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). The gene discussed is GUF1; the disease is familial long QT syndrome.