NM_194248.3(OTOF):c.5188A>T (p.Lys1730Ter)

For OTOF c.5188A>T (p.Lys1730Ter), otoferlin gene replacement remains the strongest mechanism-matched therapeutic direction because this nonsense allele is expected to abolish normal protein function in a recessive loss-of-function deafness disorder, and current OTOF programs restore a functional coding sequence rather than repair the exact codon.

ClinVar classifies OTOF c.5188A>T (p.Lys1730Ter) as pathogenic. Preclinical dual-AAV studies restored otoferlin expression and improved auditory phenotypes in DFNB9 mouse models (PMID:30782832; PMID:30509897). Early human clinical data have shown hearing restoration signals after OTOF cochlear gene transfer in children, including AAV1-hOTOF experience (PMID:38280389), with additional studies ongoing (NCT:NCT05788536; NCT:NCT05821959). Because p.Lys1730Ter is a stop-gain allele in a biallelic loss-of-function condition, replacement is more directly supported than variant-specific editing.

The available human evidence remains early-phase and disease-level rather than specific to p.Lys1730Ter. Real-world interpretation still depends on confirming biallelic OTOF-mediated disease, cochlear target-cell viability, surgical timing, and durability. The optimal age window and re-dosing constraints remain unresolved.