Read-through strategy rationale for DMD c.1950T>A (p.Cys650Ter)

For DMD c.1950T>A (p.Cys650Ter), nonsense-suppression remains the most direct currently actionable variant-class strategy because the lesion is a premature stop codon, making translational read-through better aligned with the molecular defect than therapies that would require bespoke correction at the exact site.

ClinVar classifies DMD c.1950T>A (p.Cys650Ter) as likely pathogenic. The strongest direct clinical precedent for nonsense-mutation Duchenne muscular dystrophy is ataluren, which was designed for premature stop codons and showed supportive efficacy signals across randomized and pooled analyses in ambulant nmDMD cohorts (PMID:28781359; PMID:32851872). Additional placebo-controlled data from Study 041 also reported functional benefit in a prespecified nonsense-mutation subgroup (PMID:40843507). Because p.Cys650Ter is a stop-gain DMD allele, it falls squarely within the variant class targeted by read-through therapy even though no trial was specific to this codon.

The evidence is class-level for nonsense-mutation DMD, not specific to p.Cys650Ter. Ataluren remains controversial across regulators and payers, and the European regulatory position worsened in 2024. Practical interpretation also depends on age, ambulatory status, background corticosteroid use, geography, and access. This should therefore be read as a mechanism-based rationale for a stop-gain DMD variant, not proof of allele-specific efficacy.