SFTPC
protein-codingsurfactant protein C, the group of BRICHOS domain containing
Gene summary
This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]
- SFTP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0024465
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016323
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018603
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0024465
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0018603
Submitter: ClinGen
*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).
Inheritance Pattern: AD
Disease ID:MONDO:0024465
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0024465
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Clinical Genomic Database (CGD)
Manifestation: Pulmonary
Intervention: Pulmonary
Rationale: There have been reports of individuals who received benefit from medical treatment, including hydroxychloroquine, whole-lung lavage, systemic corticosteroids, azathioprine; Lung transplantation may be indicated in individuals with severe and/or refractory disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SFTPC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001317778.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 2 | 25 | 2 | 30 | |
| missense | 5 | 14 | 69 | 14 | 3 | 105 |
| nonsense | 2 | 1 | 3 | |||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 2 | 1 | 9 | |
| splice donor/acceptor (+/-2bp) | 5 | 1 | 1 | 1 | 8 | |
| Total | 13 | 21 | 75 | 41 | 5 | 155 |
Highest pathogenic variant AF is 0.0000030987421
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001304707.1 | 5 | MANE Select | |
| Ensembl | ENSP00000505152.1 | 5 | MANE Select | |
| RefSeq | NP_001165828.1 | 5 | Standard | |
| RefSeq | NP_001165881.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Surfactant metabolism
- Lung fibrosis
- Surfactant metabolism
- Metabolism of proteins
Biological Process
- respiratory gaseous exchange
- cellular protein metabolic process
Molecular Function
- protein binding
- identical protein binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum membrane
- lamellar body
- clathrin-coated endocytic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318561
- Coding exons
- 5
- Length
- 7567
- Individuals with no LoFs
- 124781
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 124797
- p
- 0.0000641
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.849 | 90 | 116 | 0.778 | 0.00000713 | 1254 |
| Missense (PolyPhen) | 26 | 45.123 | 0.5762 | 523 | ||
| Synonymous | -1.02 | 57 | 48.0 | 1.19 | 0.00000311 | 420 |
| Loss of Function | 1.04 | 6 | 9.44 | 0.636 | 5.40e-7 | 102 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air- liquid interface in the peripheral air spaces.;
- Disease
- DISEASE: Pulmonary surfactant metabolism dysfunction 2 (SMDP2) [MIM:610913]: A rare disease associated with progressive respiratory insufficiency and lung disease with a variable clinical course, due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid-Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress. {ECO:0000269|PubMed:11991887, ECO:0000269|PubMed:15039969, ECO:0000269|PubMed:15293602, ECO:0000269|PubMed:15557112, ECO:0000269|PubMed:15572558}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Respiratory distress syndrome in premature infants (RDS) [MIM:267450]: A lung disease affecting usually premature newborn infants. It is characterized by deficient gas exchange, diffuse atelectasis, high-permeability lung edema and fibrin-rich alveolar deposits called 'hyaline membranes'. {ECO:0000269|PubMed:14735158}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.234
Intolerance Scores
- LoFtool
- 0.122
- RVIS EVS
- 0.22
- RVIS percentile EVS
- 68.13
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.516
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |