ACTN2 gene encodes α-actinin 2 protein, which binds actin. In cardiac muscle, α-actinin 2 is located in the Z-disc of the sarcomere, where it anchors myofibrillar actin filaments. A 48-years old female presented with out-of-hospital ventricular fibrillation arrest. Echocardiogram showed stage II diastolic dysfunction, elevated RVSP, and abnormal global longitudinal strain consistent with early LV systolic dysfunction. Cardiopulmonary testing indicated AHA functional class IV HF. Genetic testing identified a missense heterozygous variant of unknown significance in ACTN2 (gene previously associated with HCM and DCM), and SCNB2 (β-2 subunit of type II voltage-gated sodium channel). Histopathology demonstrated mild interstitial fibrosis of the LV free wall. We investigated the effects of the heterozygous A868T variant in α-actinin 2 on cardiac muscle mechanics. LV free wall samples were obtained from the patient's explanted heart at the time of cardiac transplantation. Permeabilized cardiac muscle preparations (CMPs) containing A868T and WT proteins displayed increased myofilament Ca2+-sensitivity of isometric force and lower maximal isometric specific force when compared to human donor samples. Sinusoidal stiffness was decreased at all levels of Ca2+-activation in A8686T CMPs. The rate of tension redevelopment (kTR) was faster at all levels of Ca2+-activation in A8686T CMPs. Computational modeling suggests that faster kTR in A868T CMPs is mainly due to faster cross-bridge detachment (g). The kinetic changes are consistent with decreased force generation by A868T CMPs being due to abnormalities in the cross-bridge interaction. Molecular dynamics simulation did not find significant differences in the interaction of A868T variant with titin and α-actinin. This project establishes the importance of α-actinin 2 variant in the Z-disc mechanosensitive interaction of thin- and thick-filament distal from its structural role in the sarcomere.