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In previous work, participants with a  G970R  mutation in cystic fibrosis transmembrane conductance regulator ( CFTR)  (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other  CFTR  gating mutations. The objective of this substudy was to characterize the molecular defect of the  G970R  mutation  in vitro  and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a  G970R/F508del  genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response  ex vivo  and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on‐treatment and off‐treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin‐induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by  G970R‐CFTR : exon 17 truncation, exons 13–15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an  ex vivo  response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of  CFTR  mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative  in vitro  model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.

G970R‐CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect