
Age-related macular degeneration can be detected by routine eye exams, with one of the most common early signs being the presence of drusen or pigment clumping. An Amsler Grid test, a pattern of straight lines that resembles a checkerboard, may also be used. In an individual with age-related macular degeneration, some of the straight lines may appear wavy or missing.
If age-related macular degeneration is suspected, fluorescein angiography and/or optical coherence tomography may be performed. Angiography involves injecting a dye into the bloodstream to identify leaking blood vessels in the macula. Optical coherence tomography captures a cross-sectional image of the macula and aids in identifying fluid beneath the retina and in documenting degrees of retinal thickening.
Treatment
There is currently no cure for macular degeneration, but certain treatments may prevent severe vision loss or slow disease progression. For dry age-related macular degeneration, there is no medical treatment; however, changing certain lifestyle risks may slow age-related macular degeneration onset and progression. The goal for wet (advanced) age-related macular degeneration is early detection and treatment aimed at preventing the formation of new blood vessels, or sealing the leakage of fluid from blood vessels that have already formed. Treatment options include laser photocoagulation, photodynamic therapy, surgery, anti-angiogenic drugs, and combination treatments. Anti-angiogenesis drugs block the development of new blood vessels and leakage from the abnormal vessels within the eye that cause wet macular degeneration and may lead to patients regaining lost vision. The Age-Related Eye Disease Study, a large study performed by the National Eye Institute of the National Institutes of Health, showed that, for certain individuals (those with extensive drusen or neovascular age-related macular degeneration in one eye), high doses of vitamins C, E, beta-carotene, and zinc may provide a modest protective effect against the progression of age-related macular degeneration.
Genetic Testing
It has been reported that genetic variants associated with age-related macular degeneration account for approximately 70% of the risk for the condition.
More than 25 genes have been reported to influence the risk of developing age-related macular degeneration, discovered initially through family-based linkage studies, and subsequently through large-scale genome-wide association studies. Genes influencing several biologic pathways, including genetic loci associated with the regulation of complement, lipid, angiogenic and extracellular matrix pathways, have been found to be associated with the onset, progression and bilateral involvement of early, intermediate, and advanced stages of age-related macular degeneration.
Loci based on common single nucleotide variants contribute to the greatest risk of age-related macular degeneration:
The long (q) arm of chromosome 10 in a region known as 10q26 contains two genes of interest, ARMS2 and HTRA1. Changes in both genes have been studied as possible risk factors for the disease; however, because the two genes are so close together, it is difficult to tell which is associated with age-related macular degeneration risk or whether increased risk results from variations in both genes.
Common and rare variants in the complement factor H (CFH) gene.
Other confirmed genes in the complement pathway include C2, C3, CFB and CFI.
On the basis of large genome-wide association studies, high-density lipoprotein (HDL) cholesterol pathway genes have been implicated, including CETP and LIPC, and possibly LPL and ABCA1. The collagen matrix pathway genes COL10A1 and COL8A1,apolipoprotein E (APOE), and the extracellular matrix pathway genes, TIMP3 and FBN2, have also been linked to age-related macular degeneration. Genes involved in DNA repair (RAD51B) and in the angiogenesis pathway (VEGFA) have also been associated with age-related macular degeneration.
Commercially Available Testing for Age-Related Macular Degeneration
Commercially available genetic testing for age-related macular degeneration is aimed at identifying those individuals who are at risk of developing advanced age-related macular degeneration.
Arctic Medical Laboratories offers Macula Risk®, which uses patient clinical information and the patient’s genotype for 15associated biomarkers in an algorithm to identify whites at high risk for progression of early or intermediate age-related macular degeneration to advanced forms of age-related macular degeneration. A Vita Risk® report is also provided with vitamin recommendations based on the CFH and ARMS2 genotype.
23andMe® includes testing for CFH, ARMS2, and C2.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Genetic testing for macular degeneration is considered investigational.
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetics Nomenclature Update
The 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. It was being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). 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 (ACMG) and the Association for Molecular Pathology (AMP) 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 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 |
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 |
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.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
04/01/2014: Approved by Medical Policy Advisory Committee.
01/12/2015: Policy reviewed; description updated. Policy statement unchanged.
07/30/2015: Code Reference section updated for ICD-10.
02/11/2016: Policy description updated regarding genetics of AMD and testing for AMD. Policy statement unchanged. Policy guidelines updated to add genetic counseling information and to update the definition of investigative.
06/07/2016: Policy number A.2.04.103 added.
03/28/2017: Policy description updated to change "mutations" to "variants." Policy statement unchanged. Policy guidelines updated regarding standard terminology for variant classification.
04/09/2018: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.
04/05/2019: Policy reviewed; no changes.
04/16/2020: Policy description updated regarding commercially available testing for age-related macular degeneration. Policy statement unchanged.
05/25/2021: Policy reviewed; no changes.
05/11/2022: Policy description updated regarding observational data. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.
04/13/2023: Policy description updated regarding new data for age-related macular degeneration. Policy statement unchanged.
04/18/2024: Policy reviewed; no changes.
04/17/2025: Policy description updated. Policy statement unchanged.
Blue Cross and Blue Shield Association Policy # 2.04.103
This may not be a comprehensive list of procedure codes applicable to this policy.
Code Number | Description |
CPT-4 | |
81479 | Unlisted molecular pathology procedure |
81599 | Unlisted multianalyte assay with algorithmic analysis |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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