<h3>Background</h3> Hereditary transthyretin amyloidosis (hATTR or ATTRv [variant]) is a progressive, and fatal disease caused by mutations in the transthyretin (<i>TTR</i>) gene. These mutations destabilize protein folding, resulting in amyloid deposits and causing multisystem dysfunction such as cardiomyopathy, whose etiology may be attributed to traditional causes of cardiovascular diseases. Genetic testing was recently added to the diagnostic armamentarium for ATTR with cardiomyopathy. Heart failure nurses, whether registered nurses or advanced practice nurses, can have a pivotal role in appropriately diagnosing hATTR as the underlying cause of heart failure. <h3>Objective</h3> A molecular diagnostic program will help improve differential diagnosis and describe prevalence and characteristics of patients with <i>TTR</i> mutations versus patients with mutations associated with other inherited cardiovascular conditions. <h3>Methods</h3> Data from patients enrolled in the hATTR Compass program, which provides confidential genetic testing to patients in the United States (including Puerto Rico) and Canada with possible hATTR with polyneuropathy or with a family history of hATTR, were analyzed. DNA next-generation sequencing was performed using a panel of 92 genes associated with inherited cardiovascular conditions. <h3>Results</h3> A total of 978 patients under the care of cardiologists were referred for testing using this panel; 74 patients were positive for <i>TTR</i> mutations and 52 were positive for other non-<i>TTR</i> cardiovascular pathogenic mutations. The most common <i>TTR</i> mutation was p.V142I (V122I). Most patients (66.2%) with a <i>TTR</i> mutation did not have a family history of hATTR. Of patients with non-<i>TTR</i> mutations, 16 had mutations in the MYBPC3 locus, associated with cardiomyopathy. Patients with <i>TTR</i> mutations were older than those with non-<i>TTR</i> mutations (mean age, 67 vs 53 years). Both groups had similar proportions of heart disease (89% TTR vs 90% other cardiovascular diseases). Some key indicators of hATTR were more prevalent in patients with non-<i>TTR</i> versus <i>TTR</i> mutations: autonomic (21% vs 14%), motor (19% vs 12%), and gastrointestinal dysfunction (17% vs 8%, respectively); however, bilateral carpal tunnel syndrome (0% vs 26%) and sensory dysfunction (15% vs 28%) were more prevalent in patients with <i>TTR</i> mutations. A limitation of this analysis was that symptoms may have been underreported because of the simplified, voluntary nature of participation and data collection. More patients with <i>TTR</i> mutations had other diagnostic tests (eg, pyrophosphate imaging, biopsy) than those with non-<i>TTR</i> mutations (34% vs 15%). <h3>Conclusion</h3> Despite newer diagnostic methods such as pyrophosphate imaging, hATTR is commonly undiagnosed. Because hATTR can progress rapidly and be fatal, it is imperative that an accurate diagnosis be made early to institute appropriate therapy; genetic testing is key for obtaining an accurate diagnosis. Heart failure nurses are uniquely positioned to recognize the multiple symptoms that should raise clinical suspicion and help in the early diagnosis of hATTR.