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BACKGROUND: Genetic variants in (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including . We further performed burden testing of in the UK Biobank. For 2 novel variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.RESULTS: We demonstrate enrichment of rare coding variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation.CONCLUSIONS: Our findings demonstrate an increased burden of rare coding variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.