Nonsense-suppression rationale for DMD c.2916T>G (p.Tyr972Ter)

For DMD c.2916T>G (p.Tyr972Ter), nonsense-suppression remains the most direct currently actionable variant-class strategy because this allele creates a premature stop codon, making translational read-through a better mechanistic fit than therapies that require bespoke editing around the exact site.

ClinVar classifies DMD c.2916T>G (p.Tyr972Ter) as pathogenic. Ataluren was developed specifically for nonsense-mutation Duchenne muscular dystrophy and has shown supportive efficacy signals across randomized and pooled analyses in ambulant nmDMD populations (PMID:28781359; PMID:32851872). More recent placebo-controlled data from Study 041 again supported functional benefit in a prespecified nonsense-mutation subgroup (PMID:40843507). Because p.Tyr972Ter is a true stop-gain DMD allele, it fits the same pathogenic class targeted by read-through therapy even though those trials were not powered for codon-level conclusions.

The direct evidence is for nonsense-mutation DMD as a class, not specifically for p.Tyr972Ter. Clinical benefit from ataluren has remained controversial, and the regulatory picture worsened after the European Medicines Agency moved against renewal in 2024. Any real-world interpretation also depends on age, ambulatory status, concomitant steroids, geography, and access. This should therefore be read as a class-based therapeutic rationale for a stop-gain DMD variant, not proof of variant-specific efficacy.