NM_000518.5(HBB):c.92+5G>C

For HBB c.92+5G>C, a splicing variant that abolishes beta-globin production, ex vivo CRISPR/Cas9 editing of the erythroid-specific BCL11A enhancer remains the clearest gene-editing fit because it reactivates fetal hemoglobin without needing to repair the HBB splice junction directly.

ClinVar lists c.92+5G>C as pathogenic for transfusion-dependent beta-thalassemia. Exagamglogene autotemcel (Casgevy) disrupts the BCL11A erythroid enhancer in autologous CD34+ cells and has shown durable transfusion independence in Phase 3 CLIMB THAL-111/121 trials, providing clinical proof that editing upstream fetal-hemoglobin regulators can offset severe HBB alleles (PMID:38657265; PMID:38661449). Additional long-term follow-up data document sustained HbF levels >30% and substantial iron-storage improvements, highlighting that the editing logic is allele-agnostic even for splice-site mutations such as c.92+5G>C.

Conditioning toxicity, manufacturing complexity, and the cost of ex vivo editing remain gatekeepers. The evidence is disease-level rather than variant-specific, so response may still vary with co-inherited HBB alleles and iron burden. Off-target editing, while low in current studies, still requires long-term surveillance and centralized follow-up. Treat this as a strong gene-editing platform argument for splice-disrupting HBB variants rather than a direct efficacy dataset for c.92+5G>C.