Proactive variant effect mapping to accelerate genetic diagnosis for pediatric cardiac arrest

While genetic testing is becoming standard of care for patients with potentially inherited cardiovascular disease, the prevalence of uncertain results severely limits its utility. One promising approach is to generate variant effect maps that report the function of all possible variants in a gene prospectively. The proactive clinical application of these maps is nascent, and requires careful integration with current American College of Medical Genetics guidelines for variant interpretation. Here, we describe three pediatric cases of cardiac arrest or sudden cardiac death with variants of uncertain significance in calmodulin genes. We demonstrate the prospective clinical utility of a calmodulin variant effect map to inform variant interpretation, and therefore diagnosis and family care, in each case. This study was approved by the Stanford University and Vanderbilt University Medical Center IRBs. Consent was waived based on low risk of de-identified retrospective data collection per the IRB.