NM_000518.5(HBB):c.118C>T (p.Gln40Ter)

For HBB c.118C>T (p.Gln40Ter), ex vivo BCL11A enhancer editing is a credible therapeutic route because it is variant-agnostic and can reduce the transfusion burden without directly repairing the stop codon. For a classic beta-zero allele like p.Gln40Ter, the strongest current editing logic is fetal-hemoglobin reactivation rather than bespoke correction of the HBB coding change.

ClinVar lists c.118C>T as pathogenic, and the variant is consistent with a severe loss-of-function beta-thalassemia mechanism. Exagamglogene autotemcel (Casgevy) received FDA approval for transfusion-dependent beta thalassemia in January 2024, and the phase 3 CLIMB THAL-111 study published in NEJM showed that most treated patients achieved transfusion independence through BCL11A erythroid enhancer editing. Because this platform edits autologous hematopoietic stem cells upstream of fetal-hemoglobin regulation, it is applicable across many severe HBB genotypes, including nonsense alleles such as p.Gln40Ter.

This is still intensive therapy: busulfan conditioning, stem-cell collection, specialized manufacturing, and prolonged follow-up are all required. The evidence is genotype-agnostic rather than specific to p.Gln40Ter, and outcomes can vary with baseline iron burden, marrow reserve, and genotype combinations on the second HBB allele. This approach also does not restore native adult beta-globin production; it compensates through fetal hemoglobin induction, so residual anemia and long-term durability still need continued surveillance.