RYR1 pathological amino acid variants aligned with corresponding RYR1 structural regions. Black numbers on top of the bars indicate the number of different variants in the corresponding RYR1 protein domains identified in patients to date, according to Kushnir et al., 2020 and Global Variome shared LOVD (https://databases.lovd.nl/shared/variants/RYR1). Red numbers indicate diagnostic MH RYR1 mutations in the corresponding RYR1 domain, according to the EMHG. Distribution of the different aa variants (n = 656, blue boxes), including MH-causative aa variants (n = 46, red boxes), throughout the RYR1 aa sequence is reported in the horizontal bar. RYR1 was subdivided into domains according to des Georges et al., 2016. The position of the initial aa of each domain is indicated. SCLP, shell-core linker peptide; TaF, thumb and forefingers domain; TMx, auxiliary transmembrane helices; Pore, channel pore domain.