Dominant missense variants in MYBPC1 have been linked to arthrogryposis syndromes and congenital myopathy with tremor, coined Myotrem. Myotrem is an untreatable congenital myopathy characterized by muscle weakness, hypotonia and myogenic tremor, linked to dominant variants in the M-domain of slow-skeletal Myosin Binding Protein-C (sMyBP-C). Herein, we report the first non-missense Myotrem variant, c.795_803dup leading to p.(Leu266_Arg268dup), referred to as LKR-duplication. Our biochemical characterization of the wild-type and LKR-mutant sMyBP-C uncovers previously unknown structure and properties of the slow-skeletal M-domain. Further, we reveal how the LKR-duplication stabilizes local helicity but alters global domain dynamics, leading to enhanced myosin binding while impairing myosin-ATPase activity and crossbridge-cycling. Our modeling studies demonstrate promise for selectively targeting cryptic sites in the LKR-mutant pathogenic protein. Our multi-modal approach sheds light on novel aspects of the pathobiology of the sMyBP-C M-domain, the Myotrem hotspot, and paves the way for targeted treatments. We further describe novel compound heterozygous variants – NM_002465.4:[c.2486_2492del];[c.2663A>G] – present in fibronectin-III (Fn-III) C7 and immunoglobulin (Ig) C8 domains, respectively, manifesting as severe, early-onset distal arthrogryposis type-1, with the carrier requiring intensive care and several surgical interventions at an early age. Computational modeling predicts that the c.2486_2492del p.(Lys829IlefsTer7) variant destabilizes the structure of the Fn-III C7 domain, while the c.2663A>G p.(Asp888Gly) variant causes minimal structural alterations in the Ig C8 domain. Although the parents of the proband are heterozygous carriers for a single variant, they exhibit no musculoskeletal defects, suggesting a complex interplay between the two mutant alleles underlying this disorder. As emerging novel variants in MYBPC1 are shown to be causatively associated with musculoskeletal disease, it becomes clear that MYBPC1 should be included in relevant genetic screenings. Beyond these two variants, we also investigate the impact of another novel intronic MYBPC1 variant at the level of tissue expression and protein structure, in addition to reviewing the role of skeletal muscle in the gastrointestinal system in health and disease, as well as the role of zinc finger transcription factors in colon cancer.