ClinVar Genomic variation as it relates to human health
NM_001317778.2(SFTPC):c.218T>C (p.Ile73Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001317778.2(SFTPC):c.218T>C (p.Ile73Thr)
Variation ID: 13208 Accession: VCV000013208.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p21.3 8: 22163096 (GRCh38) [ NCBI UCSC ] 8: 22020609 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 4, 2016 Apr 20, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001317778.2:c.218T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001304707.1:p.Ile73Thr missense NM_001172357.2:c.218T>C NP_001165828.1:p.Ile73Thr missense NM_001172410.2:c.218T>C NP_001165881.1:p.Ile73Thr missense NM_001317779.2:c.59T>C NP_001304708.1:p.Ile20Thr missense NM_001317780.2:c.218T>C NP_001304709.1:p.Ile73Thr missense NM_003018.4:c.218T>C NP_003009.2:p.Ile73Thr missense NC_000008.11:g.22163096T>C NC_000008.10:g.22020609T>C NG_016968.1:g.6426T>C NG_029659.1:g.2957T>C - Protein change
- I73T, I20T
- Other names
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- Canonical SPDI
- NC_000008.11:22163095:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SFTPC | - | - |
GRCh38 GRCh37 |
140 | 241 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000014095.38 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000731190.7 | |
Likely risk allele (1) |
no assertion criteria provided
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Jun 9, 2022 | RCV002509156.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 19, 2019 | RCV002415413.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000858972.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: yes
Allele origin:
germline
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Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001499942.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East Asia
Geographic origin: China
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058361.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013208, PS1_S). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013208, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21092132, PS3_M). The variant was observed to be de novo (3billion dataset, PS2_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.731, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Failure to thrive in infancy (present) , Gastroesophageal reflux (present) , Global developmental delay (present) , Abnormal pulmonary interstitial morphology (present) , Laryngeal cleft (present) … (more)
Failure to thrive in infancy (present) , Gastroesophageal reflux (present) , Global developmental delay (present) , Abnormal pulmonary interstitial morphology (present) , Laryngeal cleft (present) , Congenital laryngomalacia (present) , Hepatic cysts (present) , Neonatal respiratory distress (present) , Proportionate short stature (present) , Recurrent aspiration pneumonia (present) , Recurrent infections (present) , Dysphagia (present) , Laryngeal cleft (present) , Congenital laryngomalacia (present) , Dysphagia (present) , Recurrent aspiration pneumonia (present) , Respiratory distress (present) , Tracheomalacia (present) (less)
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Pathogenic
(Feb 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pulmonary alveolar proteinosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002725353.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.I73T pathogenic mutation (also known as c.218T>C), located in coding exon 3 of the SFTPC gene, results from a T to C substitution at … (more)
The p.I73T pathogenic mutation (also known as c.218T>C), located in coding exon 3 of the SFTPC gene, results from a T to C substitution at nucleotide position 218. The isoleucine at codon 73 is replaced by threonine, an amino acid with similar properties. This mutation is considered to account for approximately 30% of described mutations in the SFTPC gene. In vitro studies have demonstrated that this alteration interferes with correct processing and routing of the final protein, as well as reduction in lipid degradation (Beers MF et al. Traffic, 2011 Sep;12:1196-210). In addition, this mutation was described to track in a large kindred with multiple individuals with lung disease of variable severity (Cameron HS et al. J. Pediatr., 2005 Mar;146:370-5). One study identified 4 infants presenting with respiratory symptoms before 2 months of age who inherited the mutation from an asymptomatic parent; 3 of those infants were found to also carry an ABCA3 alteration inherited from the other parent and authors suggest the ABCA3 alterations may modify the severity of disease (Bullard JE et al. Pediatr. Res., 2007 Aug;62:176-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020084.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Accession: SCV000890884.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001433646.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
This previously reported SFTPC variant results in mistrafficking of the SFTPC pre-protein and has been identified in multiple individuals with surfactant protein C deficiency. We … (more)
This previously reported SFTPC variant results in mistrafficking of the SFTPC pre-protein and has been identified in multiple individuals with surfactant protein C deficiency. We consider this variant to be pathogenic. (less)
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Pathogenic
(Feb 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041156.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048086.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.Ile73Thr variant has been previously reported in patients affected with interstitial lung disease (Liu et al, 2019). This previously reported SFTPC variant results in … (more)
The p.Ile73Thr variant has been previously reported in patients affected with interstitial lung disease (Liu et al, 2019). This previously reported SFTPC variant results in mistrafficking of the SFTPC pre-protein and has been identified in multiple individuals with surfactant protein C deficiency. This variant has been reported to the ClinVar database as Pathogenic. This variant is novel (not in any individuals) in 1000 Genomes. The amino acid Ile at position 73 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile73Thr in SFTPC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Tachypnea (present) , Recurrent pneumonia (present) , Gastroesophageal reflux (present) , Respiratory distress (present)
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002231594.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the SFTPC protein (p.Ile73Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the SFTPC protein (p.Ile73Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with childhood interstitial lung disease (PMID: 15293602, 15572558, 15756222). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13208). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SFTPC function (PMID: 21707890). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Surfactant metabolism dysfunction, pulmonary, 2
Affected status: no
Allele origin:
unknown
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Genomic Medicine Lab, University of California San Francisco
Accession: SCV004847129.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
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Pathogenic
(Jul 01, 2009)
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no assertion criteria provided
Method: literature only
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SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034343.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016 |
Comment on evidence:
In a patient with infantile-onset of progressive respiratory insufficiency and surfactant metabolism dysfunction (SMDP2; 610913), Tredano et al. (2004) and Brasch et al. (2004) identified … (more)
In a patient with infantile-onset of progressive respiratory insufficiency and surfactant metabolism dysfunction (SMDP2; 610913), Tredano et al. (2004) and Brasch et al. (2004) identified a heterozygous de novo 1286T-C transition in exon 3 of the SFTPC gene, resulting in an ile73-to-thr (I73T) substitution in the C-terminal propeptide. The symptoms of lung disease began at the age of 1 month and lung biopsy at age 13 months showed a combined histologic pattern of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Ultrastructural studies showed abnormal transport vesicles in type II pneumocytes and biochemical studies showed that expression of mutant proSPC resulted in abnormal proprotein trafficking and accumulation of aberrantly processed proSPC within alveoli. The I73T mutation was not identified in 100 control chromosomes. Percopo et al. (2004) reported another male infant with fatal lung disease due to the I73T mutation. He developed asthmatic bronchitis at age 3 months, followed by progressive failure to thrive, dyspnea, tachypnea, and hypoxemia. Lung biopsy at age 11 months showed thickened alveolar septa, hyperplasia of type II pneumocytes, and massive alveolar proteinosis. He died 8 months later. Guillot et al. (2009) identified a heterozygous I73T mutation in 10 of 121 children with diffuse lung disease. The mutation was inherited in 6 cases and appeared de novo in 4 cases. None of the patients had neonatal onset of the disease. (less)
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Likely risk allele
(Jun 09, 2022)
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no assertion criteria provided
Method: research
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Pulmonary fibrosis
Affected status: yes
Allele origin:
germline
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Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center
Accession: SCV002547378.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic basis of surfactant dysfunction in Chinese children: A retrospective study. | Chen J | Pediatric pulmonology | 2019 | PMID: 31081264 |
A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling. | Beers MF | Traffic (Copenhagen, Denmark) | 2011 | PMID: 21707890 |
A non-BRICHOS surfactant protein c mutation disrupts epithelial cell function and intercellular signaling. | Woischnik M | BMC cell biology | 2010 | PMID: 21092132 |
New surfactant protein C gene mutations associated with diffuse lung disease. | Guillot L | Journal of medical genetics | 2009 | PMID: 19443464 |
Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. | Bullard JE | Pediatric research | 2007 | PMID: 17597647 |
A common mutation in the surfactant protein C gene associated with lung disease. | Cameron HS | The Journal of pediatrics | 2005 | PMID: 15756222 |
Variable phenotype associated with SP-C gene mutations: fatal case with the I73T mutation. | Percopo S | The European respiratory journal | 2004 | PMID: 15572558 |
Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene. | Brasch F | The European respiratory journal | 2004 | PMID: 15293602 |
Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. | Tredano M | American journal of medical genetics. Part A | 2004 | PMID: 15039969 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SFTPC | - | - | - | - |
Text-mined citations for rs121917834 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.