NM_000344.4(SMN1):c.43C>T (p.Gln15Ter)

For SMN1 c.43C>T (p.Gln15Ter), AAV9 SMN1 gene replacement is a strong therapeutic fit because this early nonsense variant is functionally equivalent to severe loss of SMN1, while the approved treatment logic is full-gene replacement rather than allele repair. In other words, this variant maps well onto the existing Zolgensma paradigm if the patient meets the labeled age and disease-stage constraints.

ClinVar classifies c.43C>T (p.Gln15Ter) as pathogenic, and the variant is expected to abolish functional SMN protein very early in the coding sequence. The current FDA label for Zolgensma, updated through 2026-04-03 in openFDA, indicates onasemnogene abeparvovec for pediatric patients younger than 2 years with spinal muscular atrophy and bi-allelic SMN1 mutations. Real-world monotherapy data from the 2024 RESTORE registry showed meaningful motor outcomes in patients treated with onasemnogene abeparvovec, supporting the disease-level validity of SMN1 gene replacement across severe genotypes rather than only a single recurrent allele.

This is still a timing-sensitive therapy. The FDA label explicitly notes that repeat dosing has not been evaluated and that use in advanced SMA, including complete limb paralysis or permanent ventilator dependence, has not been evaluated. The evidence base is disease-level rather than specific to p.Gln15Ter, and outcomes are strongly modified by age at treatment, baseline motor status, SMN2 copy number, and management of known risks such as liver injury, thrombocytopenia, and thrombotic microangiopathy.