LAMP3

Inheritance Pattern: AR

Disease ID:MONDO:0015925

Submitter: Stanford Center for Undiagnosed Diseases

Inheritance Pattern: AR

Disease ID:MONDO:0031199

Submitter: ClinGen

Lysosome-associated membrane protein 3 (*LAMP3*) was first reported in relation to autosomal recessive interstitial lung disease in 2025 (Louvrier et al., PMID: 40023045). The first report of *LAMP3* autosomal recessive inherited interstitial lung disease in an animal model was in 2020 (Dillard et al., PMID: 32150563). *LAMP3*-related disease can include but is not limited to: neonatal respiratory distress, oxygen dependency, ground-glass opacification, and dyspnea. The age of onset is not clearly described in all of the curated cases but appears to be in childhood for the cases in this curation. 7 variants (4 missense, 2 frame-shift, and 1 canonical splice-site) that have been reported in 5 probands in 2 publications (PMIDs: 40023045, 41653023) are included in this curation. 2 missense variants (Gly388Arg and Thr268Met) showed abnormal glycosylation and reduced protein expression. This gene-disease relationship is also supported by animal models and expression studies (PMIDs: 25613900, 34161347, 32150563, 40023045). The Human Protein Atlas shows *LAMP3* protein expression in Lung, Lymph node, and Tonsil tissues only. *LAMP3* encodes a lysosomal membrane glycoprotein that localizes to lamellar bodies (LB) in alveolar type II (AT2) cells, the specialized epithelial cells responsible for surfactant production and secretion. Both humans and mice show LAMP3 dysfunction resulting in conspicuous LBs within AT2 cells. LAMP3 dysfunction was inherited in an autosomal recessive pattern in a pedigree of Airedale Terrier and recapitulated human phenotypes like: failure to thrive, poor suck, and neonatal respiratory distress which presented as a refusal to suckle and lethargic at birth in Airedale Terriers. *LAMP3* is involved in surfactant protein metabolism, through at least the interaction with SP-B and SP-C, and that *LAMP3* abnormalities may be associated with an alteration in surfactant protein homoeostasis. Additionally, SFTPC and SFTPB are curated definitive by the ILD GCEP for SFTPC-related interstitial lung disease and surfactant metabolism dysfunction, pulmonary, 1 respectively. In summary, there is strong evidence supporting the relationship between *LAMP3* and autosomal recessive *LAMP3*-related interstitial lung disease. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen ILD GCEP on the meeting date August 18 2026 (SOP Version 12).