The following are key points to remember from the European Society of Cardiology Council on Cardiovascular Genomics on the interpretation and actionability of genetic variants in cardiomyopathies:

1. The American College of Medical Genetics and College of American Pathologists use 16 criteria to establish pathogenicity of a genetic variant and 12 criteria that support benign interpretation. These criteria are based on clinical genetic and phenotype information, genetic population data, predictive data, and characteristics of the mutation being studied.
2. Variants classified as variants of uncertain significance (VUS) or pathogenic at initial evaluation may be subsequently reclassified. The likelihood that a gene initially classified as benign is reclassified as pathogenic is very low.
3. Patients should be counseled on possibility of reclassification of a genetic variant during pretest counseling. Once a variant is reclassified, participants should be contacted and provided updated results if it is reasonably expected to affect medical management.
4. A VUS is not clinically actionable. However, if a VUS is reclassified as pathogenic, it has several practical implications such as clinical monitoring, early initiation of therapy, prenatal diagnosis, etc.
5. In clinical practice, whole exome or whole genome sequencing can identify variants in genes unrelated to primary medical reason for testing, The possibility of such incidental findings should be properly communicated before testing and patients should consent to receiving such results. This list of actionable genes includes 19 cardiomyopathy genes.
6. Clinical data are informative both at baseline and during follow-up evaluations of patients and families. For several cardiomyopathy subtypes, due to age-related expression of the disease, phenotype may manifest only in adult life.
7. Some pathogenic variants occur de novo but evaluation of both parents of the affected individual is needed for confirmation. If paternity is not established, the expert panel suggests using classifying the variant as proven de novo when at least three proven de novo occurrences have been reported.
8. A high frequency of a de novo variant in population databases should raise doubts about pathogenicity.
9. Segregation criterion refers to occurrence of a variant in a gene known to cause disease and co-segregates in multiple affected family members. Evidence of co-segregation in families, enhances confirmation of pathogenicity of a variant. As many relatives as possible should be evaluated including documentation of disease in deceased individuals. Post-mortem genetic tests can sometimes be performed, and these can contribute to variant classification.
10. Nonsegregation criteria for establishing a genetic variant as benign applies when one family member has the disease but does not carry the genetic variant interpreted as disease causing in the family.
11. Cis variants occur in the same copy of the gene or in two adjacent genes that are jointly inherited. Trans variants are in different copies of the gene or in two different genes that are independently transmitted. Interpreting effect of cis or trans variants depends on the inheritance, i.e., if the condition is autosomal dominant or recessive.
12. Most cardiomyopathies are characterized by similar phenotypes manifested by several different genetic variants. However, presence of another predisposing condition does not alter the pathogenicity of a variant for ex: drug abuse in an individual with a pathogenic variant for cardiomyopathy may predispose the person to develop cardiomyopathy.
13. Clinical markers may be of assistance in identifying specific disease phenotypes such as Danon’s disease (short PR interval, Wolff-Parkinson-White syndrome).
14. In-lab assessment of pathogenicity of genetic variants is complex and time consuming. Pathological tissue findings are useful only in some cardiomyopathies such as disorders of metabolism (Fabry’s disease). Gene-specific biomarkers do not exist for most cardiomyopathies. Commonly available lab tests only establish myocyte damage or involvement of extracardiac disease but not their cause. Functional level of genetic diseases may be obtained in some causes such as lysosomal diseases by assessing enzyme levels.
15. Results of a genetic test when positive provide the opportunity to help with early screening and diagnosis of other at-risk family members. When a genetic test is negative, patients should be educated about limitations in the number of genes analyzed and available information on genes. Accordingly, clinical screening of at-risk family members should be continued in this situation.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Genetic Arrhythmic Conditions, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biomarkers, Cardiomyopathies, Genes, Genetic Counseling, Genetic Testing, Genetics, Genetics, Medical, Heart Failure, Lysosomes, Mutation, Phenotype, Virulence, Virulence Factors, Whole Genome Sequencing

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