Catecholaminergic polymorphic ventricular tachycardia (CPVT) and Long-QT Syndrome (LQTS) are two major inherited lethal cardiac channelopathies responsible for sudden death predominantly among young population. Of late, mutations in the highly conserved calcium (Ca2+) sensor protein calmodulin (CaM) have been linked to these cardiac arrhythmia syndromes in human patients. CaM regulates the activity of ion channels and several critical proteins in the heart either via direct binding or indirectly through the activation of Ca2+/CaM-dependent protein kinase II delta (CaMKIIδ). However, there is a major gap in understanding the precise molecular mechanism of CaM-associated cardiac conditions. One of the ion channels regulated by CaM is the voltage-gated Ca2+ channel Cav1.2, which is essential for maintaining Ca2+ homeostasis in the cell. CaM binds Cav1.2 in the N-terminal (NSCaTE) and the C-terminal regions (IQ and C domains). The CaM binding site in CaMKIIδ consists of the amino-acid region 294-315 (CaMKIIδ294-315). Short synthetic peptide encompassing the CaM binding domains were used for the characterisation of CaM-target interactions. The binding kinetics of CaM with each peptide, in Ca2+-free (5 mM EGTA) and Ca2+-saturated conditions (5 mM CaCl2), were measured using isothermal titration calorimetry (ITC). The atomistic details of binding were obtained through X-ray co-crystallisation experiments. Using ITC, we showed that none of the peptides bind to CaM in Ca2+-free conditions whereas all the peptides bind Ca2+-CaM with CaMKIIδ294-315 showing the highest affinity (23 ± 5 nM, n = 6). Amongst the Cav1.2 peptides, Cav1.2IQ showed the highest affinity towards CaM-WT (415 ±19 nM, n = 10) followed by Cav1.2NSCaTE (2.0 ± 0.2 µM, n = 4) and Cav1.2C (8.0 ± 0.4 µM, n = 6). We showed that the binding affinity of CaMKIIδ294-315 for the CPVT-associated CaM variants is comparable to CaM-WT, whereas it is reduced by ~5 fold for the LQTS-associated variant. CPVT-associated mutations did not significantly affect the interaction of CaM with Cav1.2IQ peptide, however Kd increased to 169 ± 4 nM (n = 5) for the LQTS variant when compared to wild-type. The LQTS-associated mutation induced a 65-fold reduction in affinity (134 ± 8.7 µM, n = 5) for CaM:Cav1.2NSCaTE, when compared to the wildtype. We showed that binding of CaM to the Cav1.2C peptide can be reduced up to 5-fold by arrhythmia-associated mutations (40 ± 2 µM, n = 5). We obtained high resolution crystal structures for CaM variants in complex with CaMKIIδ294-315 or Cav1.2IQ peptides (2.0 Å – 2.8 Å). We did not observe noticeable structural difference between the CaM-WT and mutant peptide complexes. For the LQTS-associated CaM variant, impaired binding to Cav1.2 could result in dysregulation of Ca2+ signalling and consequently, generate irregular heartbeats characteristic of the disease. In contrast, Ca2+-CaM:Cav1.2 interaction is not altered in CPVT which suggests a distinct molecular mechanism.