Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

**History/Background and/or General Information**

With advancement in science and technology comes the ability to incorporate
genetic testing for hereditary cardiovascular disease into clinical care, with
the goal of improved patient outcomes. The scope of this LCD is genetic
testing in the practice of cardiovascular medicine in the Medicare population.

The genetic basis of cardiovascular disease is an area of rapidly expanding
knowledge. To date, identification of genetic variants associated with
cardiovascular disease includes hypertrophic and dilated cardiomyopathy
(associated with mutations in sarcomere and structural genes), arrhythmogenic
cardiomyopathy (associated with mutations in desmosome genes), inherited
arrhythmias (associated with mutations in transmembrane ion channels genes),
and Marfan and related syndromes (associated with mutations in genes encoding
connective tissue elements). Association does not necessarily translate to
improvement in patient care.

In certain circumstances, genetic testing for inherited cardiovascular disease
in patients with the corresponding appropriate phenotypic medical condition
could have the potential to assist patient management in the Medicare
population. However, given the complexity and rapidly expanding knowledge in
this topic area, there is also a potential for testing that does not help the
patient or leads to confusion. Specialized clinical expertise in
cardiovascular medicine in addition to advanced knowledge in both genetic
variation and effect on gene function is required to facilitate optimal
outcomes for patients.

**Covered Indications**

Genetic testing for hereditary cardiovascular disease will be considered
medically reasonable and necessary if:

  1. The patient has rigorous disease-appropriate phenotyping to establish clinical diagnosis or suspected diagnosis for which the test results would directly impact the management of the patient's condition, prior to ordering the test  
 **AND**

  2. The evidence for the gene-disease association is evaluated by the evidence-based, transparent, peer-reviewed process of the National Institutes of Health (NIH) sponsored Clinical Genome Resource (ClinGen) and is determined to demonstrate actionability in clinical decision making, meeting all bulleted metrics: 
    * Disease severity of sudden death, possible death or major morbidity, modest morbidity
    * Substantial or moderate evidence of a >40% likelihood of disease
    * Substantial or moderate evidence of a highly effective or moderately effective intervention
    * The nature of intervention is either low risk/medically acceptable/low intensity intervention or moderately acceptable/risk/intensive interventions,  
 **AND**

  3. Clinical validity and qualitative descriptors from Moderate, Strong & Definitive with contradictory evidence NOT being reported as disputed or refuted.

**Limitations**

The following are considered not medically reasonable and necessary:

  1. A genetic test where either analytical validity, clinical validity, or clinical utility has not been established.
  2. Genetic testing in patients who do not demonstrate the disease-appropriate phenotype of the gene-disease association.
  3. Genetic testing of asymptomatic patients.
  4. Genetic testing solely for purposes of proband identification.
  5. Genetic testing with family history as the only indication.
  6. Gene tests for cardiovascular disease are considered germline testing, and therefore only permitted once per beneficiary's lifecycle.

**Provider Qualifications**

The ordering provider of a genetic test for a patient with a cardiovascular
disease-appropriate phenotype:

  * Must be the treating clinician who is responsible for the cardiovascular disease management of the patient's condition; and,
  * Understands how the test result will impact the patient's condition; and,
  * Has presented this information to the patient eliciting patient understanding.

**Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

**Introduction**

The focus of this evidence review is on genetic testing to assess clinical
actionability in cardiovascular disease, and whether the evidence is adequate
to draw conclusions about improved health outcomes for the Medicare
population. In general, improved health outcomes of interest include patient
mortality and morbidity, as well as patient quality of life and function. For
genetic testing to be considered medically reasonable and necessary in the
Medicare population, standardized evaluation of analytical validity, clinical
validity, and clinical utility should be fully elucidated, and reflect the
level of confidence that the performance of this test will directly benefit
patients. Tests with analytic and clinical validity, with demonstrated
clinical utility that provide confidence to accurately enhance clinician
decision-making and satisfy requirements for accurate patient information,
have the potential to alter clinical management leading to improved patient
outcomes. Ideal patient outcomes demonstrate reduced mortality and morbidity
and improved patient quality of life and function.

Genetic testing for genetic variants associated with cardiovascular disease
endeavors to improve patient outcomes by guiding appropriate treatment,
thereby maximizing treatment effectiveness. Outcomes of interest remain the
patient-centered outcomes noted above.

**Internal Technology Assessment**

PubMed was searched for publications of clinical trials including the terms
molecular cardiac and molecular cardiovascular, looking for evidence of
clinical health outcomes. All countries of origin were included if broad
inclusion for the clinical studies met the criteria with only publications in
English considered. No studies were located. A search utilizing the terms
cardiovascular genomics found no new studies. The terms panel and
cardiac/cardiovascular had >100 results. A cardiovascular gene search within
the Journal of Genetic Counseling had 38 results and PubMed had 28 results
respectively. These studies were then screened for inclusion of adults and
Medicare population that demonstrated evidence of clinical health outcomes,
resulting in no applicable studies.

In a search for professional society guidelines for genetic testing in
cardiovascular diseases, a professional society scientific statement was
identified. A government funded publicly available resource was identified in
the professional society statement article. Another professional society
statement was identified in addition to a guideline within the same article.

**Guidelines**

Hershberger et al1 is a practice guideline for genetic evaluation of
cardiomyopathy, done in collaboration between the Heart Failure Society of
America (HFSA) and the American College of Medical Genetics and Genomics
(ACMG). Recommendations are considered expert opinion as no systematic
approach to literature review was conducted.

**Professional Society Statements**

Ackerman et al2 is an international consensus statement developed in
partnership between the Heart Rhythm Society (HRS) and the European Heart
Rhythm Association (EHRA) to provide the state of genetic testing for
channelopathies and cardiomyopathies in 2011. Recommendations are based on
consensus of the writing group following the Heart Rhythm Society's consensus
process.

Musunuru et al3 is a scientific statement from the American Heart Association
regarding genetic testing for inherited cardiovascular diseases. The statement
"summarizes current best practices with respect to genetic testing and its
implications for the management of inherited cardiovascular diseases."3
Included in this publication are: an approach to the evaluation of patients
with confirmed or suspected diagnosis of inherited cardiovascular disease; an
approach to the evaluation of individuals with secondary or incidental genetic
findings; a table listing genetics-guided diagnosis and management of
cardiovascular conditions with condition listed, role in diagnosis, role in
management, and source of information; and, a list of genes to be considered
for testing from guidelines and statements. The authors note a "dearth of
clinical trial evidence for the use of genetic testing in the practice of
cardiovascular medicine."3

Decision of the scope of testing is important. Testing can range from a single
gene or a few genes to large panels. Next-generation sequencing has made
complete genome sequencing readily available. However, these panels can
include genes with little support for the gene-phenotype under investigation
and may not increase the likelihood of clinically actionable results. These
panels may also increase the number of variants of uncertain significance
identified, or pick up secondary or incidental findings, causing confusion and
uncertainty for both provider and patient. The authors note ClinGen is engaged
in efforts to develop lists of genes with strong evidence linking them to
diseases.3 Generally, genetic testing may not reveal a cause or confirm a
diagnosis as the yield of genetic testing for any inherited cardiovascular
disease is usually much less than 100%.1

Interpreting and acting on genetic test results for a patient should include
post-test genetic counseling. As a result of the current rapid gain in
knowledge and privately held information, interpretations can vary between
genetic testing laboratories as well as providers, and over time. The ACMG and
the Association for Molecular Pathology have published a variant framework to
promote standardization, and ClinGen is engaged in modifying the framework for
specific genes. The authors state, "It is the implicit responsibility of
patients' providers to ensure that genetic testing is up to date, although
formal mechanisms by which providers can ensure that this happens remain to be
established."3

It is acknowledged there is sparse clinical trial evidence for the use of
genetic testing for clinical management in cardiovascular medicine. Guidance
for disease specific testing from guidelines and statements include
information from the HFSA, the ACMG, the Heart Rhythm Society/European Heart
Rhythm Association, and the NIH-funded ClinGen. Methodologic evaluation of
evidence is not included in this publication. Condition and gene association
are listed.2

The authors note the field of clinical genetics is changing rapidly and that
reliable classification of variants identified in genetic testing will remain
a challenge.3 Efforts by ClinGen will be critical to refine gene-specific
variant classification criteria.

**National Institute of Health funded Clinical Genome Resource (ClinGen)**

Strande et al4 describes a framework to define and evaluate the clinical
validity of gene-disease pairs developed by the NIH-funded ClinGen. The
framework evaluates evidence supporting or contradicting a gene-disease
relationship. Validation of the posted framework using a set of representative
gene-disease pairs is demonstrated. The framework provides a strength of
evidence for the relationship. This standardized framework was developed as
there is substantial variability in the level of evidence supporting claims of
gene-disease relationships; therefore, a systematic method is needed to more
confidently determine the clinical validity of a gene-disease relationship.
The authors state, "This framework aims to provide a systematic, transparent
method to evaluate a gene-disease relationship in an efficient and consistent
manner suitable for a diverse set of users."4

The framework classifies gene-disease relationships by both quantity and
quality of evidence. The validity classification of evidence includes the
levels definitive, strong, moderate, limited, no reported evidence, and
conflicting evidence reported, with descriptions of each. Classes of genetic
evidence and their relative weights used in the ClinGen clinical validity
framework is provided, dividing the genetic evidence into the two categories
of case-level data and case-control data with separate subtypes. Scoring
varies based on a scoring matrix with detailed guidance. Additionally,
experimental evidence at the gene-level is scored based on a separate
framework.4

Use of the framework was evaluated with a number of gene-disease pairs.
Reproducibility was examined. Experts agreed with the preliminary
classifications for 87.1% of the gene-disease pairs with published evidence.
Discrepancies between expert and curator classification were discussed and
explained and differed only by a single category. The authors conclude,
"Ultimately, our systematic, evidence-based method for evaluating gene-disease
associations will provide a strong foundation for genomic medicine."4

Hunter et al5 explains the approach of the NIH sponsored ClinGen to assess
clinical actionability of genetic disorders associated with genomic variation.
The assessment of clinical actionability is part of the effort to create a
central resource of information for the clinical relevance of genomic
variation. They developed a standardized protocol to identify evidence,
generate a summary report of actionability with an applied metric for an
actionability score. This effort is aimed at improving patient health
outcomes.

In general, the evidence supporting clinical actionability for most genetic
disorders varies significantly. Therefore, ClinGen developed and implemented a
standardized, evidence-based method to determine actionability of genomic
testing, as described in this article.5 The intent is to identify genetic
disorders with greater clinical utility when identified by testing in
previously undiagnosed adults. The working definition of clinical
actionability is a clinically prescribed intervention specific to the genetic
disorder under consideration, effective for prevention or delay of clinical
disease, lowered clinical burden, or improved clinical outcome in a previously
undiagnosed adult.5 Intervention included patient management, but also
interventions to improve outcomes for at-risk family members, however genetic
testing recommendations for at-risk family members alone did not meet the
criteria for actionability.

The method for knowledge synthesis is described in the article and
accompanying supplemental materials.5 The NIH funded ClinGen is a consortium
of researchers and clinicians. They create the open-access and centralized
resource to define the clinical relevance and actionability based on the
documented framework. The clinical actionability scoring metric is described.
The final product summary includes scoring for severity of disease, likelihood
of disease, effectiveness of specific interventions, nature of intervention,
and state of the knowledge base, i.e., level of evidence.

Furthermore, ClinGen provides a resource which is available to all clinicians
and patients. It is a publicly available website that "provides a structure to
enable research and clinical communities to make clear, streamlined, and
consistent determinations of clinical actionability based on transparent
criteria to guide analysis and reporting of genomic variation."5(p2)

The authors conclude, "The ClinGen framework for actionability assessment will
assist research and clinical communities in making clear, efficient, and
consistent determinations of actionability based on transparent criteria to
guide analysis and reporting of findings from clinical genome-scale
sequencing."5(p10)

Genetic testing for inherited cardiovascular disease seeks the goal of
improving health through more accurate and precise patient management.
Knowledge of gene-disease associations is accelerating. Despite the rapid
acquisition of information, it is acknowledged there is a lack of clinical
trial evidence demonstrating improved patient outcomes. Gene-disease
association does not necessarily translate to improved health outcomes. A
search for clinical trial data demonstrating outcomes of mortality and
morbidity reduction, or improvement of function or quality of life in the
Medicare population was non-yielding. However, clinical recommendations for
testing are available. For determination of medically reasonable and
necessary, a test must have analytic validity, clinical validity, and clinical
utility. Recommendations with higher confidence demonstrate a standardized,
transparent, systematic, peer-reviewed approach to evidence evaluation.
Considering a dearth of clinical studies, recommendations for genetic testing
for inherited cardiovascular diseases were examined within this framework.

Genomic tests must demonstrate analytic validity, clinical validity, and
clinical utility for Medicare coverage. Substantial variability exists in the
level of evidence supporting claims of clinical validity and clinical
utility.4 Strande et al outlines the standardized approach developed by the
Clinical Genome Resource to define and evaluate the clinical validity of gene-
disease pairs. The ClinGen Gene Curation Working Group is comprised of a broad
base of experts. The strength of evidence of a gene-disease relationship is
based on a standard semiquantitative approach to evaluate available evidence
and arrives at a defined classification.

In many instances, currently, clinical utility of genetic testing can be
challenging to demonstrate with patient-oriented outcomes. Clinical utility
addresses demonstrated improvement of health outcomes, with the health
outcomes of interest in the Medicare population as noted previously. Hunter et
al,5 which outlines work by the ClinGen Actionability Working Group (ClinGen
AWG), defines actionability as clinically prescribed interventions specific to
the genetic disorder under consideration that are effective for prevention or
delay of clinical disease, lowered clinical burden, or improved clinical
outcomes in a previously undiagnosed adult. This definition of actionability
provides a framework for genetic testing health outcomes consideration.
Evidence supporting clinical actionability for most genetic disorders varies
widely, necessitating a standardized assessment. Presenting the method of
ClinGen AWG systematic assessment, Hunter et al5 provides the standardized
framework for clinical actionability of genes and associated disorders.
Actionability including interventions to improve outcomes for at-risk family
members is included, though this alone would not be a basis for Medicare
coverage, and was not considered sufficient to meet criteria for
actionability.

Genetic testing for inheritable cardiovascular disease, after a patient has
received rigorous disease-appropriate phenotyping, is recommended by certain
cardiovascular professional organizations. As Musunuru et al3 notes, a
rigorous evaluation for disease-appropriate clinical manifestations must be
determined before testing. The decision to perform genetic testing should be
reserved for patients with a confirmed or suspected diagnosis of an inherited
cardiovascular disease or for individuals at high risk from a previously
identified pathogenic variant in their family. However, Medicare does not
cover genetic screening for cardiovascular disease, in which case family
history alone would be insufficient for coverage. A crucial element is
rigorous, disease-appropriate phenotyping. Genetic testing does not provide a
definite diagnostic result in most circumstances.

Adverse events can occur from genetic testing. Interpretation of clinical
importance of a variant can differ between multiple laboratories.6 Patient
care could be compromised if the interpretation is incorrect or based on data
that is not broadly applicable. Patients could receive an inappropriate
therapy or could fail to receive an appropriate therapy. In addition,
stakeholders could have proprietary database of variant interpretations, which
prevents the broad use of critical data.6 Broad, publicly available
information derived from a systematic process by a group of experts in their
respective fields is ideal.

The National Institutes of Health (NIH) funded ClinGen created an open-access
resource to better define clinically relevant genes and variants based on a
published, standardized, transparent, evidence assessment framework.3 The 2020
Scientific Statement for the American Heart Association notes the importance
of ClinGen's efforts. With the data and evidence available, this will prevent
"panels that include genes with little support for the gene-phenotype
association under investigation that may not increase the likelihood of
clinically actionable results in adult patients."3

In summary, reliable evidence for variants identified in genetic testing is
critical. The information must be actionable for that patient, with the
ability to improve patient management. Prior to testing, a rigorous disease-
appropriate phenotyping is necessary. The NIH funded ClinGen follows a
standardized protocol for evidence generation that is transparent, with
working groups comprised of scientific and clinical experts. The information
is available for public use. Coverage for genetic testing for inheritable
cardiovascular disease is based on ClinGen gene-disease scoring where patients
are likely to have beneficial health outcomes.