Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Macular Degeneration

Description:

Age-related macular degeneration (AMD) 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 AMD. 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 (e.g., 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 (AMD). AMD has an estimated prevalence of 1 in 2,000 people in the United States and affects individuals of European descent more frequently than African Americans in the United States.

There are two major types of AMD, 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 AMD, 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. AMD is generally thought to progress along a continuum from dry AMD to neovascular wet AMD, with approximately 10% to 15% of all AMD patients eventually developing the wet form. Occasionally patients with no prior signs of dry AMD present with wet AMD as the first manifestation of the condition.

The wet form of AMD 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 AMD include older age, cigarette smoking, cardiovascular diseases, nutritional factors, and certain genetic markers. Age appears to be the most important risk factor, as 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 AMD include high blood pressure, heart disease, a high-fat diet or one that is low in certain nutrients (such as antioxidants and 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 (e.g., smoking and low dietary intake of vegetables, fruit, and fish) (Colijn, 2021).

Clinical diagnosis of AMD

AMD can be detected by routine eye exam, with one of the most common early signs being the presence of drusen or pigment clumping. An Amsler grid, a pattern of straight lines that resemble a checkerboard may also be used. In an individual with AMD, some of the straight lines may appear wavy or missing.

If AMD is suspected, fluorescein angiography and/or optical coherence tomography (OCT) may be performed. Angiography involves injecting a dye into the bloodstream to identify leaking blood vessels in the macula. OCT captures a cross section image of the macula and aids in identifying fluid beneath the retina and in documenting degrees of retinal thickening.

Treatment of AMD

There is currently no cure for macular degeneration, but certain treatments may prevent severe vision loss or slow the progression of the disease. For dry AMD, there is no medical treatment; however, changing certain life style risks may slow the onset and progression of AMD. The goal for wet (advanced) AMD 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, antiangiogenic 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. A large study performed by the National Eye Institute of the National Institutes of Health, the Age-Related Eye Disease Study (AREDS), showed that for certain individuals (those with extensive drusen or neovascular AMD in one eye) high doses of vitamins C, E, beta-carotene, and zinc may provide a modest protective effect against the progression of AMD (AREDS, 2001).

Genetics of AMD

It has been reported that genetic variants associated with AMD account for approximately 70% of the risk for the condition (Gorin, 2012).

More than 25 genes have been reported to influence the risk of developing AMD, discovered initially through family-based linkage studies, and subsequently through large-scale genome-wide association studies. Genes influencing several biological 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 AMD (Lim, 2012).

Loci based on common single nucleotide polymorphisms (SNPs) contribute to the greatest AMD risk:

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 gene is associated with age-related macular degeneration risk, or whether increased risk results from variations in both genes.

two major loci in the complement factor H (CFH) gene.

Other confirmed genes in the complement pathway include C2, C3, CFB and CFI (Lim, 2012).

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. (Lim, 2012) 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 AMD (Lim, 2012). Genes involved in DNA repair (RAD51B) and in the angiogenesis pathway (VEGFA) have also been associated with AMD.

Commercially available testing for AMD

Commercially available genetic testing for AMD is aimed at identifying those individuals who are at risk of developing advanced AMD.

Arctic Medical Laboratories offers Macula Risk®, which uses patient clinical information and the patient’s genotype for 15 associated biomarkers in an algorithm to identify Caucasians at high risk for progression of early or intermediate AMD to advanced forms of AMD. 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.

Coding

If the testing is specific to particular genes that have been codified and doesn’t involve any risk algorithm, the test can be reported with the Tier 2 CPT code(s).

Under code 81401:

APOE (apolipoprotein E) (e.g., hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (e.g., *2, *3, *4)

CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (e.g., macular degeneration), common variants (e.g., Y402H [CFH], A69S [ARMS2])

Under 81405:

HTRA1 (HtrA serine peptidase 1) (e.g., macular degeneration), full gene sequence

Under code 81408:

ABCA4 (ATP-binding cassette, sub-family A [ABC1], member 4) (e.g., Stargardt disease, age-related macular degeneration), full gene sequence

If the specific testing is not listed in Tier 2, the unlisted molecular pathology code 81479 would be reported. If the testing involves multiple analytes and an algorithm, the unlisted multianalyte assay with algorithmic analysis (MAAA) code 81599 would be reported.

Effective 10/1/2020, HCPCS code 0205U may be reported for genetic testing for macular degeneration.

Policy/
Coverage:

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for macular degeneration does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for macular degeneration is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

This policy was created in 2013 and is based on a search of the MEDLINE database through September 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for macular degeneration was sought.

Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)

According to a major laboratory’s website, the analytic sensitivity and specificity of testing for mutations in the ARMS2 gene and CFH gene by polymerase chain reaction is 99% (www.aruplab.com).

Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)

How well can the test predict the risk of developing advanced age-related macular degeneration (AMD)?

Current models for predicting AMD risk include various combinations of epidemiologic, clinical and genetic factors, and give areas under the curve (AUC) of approximately 0.8. (5-8) (By plotting the true and false positives of a test, an AUC measures the discriminative ability of the test, with a perfect test giving an AUC of 1).

An analysis by Seddon and colleagues demonstrated that a model of AMD risk that included age, gender, education, baseline AMD grade, smoking and body mass index had an AUC of 0.757 (Seddon, 2009) . The addition of the genetic factors SNPs in CFH, ARMS2, C2, C3 and CFB, increased the AUC to 0.821. Klein and colleagues showed that an individual’s macular phenotype, as represented by the Age-Related Eye Disease Study (AREDS) Simple Scale score, which rates the severity of AMD based on the presence of large drusen and pigment changes to predict the rate of advanced AMD, has the greatest predictive value (Klein, 2011). The predictive model used in this analysis by Klein included age, family history, smoking, the AREDS Simple Scale score, presence of very large drusen, presence of advanced AMD in one eye, and genetic factors (CFH and ARMS2). The AUC was 0.865 without genetic factors included and 0.872 with genetic factors included (www.revophth.com).

Although these risk models suggest some small incremental increase in the ability to assess risk of developing advanced AMD based on genetic factors, the clinical utility is not established.

Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)

What can be done for an individual whose genetic test indicates that he or she is at high risk for vision loss from AMD? The possible clinical utility of genetic testing for AMD can be divided into disease prevention, disease monitoring and therapy guidance, as discussed in more detail below.

Prevention: Genetic testing and risk prediction for AMD would have clinical utility if a preventive therapy existed that involved an intervention that went beyond good health practices (e.g., no smoking, balanced diet, exercise, nutrient supplements). If a preventive therapy existed, the optimal risk-benefit point along the AMD risk profile for every given age would need to be established so that the decision could be made which individuals should receive those treatments and at what age to start the intervention. Currently, the only preventive measures available are high-dose antioxidants and zinc supplements (www.aruplab.com).

Monitoring: If a patient is identified as high risk, changes in the frequency of monitoring may occur and could include the possibility of home monitoring devices, or the use of technology such as preferential hyperacuity perimetry to detect early or subclinical wet AMD. However, the impact of more frequent monitoring for high-risk patients is not known (www.revophth.com).

Guide therapy: There have been no consistent associations between response to anti-VEGF (vascular endothelial growth factor) therapy and genotype (www.revophth.com).

Summary

Age-related macular degeneration (AMD) is a complex disease which is divided into the dry form, associated with slowly progressive vision loss, or the wet form, which may be associated with rapidly progressive and severe vision loss. The risk of AMD and of the development of the wet form is associated with genetic and non-genetic (e.g., age, smoking) influences.

The analytic validity of genetic testing for assessing the risk of progression to advanced AMD is high, and the clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on non-genetic risk factors. However, the clinical utility of genetic testing for AMD is limited in that there are currently no preventive measures that can be undertaken, outside of good health practices, nor is there a known association with specific genotypes and specific therapies.

Ongoing Clinical Trials

A search of online site clinicaltrials.gov found two Phase 3 trials.

One prospective, observational study will follow a group of patients at the highest risk of developing advanced AMD and monitor visual function. The study will monitor the effect of vitamin supplementation and blood levels and inherited predispositions through genetic analysis. The primary outcome measures are the progression of AMD status according to an international classification/grading system. The estimated enrollment is 200, with an estimated study completion date of March 2017. (NCT00987129)

A completed interventional, non-randomized trial measured the clinical treatment response to intravitreal ranibizumab. The objective of the study was to establish the association between genetic factors and the treatment response to the drug. Single nucleotide polymorphism (SNP)-genotyping was performed along with environmental risk factor variables. The estimated enrollment was 150, with a primary completion date of April 2010. (NCT00469352)

Practice Guidelines and Position Statements

The American Academy of Ophthalmology (AAO) published recommendations for genetic testing for inherited eye diseases, and states that at this time, genetic testing for complex eye diseases, including AMD, should be avoided (www.aao.org) . The organization discourages patients from undergoing such testing until treatment or surveillance strategies can be shown to be of benefit to individuals with specific disease-associated genotypes and urges medical personnel to confine the genotyping of such patients to research studies. The Academy believes that currently marketed genetic tests offer little benefit or additional insight regarding whether a patient is significantly predisposed to a particular disease. Furthermore, the organization strongly believes that a comprehensive eye exam is significantly more effective than any currently available genetic test for identifying treatable disease.

Regulatory Status

No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).

2014 Update

A literature search conducted using the MEDLINE database through October 2014 did not reveal any new information that would prompt a change in the coverage statement. No studies were identified that assessed the clinical utility of the commercially available algorithms.

The 2014 American Academy of Ophthalmology (AAO) Task Force on Genetic Testing recommendations specific to genetic testing for complex eye disorders like AMD state that the presence of any one of the disease-associated variants is not highly predictive of the development of disease (American Academy of Ophthamology, 2014). The AAO Task Force finds that in many cases, standard clinical diagnostic methods like biomicroscopy, ophthalmoscopy, tonography, and perimetry will be more accurate for assessing a patient’s risk of vision loss from a complex disease than the assessment of a small number of genetic loci. AAO concludes that genetic testing for complex diseases will become relevant to the routine practice of medicine when clinical trials demonstrate that patients with specific genotypes benefit from specific types of therapy or surveillance; until such benefit can be demonstrated, the routine genetic testing of patients with complex eye diseases, or unaffected patients with a family history of such diseases, is not warranted.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in October 2014 found the following prospective trials on the association between gene polymorphisms and treatment outcome:

NCT00987129 will follow a group of patients at the highest risk of developing advanced AMD and monitor visual function. The study will monitor the effect of vitamin supplementation and blood levels and inherited predispositions through genetic analysis. The primary outcome measures are the progression of AMD status according to an international classification/grading system. The estimated enrollment is 200, with an estimated study completion date of March 2017.

NCT01676506 will assess the impact of genetic polymorphisms on ranibizumab treatment outcomes in AMD. The study is funded by the Russian Academy of Medical Sciences. It has an estimated enrollment of 300 patients with completion expected October 2015.

2016 Update

A literature search conducted through October 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

An analysis by Seddon and colleagues in 2009 demonstrated that a model of AMD risk that included age, gender, education, baseline AMD grade, smoking and body mass index had an AUC of 0.757. The addition of the genetic factors SNPs in CFH, ARMS2, C2, C3, and CFB, increased the AUC to 0.821. In a 2015 report by Seddon and colleagues, 10 common and rare genetic variants were included in their risk prediction model, resulting in an AUC of 0.911 for progression to advanced AMD (Seddon, 2015).

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed below:

(NCT01115387) GARM II: A study on the Genetics of Age-related Maculopathy; planned enrollment 7000; projected completion date August 2016.

(NCT01650948) an industry-sponsored or cosponsored trial. Evaluation of Genetic Variants in Patients Under Treatment for Choroidal Neovascular (CNV) Age-related Macular Degeneration (AMD), Receiving Intravitreal anti-VEGF Injections to Evaluate the Association Between Genetic Load and Phenotypes Associated With More Aggressive Forms of Disease; planned enrollment 100; completed December 2013. No study results published.

The evidence for genetic testing in individuals who are asymptomatic with risk of developing AMD includes genetic association studies and risk prediction models. Outcomes of interest are test validity, change in disease status, and functional outcome. The analytic validity of genetic testing for AMD is high, and the clinical validity of genetic testing appears to provide a small, incremental benefit to risk stratification based on nongenetic risk factors. The clinical utility of genetic testing for AMD is limited, in that there are currently no preventive measures that can be undertaken. No studies have shown improvement in health outcomes in patients who have been identified as being at high risk based on genetic testing. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence for genetic testing in individuals who have AMD includes genetic association studies and risk prediction models. Outcomes of interest are test validity, change in disease status, and functional outcomes. The analytic validity of genetic testing for assessing the risk of progression to advanced AMD is high. The clinical utility of genetic testing in patients who have AMD is limited, in that genetic testing has not been shown to be superior to clinical evaluation in determining the risk of progression of disease. In addition, there is no known association with specific genotypes and specific therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

2017 Update

A literature search using the MEDLINE database through October 2017 did not reveal any new literature that would prompt a change in the coverage statement.

2018 Update

A literature search was conducted through October 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

American Society of Retina Specialists

The American Society of Retina Specialists published special correspondence on the use of genetic testing in the management of patients with AMD (ASRS, 2017). The Society concluded that:

While AMD genetic testing may provide information on progression from intermediate to advanced AMD, there is no clinical evidence that altering management of genetically higher risk progression patients results in better visual outcomes compared with patients lower risk progression patients.
AMD genetic testing in patients with neovascular AMD does not provide clinically relevant information regarding response to anti-vascular endothelial growth factor (VEGF) treatment and is therefore not recommended for this population.
Currently, there is insufficient evidence to support the use of genetic testing in patients with AMD in regard to nutritional supplement recommendations.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

No consistent associations between response to vitamin supplements or anti-vascular endothelial growth factor therapy and VEGF gene variants have been established (Fauser, 2015; Chew, 2014; Hagstrom, 2015; Hagstrom, 2014; Awh, 2013; Balikova, 2019).

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Govindaiah et al reported that a prediction model for development of age-related macular degeneration using AREDS data had an area under the curve of 0.69 using genetic data only, 0.77 using genetic and sociodemographic data, and 0.92 using genetic, sociodemographic, and retinal imaging data (Govindaiah, 2021). Ajana et al also reported an area under the curve at 5 years of 0.92 for an age-related macular degeneration model that included clinical, genetic, and lifestyle factors (Ajana, 2021). de Breuk et al and the EYE-RISK consortium found that patients with late age-related macular degeneration had significantly higher genotype assay risk scores than patients with early or intermediate disease (p<.001) or no disease (p<.001) based on a European case-control population (N=4740) (de Breuk, 2021).

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

In 2019, approximately 19.8 million Americans 40 years of age and older were living with age-related macular degeneration (CDC, 2022).

Current models for predicting age-related macular degeneration risk include various combinations of epidemiologic, clinical, and genetic factors, and give areas under the curve of approximately 0.8 (Kim, 2012).

The Age-Related Eye Disease Study (AREDS) Simple Scale, which rates the severity of age-related macular degeneration based on the presence of large drusen and pigment changes to predict the rate of advanced age-related macular degeneration, is considered to have the greatest predictive value (Kim, 2012).

Monitoring: If a patient is identified as high-risk, changes in the frequency of monitoring may occur and could include home monitoring devices or the use of technology such as preferential hyperacuity perimetry to detect early or subclinical wet age-related macular degeneration. However, the impact of more frequent monitoring for high-risk patients is not known (Kim, 2012).

The 2014 American Academy of Ophthalmology (AAO) recommendations specific to genetic testing for complex eye disorders like age-related macular degeneration have indicated that the presence of any 1 of the disease-associated variants is not highly predictive of disease development (Stone, 2014).

In 2019, AAO published a Preferred Practice Pattern on age-related macular degeneration, which noted that the routine use of genetic testing is not recommended at this time due to lack of prospective clinical evidence (Flaxel, 2019).

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

0205U	Ophthalmology (age-related macular degeneration), analysis of 3 gene variants (2 CFH gene, 1 ARMS2 gene), using PCR and MALDI-TOF, buccal swab, reported as positive or negative for neovascular age-related macular-degeneration risk associated with zinc supplements
81401	Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, 2, 3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G>A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G>A, 1138G>C, 1620C>A, 1620C>G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G>A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A>G, m.1494C>T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81408	Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)
81479	Unlisted molecular pathology procedure
81599	Unlisted multianalyte assay with algorithmic analysis

References:

Age-Related Eye Disease Study Research G.(2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119(10):1417-36.

Ajana S, Cougnard-Gregoire A, Colijn JM, et al.(2021) Predicting Progression to Advanced Age-Related Macular Degeneration from Clinical, Genetic, and Lifestyle Factors Using Machine Learning. Ophthalmology. Apr 2021; 128(4): 587-597. PMID 32890546

American Academy of Ophthamology (AAO).(2014) Recommendations for genetic testing of inherited eye diseases. 2014; http://one.aao.org/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d. Accessed October 29, 2014.

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