Reply to “Familial Segregation Highlights Challenges in Rare <scp>SFTPA2</scp> Variant Classification”

We have read with great interest the correspondence related to our publication. In this letter, the authors identified the same SFTPA2 c.635_654del p.(Tyr212Serfs*17) variant that we reported, in a patient with familial pulmonary fibrosis who also carries a TERT variant. In this family, the disease segregated with the TERT variant, but not with the SFTPA2 variant. Based on this observation, the authors concluded that the SFTPA2 c.635_654del variant should be considered a variant of uncertain significance, rather than likely pathogenic. This report highlights the challenges of classifying SFTPA2 variants and the crucial need to perform functional studies. The SFTPA2 variant is located in the same functional domain (carbohydrate recognition domain) as all previously reported SFTPA1 and SFTPA2 pathogenic variants. As described by J. van der Vis and JM. Fellrath in the correspondence, the c.635_654del variant lies in the last exon of SFTPA2, and consequently, it is predicted to escape nonsense-mediated mRNA decay (NMD), resulting in a truncated protein. To understand the potential functional effects of this variant, we are currently conducting an in vitro study of the variant in HEK293T cells. Our preliminary results show an absence of protein secretion and reduced protein stability following the transient expression of the mutant protein, as it has been previously reported for well-known pathogenic missense variants [1, 2]. This study is ongoing, and we plan to publish these results, along with the functional studies of other unreported SFTPA1 and SFTPA2 variants, in a few months. The authors have nothing to report. The authors declare no conflicts of interest.