MolDX: Molecular Testing for Identification and Management of Hereditary Transthyretin Amyloidosis

LCD Information Document Information Source LCD ID N/A LCD ID L39940 Original ICD-9 LCD ID Not Applicable LCD Title MolDX: Molecular Testing for Identification and Management of Hereditary Transthyretin Amyloidosis Proposed LCD in Comment Period N/A Source Proposed LCD DL39940 Opens in a new window Original Effective Date For services performed on or after 08/17/2025 Revision Effective Date For services performed on or after 03/19/2026 Revision Ending Date N/A Retirement Date N/A Notice Period Start Date 07/03/2025 Notice Period End Date 08/16/2025 CPT codes, descriptions, and other data only are copyright 2025 American Medical Association. All Rights Reserved. Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. 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Issue Issue Description This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity. Issue - Explanation of Change Between Proposed LCD and Final LCD The final LCD was modified based on comments received during the Comment period. CMS National Coverage Policy Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary. 42 CFR §410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes Coverage Indications, Limitations, and/or Medical Necessity This contractor will cover molecular diagnostic tests for use in the evaluation and management of beneficiaries suspected of having Hereditary Transthyretin Amyloidosis (hATTR) when all the following criteria are met: The patient has a clinical diagnosis of ATTR; OR Has cardiac features suggestive of ATTR-cardiomyopathy; AND Is of African ancestry; OR Has a first-degree relative with an hATTR diagnosis; OR Has at least one additional feature suggestive of hATTR according to expert consensus and society guidelines. Has progressive sensorimotor and/or autonomic neuropathy; AND Has a first-degree relative with an hATTR diagnosis; OR Has at least one additional feature suggestive of hATTR according to expert consensus and society guidelines. The patient has been offered counseling regarding the test and potential results. The results of the test will be used to aid in treatment decisions. The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence required for clinical decision making for its intended use that can be reasonably detected by the test. The test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes. A single variant may be tested if it is the only variant considered to be reasonable and necessary for a patient given that it is a known familial variant. The test has successfully completed a technical assessment (TA) that ensures the test is reasonable and necessary as described above. Summary of Evidence Background Transthyretin is a protein produced in the liver, choroid plexus, and retinal pigment epithelium and transports thyroid hormone thyroxine and the retinal-binding protein bound to retinol.1,2 In transthyretin amyloidosis (ATTR) the homotetrameric protein is destabilized, leading to monomers that misfold, aggregate and form amyloid fibrils. These fibrils are deposited in certain organs including the heart, eyes, digestive tract, nervous system, and kidneys.3 There are two types of ATTR: a sporadic, non-genetic form known as wild-type ATTR (wtATTR) and a hereditary form (hATTR, also referred to as the variant form ATTRv) caused by pathogenic variants in the TTR gene inherited in an autosomal dominant (AD) manner. In patients with wtATTR, amyloid fibrils are deposited almost entirely in the myocardium, resulting in ATTR cardiomyopathy (ATTR-CM).4,5 In contrast, hATTR may present as ATTR-CM, polyneuropathy (ATTR-PN), or a mixed phenotype of both through the deposition of the misfolded protein in both the cardiovascular and peripheral nervous systems.3,6 The true prevalence of wtATTR is unknown; however autopsy studies have suggested that it is higher than previously recognized with some studies showing that ~25% of individuals 80 or older have wild-type fibrils, regardless of symptoms.5,7-9 Historically, hATTR was thought to be endemic to certain regions including northern Portugal, northern Sweden and Japan with a prevalence of 1-10 per 10,000 individuals. However, to date the disorder has now been reported in multiple countries with an estimated global prevalence of 5000-40,000 individuals.9-11 Diagnosis Symptoms of patients with ATTR-CM include those commonly seen in heart failure including fatigue, exercise intolerance, palpitations, conduction abnormalities, and arrhythmias.4,5 Other early indicator disease characteristics include elevated troponin or N-terminal pro-brain natriuretic peptide levels, an intolerance of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, carpel tunnel syndrome (CTS), lumbar spinal stenosis, and biceps tendon rupture.4,12,13 The age of onset of wtATTR-CM is generally above the age of 60, whereas that of hATTR-CM varies from 30-80 years old depending on the TTR variant. The median survival after diagnosis is ~3.5 and ~2.5 years respectively for wtATTR-CM and hATTR-CM.4 The clinical presentation of patients with hATTR-PN is also variable with no specific signs or symptoms uniquely associated with the disease. However, a number of “red flags” have been identified that should raise suspicion.14 Karam et al. reported that the most important features suggestive of hATTR are the rate of neuropathy progression and comorbidities such as gastrointestinal dysmotility, heart failure with preserved ejection fraction, autonomic failure and CTS.15 For example, although common in the general population, CTS in patients with hATTR is more often bilateral, more prone to recurrence and more refractory to treatment. A family or personal history of idiopathic neuropathy that does not respond to treatments for other neuropathies or is rapidly progressing is also suggestive for hATTR. Due to the variability of clinical presentation and overlap with other disorders, misdiagnoses are common. Studies have suggested that 32-74% of patients with hATTR have received at least one misdiagnosis with 18% receiving multiple misdiagnoses.3 For example, the resulting heart failure in ATTR-CM may be attributed to other more common disorders such as hypertrophic cardiomyopathy, aortic stenosis and hypertensive heart disease.5 The peripheral neuropathy is often mistaken for other neurologic conditions such as chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy or motor neuropathy.3,15 Historically, a diagnosis of hATTR was made through identification of amyloid deposits through biopsy followed by confirmatory gene sequencing. This often requires assessment of multiple tissue sites and interpretation of pathology can be variable with a reported sensitivity of 60-80% depending on the tissue type.16,17 Therefore, a negative biopsy does not definitively exclude a diagnosis and further testing, including additional biopsies, are necessary. Cardiac technetium (99mTc)-based tracer scintigraphy scanning may also be utilized if available. A positive grade 2 or 3 myocardial uptake of radiotracer and the absence of a clonal plasma cell process has shown a positive predictive value of 100% for ATTR-CM.18 However, detection of a pathogenic variant in the TTR gene is definitive for hereditary disease. To date, nearly 150 different pathogenic variants in TTR have been associated with hATTR. Penetrance is variable and is highest in endemic regions due to founder mutations.3,9 However, the penetrance increases with age reaching nearly 100% by the ninth decade regardless of the variant.19-21 The p.Val50Met (legacy p.Val30Met) variant was the first discovered and is the most common word wide. It leads to a variable clinical presentation ranging from asymptomatic to systemic disease with both early (age <50 years) and late (age ≥50 years) onset forms.9,11,22 The early onset disease is highly penetrant and presents as ATTR-PN with sensorimotor symptoms beginning in the lower extremities with relatively mild autonomic symptoms whereas late onset typically presents with peripheral rather than autonomic neuropathy, is more likely to occur in males, and penetrance increases with age. In the United States, the most common pathogenic variant associated with hATTR is p.Val142Ile (legacy p.Val122Ile).11,23 In contrast to p.Val50Met, the clinical presentation is almost exclusively cardiac. Population studies suggest it is present in 3.4% of individuals of African descent with a disease penetrance of ~40% and has been reported in 10% of African Americans older than 65 with severe congestive heart failure.23-25 Given the increased availability of effective therapies, gene sequencing performed earlier in the diagnostic strategy confirms an hATTR diagnosis and facilitates optimal treatment choices. This strategy is endorsed by multiple societies, associations, and disease experts.4,26-28 Therapeutic strategies Historically, liver transplantation was the only available treatment for hATTR. Since transthyretin is primarily produced in the liver, a transplant stops the production of mutant protein, decreasing amyloid formation and inhibits disease progression.29,30 However, studies have suggested that outcomes are less favorable for patients with alterations other than p.Val50Met and those with late onset or more advanced disease.30,31 Also, transplantation eliminates the production of abnormal but not wild-type transthyretin, so further deposition of wild-type transthyretin continues after transplantation. In addition, production of abnormal protein from the ocular and central nervous systems continues and cardiovascular complications post-transplant are more common than in patients undergoing transplant for end stage liver disease.30 Today, available treatments target different aspects of the production of amyloid deposits that when administered early in the course of disease slow it’s progression. In the early 1990s, it was reported that patients with a p.Thr139Met (legacy p.Thr119Met) variant in a compound heterozygous state with p.Val50Met had no or mild symptoms of disease.32 Functional studies demonstrated that this amino acid change increased the kinetic stability of the tetramer, slowing dissociation and suppressing disease.33,34 Further studies established that the dissociation was the first and slowest step of the aggregation cascade and that small molecules that bind to and stabilize the tetramer would have a similar effect.35-37 These studies led to the identification of tafamidis (trade name: Vyndaqel®) a small molecule that binds selectively to unoccupied thyroxine-binding sites and kinetically stabilizes the tetramer.38,39 Based on clinical trial outcomes, tafamidis was approved for use in stage 1 patients with ATTR-PN in Europe, Japan, and Mexico.40-42 More recently in the US, clinical trial outcomes showed patients that were prescribed tafamidis had a decrease in all-cause mortality, rates of cardiovascular hospitalizations, and reduced functional capacity43 and in 2019 tafamidis became the first FDA-approved medication for use in ATTR-CM as a TTR stabilizer. The non-steroidal anti-inflammatory drug (NSAID) diflunisal is also a strong stabilizer and has shown to be effective.44 However, NSAIDs are relatively contraindicated in patients with heart failure and therefore it is not an optimal choice for patients with cardiac manifestations. Gillmore et al. recently reported results of the ATTRibute-CM trial in which patients that received acoramidis, a novel TTR stabilizer, had significantly better outcomes in mortality, morbidity and function than the placebo group.45 A more recent therapeutic strategy is RNA interference (RNAi), a process by which small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs) mediate the cleavage of target mRNA resulting in a robust decrease in the expression of the gene of interest thereby preventing the production of protein.46,47 There are currently four FDA-approved RNAi therapies targeting hepatic messenger RNA (mRNA) available for patients with hATTR. The Neuro-TTR Trial demonstrated that inotersen (trade name: TegsediTM), an antisense oligonucleotide (ASO) that targets the 3’ untranslated region (UTR) of TTR, was shown to improve the course of neurologic disease and quality of life in patients with hATTR when administered as a weekly subcutaneous injection.48 However, there were some safety concerns around thrombocytopenia and glomerulonephritis requiring additional monitoring after FDA approval. In a similar study published simultaneously, data from the landmark APOLLO trial showed that intravenous administration every three weeks of patisiran (trade name: Onpattro), an siRNA also targeting the 3’ UTR, reduced the mean serum levels of TTR by ~80% and significantly improved neuropathy with all study endpoints better than placebo regardless of age of onset, stage of the disease or TTR variant.49 Vutrisiran (trade name: Amvuttra) is a second-generation form of patisiran with an enhanced stabilizing chemistry administered every three months subcutaneously approved by the FDA in 2022.50 The most recent therapy to receive FDA approval in 2023, eplontersen (trade name: WainuaTM), is a second-generation version of inotersen with an enhanced delivery method that increases the potency of the molecules by 20 to 30-fold allowing for lower effective doses.51 Studies on newly emerging therapies such as gene editing, amyloid disruption, and aggregation inhibition as well as the results of combination therapies are also underway.52,53 Analysis of Evidence (Rationale for Determination) Transthyretin amyloidosis (ATTR) is a historically under-recognized cause of cardiomyopathy and neuropathy. The hereditary form is a systemic disease presenting as either cardiac disease, peripheral neuropathy, or a mix of both. It is progressive and associated with a poor prognosis, therefore early disease identification and timely therapeutic intervention are key to improving outcomes for patients. Several different therapeutic options are available and underscore the need for diagnosis as early as possible. Identification of causative variants in TTR is definitive for disease, however multi-gene panels that contain genes in addition to TTR may be considered reasonable and necessary to rule out or confirm other hereditary disorders with overlapping clinical features. For example, when presented with males of known African ancestry over the age of sixty with signs and symptoms of diastolic dysfunction confirmed by echocardiography, hATTR should be considered and genetic testing should be performed. In addition, due to the potential of unexpected results or the identification of variants of uncertain significance, pre- and post-test counseling should be provided. Given the clinical overlap with other disorders, availability of treatment options and published society recommendations and guidelines, this contractor finds that molecular tests that aid in identifying patients with hATTR are reasonable and necessary. This contractor will continue to monitor the evidence, and coverage may be re-evaluated following any substantial new evidentiary developments or guideline changes.

This contractor will cover molecular diagnostic tests for use in the evaluation and management of beneficiaries suspected of having Hereditary Transthyretin Amyloidosis (hATTR) when all the following criteria are met: The patient has a clinical diagnosis of ATTR; OR Has cardiac features suggestive of ATTR-cardiomyopathy; AND Is of African ancestry; OR Has a first-degree relative with an hATTR diagnosis; OR Has at least one additional feature suggestive of hATTR according to expert consensus and society guidelines. Has progressive sensorimotor and/or autonomic neuropathy; AND Has a first-degree relative with an hATTR diagnosis; OR Has at least one additional feature suggestive of hATTR according to expert consensus and society guidelines. The patient has been offered counseling regarding the test and potential results. The results of the test will be used to aid in treatment decisions. The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence required for clinical decision making for its intended use that can be reasonably detected by the test. The test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes. A single variant may be tested if it is the only variant considered to be reasonable and necessary for a patient given that it is a known familial variant. The test has successfully completed a technical assessment (TA) that ensures the test is reasonable and necessary as described above.