Mutations in the Fukutin-related protein gene (FKRP) lead to a alpha-dystroglycanopathy, a genetically heterogeneous group of muscular dystrophies associated with a wide range of phenotypes, from a mild Limb-Girdle Muscular Dystrophy (LGMD2I) to a severe congenital muscular dystrophy (CMD) with brain involvement. The aim of this study was to reinforce the scarce data associated with the uncommon c.919T>A missense mutation in order to clarify the genotype-phenotype correlation and to confirm the severity of this mutation. We report a new homozygous patient and reviewed the only 5 patients previously published (4 heterozygous and 1 homozygous). To understand the pathogenesis of the disease, two mice models, one with the mutation alone (FKRPTyr307Asn) and the second with a neomycin cassette (FKRP-NeoTyr307Asn), have been also generated. The two homozygous patients presented at birth with a severe muscle-eye-brain phenotype associated with mental retardation and severe structural eye and CNS involvement, such as lissencephaly and cerebellar hypoplasia. The three heterozygous patients, carrying the common c.826C>A mutation, developed a LGMD milder phenotype: two a Duchenne-like phenotype and one a Becker-like phenotype. The last heterozygous patient carrying a rare c.1012C>T mutation showed a CMD intermediate phenotype with eye and cerebellar malformation, but normal cognitive development. All six patients required early ventilatory support and three died from respiratory complications. All muscle biopsies showed a dystrophic pattern of variable severity. Although the homozygous FKRPTyr307Asn mice had an unexpected normal phenotype, the FKRP-NeoTyr307Asn mice showed a reduction in muscle mass, hypoglycosylation of α-DG, structural defects in eyes and CNS, and died after birth. Taken together, these findings strongly support our previous observations that this mutation is particularly severe when present either in homozygous or in heterozygous with the non-common mutation.