This variant is classified as a variant of unknown significance because its contribution to pulmonary surfactant metabolism dysfunction (see, e.g., SMDP1, 265120) has not been confirmed.
In a 2-year-old Pakistani girl with global developmental delay, dysmorphic features, and progressive interstitial lung disease due to pulmonary surfactant metabolism dysfunction (SMDP), Huang et al. (2022) identified a de novo heterozygous c.406G-C transversion (c.406G-C, NM_002868.3) in the RAB5B gene, resulting in an asp136-to-his (D136H) substitution at a highly conserved residue in the fourth region of the small GTPase nucleotide binding domain. The variant, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Patient lung tissue showed a significant (80%) reduction in RAB5B immunostaining in AT2 cells compared to controls, which may have resulted from degradation of the aberrant protein. ProSP-B (SFTPB; 178640) and proSP-C (SFTPC; 178620) were present at normal levels in patient AT2 cells, but mature SP-B and SP-C were significantly reduced, indicating a defect in trafficking and impaired processing of surfactant proteins in the vesicular pathway. EEA1 levels were also reduced, consistent with a defect in the early endosomal pathway. The findings were consistent with surfactant dysfunction causing interstitial lung disease in the proband. Generation of the orthologous D135H variant in C. elegans was lethal at the larval stage in the homozygous state. Heterozygous animals showed decreased locomotion and had decreased size compared to controls, with a strong dominant-negative effect. Heterozygous animals had defects in endocytic trafficking; early endosomes were puncta-sized and failed to mature into larger ring-shaped endosomes, suggesting defective early endosome fusion. At age 6 months, the patient showed hypotonia, broad nasal bridge with telecanthus, short squared digits and overlapping toes. She had profound developmental delay with static encephalopathy. At 11 months of age, she developed respiratory insufficiency and digital clubbing associated with diffuse ground-glass opacities on imaging, consistent with interstitial lung disease and suggestive of a surfactant dysfunction disorder. Histology revealed pulmonary alveolar proteinosis, AT2 cell hyperplasia, lobar remodeling, and early fibrosis. Levels of SFTPB were decreased in AT2 cells. She died of respiratory failure at 2 years of age. Variants in known surfactant disorder genes were excluded.