ABCA3 was first reported in relation to autosomal recessive interstitial lung disease due to ABCA3 dysfunction in 2004 (Shulenin et al., PMID: 15044640). ABCA3 encodes the ATP-binding cassette protein A3 which is primarily expressed in the alveolar type 2 cells of the lung and functions as a phospholipid transporter to move phospholipids into the lamellar body. Individuals with variants in ABCA3 are often reported to have surfactant deficiency, respiratory distress, and failure in the neonatal period or in infancy, but variants have also been found in older children and adults with isolated chronic interstitial lung disease (PMID: 19220077). Of note, ABCA3 has also been seen in monoallelic cases of ILD where another variant was also present (SFTPC p.I73T), but ABCA3 was described as a modifier gene in those cases and they were not included in this curation (PMIDs: 17597647, 20371530).
Fourteen variants (10 missense, 2 nonsense, 1 frameshift, 1 canonical splice site) that have been reported in 10 probands in 2 publications (PMIDs: 15044640, 32238781) are included in this curation. c.875A>T (p.Glu292Val) has been identified as a common variant seen in numerous patients with varying phenotypes (PMID: 32238781). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be loss of function.
This gene-disease relationship is also supported by the biochemical function being shared with other known genes (SFTPB and SFTPC) in the disease of interest (PMID: 19220077), expression data showing high expression in lung tissue (PMID: 23715323), functional alteration assays modeling the disrupted intracellular trafficking and impaired ATPase-mediated phospholipid transport into the lamellar bodies of ABCA3 variants in A549 cells (PMID: 32196812) mouse models that exhibit respiratory failure, neonatal death, and abnormal lamellar bodies similar to the human phenotype (PMIDs: 17142808, 17577581, 17267394), and cell culture models displaying abnormal-appearing lamellar body–like vesicles with significantly smaller vesicle diameters (P < 0.001) compared to WT (PMID: 32692933).
In summary, there is definitive evidence supporting the relationship between ABCA3 and autosomal recessive interstitial lung disease due to ABCA3 dysfunction. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on September 17, 2024 (SOP Version 10).
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