SFTPC was first reported in relation to autosomal dominant SFTPC-related interstitial lung disease (MONDO:0018603) in 2001 (Nogee LM et al., 2001 PMID:11207353). SFTPC-related ILD is a genetic disorder that affects the lungs. It is caused by variants in the SFTPC gene, which encodes a protein that is important for the function of surfactant, a substance that lines the alveoli and helps to prevent them from collapsing. This disorder is characterized by a wide range of symptoms, from severe respiratory insufficiency in infants to adults with progressive pulmonary fibrosis. The typical presentation in infancy includes dyspnea, cough, wheezing, pulmonary infiltrates on chest radiographs, and gradual cyanosis, with or without failure to thrive (Clement A et al., 2010, PMID: 20727133).
More than 241 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level and experimental data. Seventeen variants (14 missense, 2 splice donor, 1 synonymous) that have been reported in 29 probands across 12 publications (Nogee LM, et al., 2001, PMID:11207353; Tredano M, et al., 2004, PMID:15039969; Thomas AQ, et al., 2002, PMID:1199188; van Moorsel CH, et al., 2010, PMID:20656946; Ono S, et al., 2011, PMID:21828032; Peca D, et al., 2015, PMID:25782673; Tang X et al., 2019, PMID: 32851322; Katzen J, et al., 2019, PMID: 30721158; Kazzi B, et al., 2018, PMID: 30094155; Litao MK, et al., 2017, PMID: 27362365; Fattori A, et al., 2019, PMID: 30955586; Terpe F, et al., 2023, PMID: 37232099) are included in this curation. While the precise molecular mechanism may depend on the specific variant (PMID: 22461427), the disease mechanism is related to a gain-of-toxic function. Loss-of-function (nonsense) variants have not been clearly associated with disease. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is also supported by biochemical functions, tissue specific expression and animal models (GTEx Consortium, 2013, PMID: 23715323; Katzen J et al., 2019, PMID: 30721158; Nureki SI et al., 2018, PMID: 29920187; Lawson WE, et al., 2011, PMID: 21670280).
In summary, there is definitive evidence to support the relationship between SFTPC-related interstitial lung disease. 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 the meeting date July 16, 2024 (SOP Version 10).
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