The p.Arg258Gly mutation in intracellular loop 2 of CFTR is associated with CFTR-related disorders.

Missense mutations account for approximately 50% of the mutations described in the CFTR gene. However, their proportion is higher in CFTR-related disorders (CFTR-RD) than in cystic fibrosis (CF), suggesting a different mutational spectrum. The uncertainty surrounding many of these mutations prevents suitable genetic counseling. Thus, it is crucial to determine whether a missense mutation has clinical expression, and if it does, to then define the associated phenotype. Herein we have assessed the phenotype associated with the p.Arg258Gly (R258G) mutation, checking our cohorts of patients (CF and CFTR-RD) and control subjects (CF carriers, fertile males, and general population). We also performed in silico predictive studies on the possible consequences of this mutation at the protein level. Lastly, we exhaustively reviewed the literature on this mutation. To date, R258G has only been found in six patients: a French congenital bilateral absence of vas deferens patient, reported in 1995 and five unrelated subjects from our cohort of non-CF patients, described here. Based on these findings, we postulate that R258G is primarily a CFTR-RD-associated mutation.