To provide evidence supporting the pathogenicity of the c.2623-3 C>G splice acceptor site mutation as it relates to the Duchenne Muscular Dystrophy phenotype.

Duchenne and Becker Muscular Dystrophy (DMD and BMD) result from dystrophin gene mutations. The gene encodes for the dystrophin protein which is critical to muscle fiber health. If the protein is abnormal, the muscle fibers degenerate causing progressive weakness. Dystrophin gene mutations include exon deletions, partial gene duplications, microdeletions/insertions and single nucleotide/splice site variants. Mutations disrupting the gene's open reading frame (ORF) result in nonfunctional dystrophin protein (severe DMD phenotype), and ORF-sparing mutations result in semi-functional protein (milder BMD phenotype). One published case describes a splice acceptor site mutation, c.2623-3 C>G, which resulted in a frameshift, causing the DMD phenotype. This mutation is currently deemed “likely pathogenic” by the ACGM. Our case report describes two brothers with the DMD phenotype who have this same mutation.

Genetic testing for our two DMD patients support the pathogenicity of the c.2623-3 C>G mutation. In addition to the one published DMD case with this same mutation, there are two similar splice acceptor site mutations (c.2623-2 A>G, c.2623-1 G>T) which are implicated in DMD. The NCBI designates the c.2623-1 G>T mutation as “pathogenic." We believe that the DMD phenotype due to the c.2623-3 C>G mutation in our patients, in conjunction with data regarding DMD in nearly identical mutations, suggests that the c.2623-3 C>G mutation should be designated as definitively "pathogenic."