MINNEAPOLIS — By definition, a variant of unknown significance identified in an individual with cardiomyopathy can leave physicians wondering what to do with the information.

Don’t discard so-called variants of unknown significance outright, though, members of an expert panel on the evolving genetics of cardiomyopathy advised at the Heart Failure Society of America (HFSA) 2025 Annual Scientific Meeting. A variant of unknown significance today could be a relevant clinical finding in the future: one that guides risk counseling in a patient and their relatives, becomes an essential component of a genetic test panel, and/or leads researchers to develop an effective, targeted therapy.

Practice guidelines from HFSA, developed in collaboration with the American College of Medical Genetics and Genomics, are more straightforward about genetic changes already linked to an increased risk for cardiomyopathy. Examples include changes in genes orchestrating sarcomeric proteins in hypertrophic cardiomyopathy and the role of the TTR gene in the restrictive form of the condition.

Testing Inequity

More Black people carry TTR genetic anomalies than people of European ancestry. These mutations cause TTR proteins to misfold, clump together, and lead the heart muscle to thicken and stiffen, eventually resulting in heart failure.

The current state of testing for TTR differences raises questions regarding the equity of genetic testing.

“It’s known that Black patients have this propensity. The majority of patients getting tested are White, even if we look geographically, even in the parts of the country where there is perhaps a different racial makeup or more equal racial makeup,” Mustafa M. Ahmed, MD, professor of medicine in the Division of Cardiovascular Medicine at the University of Florida in Gainesville, Florida, said during the packed panel session.

Whether and how much access to providers, the availability of testing, or other factors are driving this disparity is uncertain, Ahmed added.

Familiarity With Uncertainty

Cardiologists routinely face uncertainty in the management of heart failure, said Elizabeth Jordan, MMSc, a licensed cardiovascular genetic counselor and associate professor of internal medicine at The Ohio State University in Columbus, Ohio. So it’s not that cardiologists cannot handle genetic uncertainty, but the tools and expertise to interpret the results “just aren’t as routinely available within the heart failure team.”

Society guidelines on genetic testing in this patient population are updated periodically. In the interim, specific genes and their potential part in cardiomyopathy can be checked in the ClinVar database maintained by the National Library of Medicine.

The HFSA is also relaunching an initiative called the Research and Education to Increase Awareness, Genetic Investigation, and Treatment in Heart Failure (REIMAGINE-HF) to address some critical gaps in the diagnosis and management of genetic cardiomyopathies.

Overcoming multiple barriers to testing and improving low adherence rates are among the aims. “Only about 1% of patients are being tested, and that’s just based on claims data...so it’s likely an underestimation,” Ahmed said.

The low percentage is not from a lack of awareness regarding the importance of genetic testing, said Neal K. Lakdawala, MD, clinical director of cardiovascular genetics at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. Health record systems tend to store genetic reports as PDFs so the data are not easily retrievable. If ordering genetic testing could be streamlined within the electronic health record “without all the hoops we have to jump through,” Lakdawala, said, testing rates would rise to 25%-50%.

Not ‘Hocus Pocus’

The genetic changes driving hypertrophic, dilated, or restrictive forms of cardiomyopathy, as well as those responsible for arrhythmogenic right ventricular cardiomyopathy, are further classified into pathogenic, likely pathogenic, negative, and variants of unknown significance. In addition, variants of unknown significance can be categorized as having a low, medium, or high probability of pathogenicity.

“If this sounds like a bunch of hocus pocus to you, I reassure you that this is highly structured and rigorous,” Jordan said. “But you’re not totally wrong to feel that way because there is a dynamic and probabilistic nature to all of this.”

Up to 50% of patients with cardiomyopathy will have a variant of unknown significance result as their “worst variant,” Jordan added. But a variant of unknown significance can mean insufficient evidence at this time. Variant of unknown significance results should not be used for individual decision-making or for screening families, she added.

Classifications also can change over time with more discoveries. A meeting attendee asked who is responsible for following up on variants of unknown significance in case they later transform into relevant genetic findings. If a commercial laboratory did the testing, they should be tracking updates and recontacting providers when warranted, Jordan said. However, it also falls on the provider to track a variant of interest, she added.

How to counsel an asymptomatic patient who tests positive for riskier genetic mutations is another conundrum. This “gene-positive, phenotype-negative” person could be a family member of someone with confirmed cardiomyopathy, for example.

Striking a balance between informing an asymptomatic person of their elevated genetic risk without causing unnecessary levels of anxiety can be a challenge. Involving a genetic counselor on your team can help with these conversations.

“I know that’s hard to do. But honestly, it’s not my idea — it’s yours,” she added. Getting more genetic counselor help was a main theme of a survey regarding dilated cardiomyopathy conducted by the DCM Consortium.

Family Matters

The best tool in the clinic for detecting inherited cardiomyopathy that is available now, Jordan said, is the family: “It could be all you need to better understand what is going on.”

For example, a three-generation family pedigree created by genetic healthcare professionals can improve the rate of detection of a familial process over routine care, according to the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The guidelines also highlight the value of cascade screening of undiagnosed family members who could benefit from “management that otherwise would not be initiated.”

Genetic Testing for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is believed to be predominantly a disease of the sarcomere, a component of myocardium, Lakdawala said. Mutations in proteins responsible for the sarcomeres can change how the heart contracts.

But more than one genetic loci can be responsible for the same phenotype of the condition, Lakdawala said, which is why panel testing is essential for these patients.

Also consider age-related penetrance of these mutations. Although some people with sarcomeric hypertrophic cardiomyopathy present in infancy, most present in adulthood. “This is why longitudinal, lifetime screening of at-risk family members is advised,” he said.

Targeted therapies developed through these advances hold the most promise, Lakdawala said. Clinicians can already treat TTR cardiomyopathy and Fabry disease based on genetic test results, and progress to do the same is underway for Danon disease. Such treatments are likely on the way for other causes of hypertrophic cardiomyopathy and genocopies, which mimic the disorder but are caused by different genetic mutations.

Collecting Data to Learn More

The REIMAGINE-HF project aims to create regional models of care to facilitate referrals to centers that might have more robust infrastructure for testing and counseling. The initiative is collecting aggregated data through a partnership between HFSA and LabCorp. The database contains information on almost 250,000 patients to date. Approximately 25% have a pathogenic result.

Roughly one third of referring providers are adult cardiologists, and the remaining clinicians are about equally divided among pediatric providers, genetic specialists, and internal medicine physicians. Therefore, “if you’re going to create an intervention, the intervention has to go beyond the adult cardiologist,” Lakdawala said.

The next phase of REIMAGINE-HF includes selection of pilot sites and development of a care pathway. The goal is to “improve utilization of genetic testing, improve its yield, and decrease barriers, both on the clinician and patient side,” Lakdawala said. “We may be on the precipice of producing something helpful for everyone.”

Jordan reported having no relevant financial relationships. Ahmed disclosed being a member of the Advisory Panel for EVAHEART, INC. — a device manufacturer/distributor. Lakdawala reported being a consultant for Cytokinetics, Tenaya, Sarepta, Akros, Nuevocor, Alexion, Bayer, and Gemma and being a consultant and receiving research support from BMS. He also reported receiving unrestricted foundational support from the O’Hare family, Steggall family, and MacKenzie. 

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health, and environmental reporting/journalism. He works out of a home office in Miami, with a 100-pound chocolate lab known to snore under his desk during work hours.