In this work, we clarify some of these aspects by providing a structural, kinetic and thermodynamic comparison of the recognition process between the CaM-interacting region of RyR2 and both wild type CaM and five missense variants associated with LQTS localized in the C-terminal lobe (Fig. 2a), specifically in EF3 (D95H, D95V) [20] and EF4 (D129V [21], D131E [22], and D131H [23]; note that the nomenclature of CaM variants in this work is based on the mature protein that lacks the Met in position 1). Here, CALM1 is linked to familial long QT syndrome.