ABCA3 p.Asn1418Ser
| Predicted by SNAP2: | A: D (66%), C: D (66%), D: N (57%), E: N (53%), F: D (75%), G: D (53%), H: N (57%), I: D (71%), K: N (57%), L: D (75%), M: D (71%), P: D (66%), Q: N (53%), R: N (53%), S: N (66%), T: N (66%), V: D (66%), W: D (91%), Y: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] An intronic ABCA3 mutation that is responsible for... Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15. Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, Harrison K, Nogee LM
An intronic ABCA3 mutation that is responsible for respiratory disease.
Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15., [PMID:22337229]
Abstract [show]
INTRODUCTION: Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease. METHODS: ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF. RESULTS: ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes. DISCUSSION: These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.
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85 Mutation associated with disease in other patients, lung histopathology Alive with ILD K Caucasian ILD p.N1418S ?
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ABCA3 p.Asn1418Ser 22337229:85:105
status: NEW[hide] Single ABCA3 mutations increase risk for neonatal ... Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19. Wambach JA, Wegner DJ, Depass K, Heins H, Druley TE, Mitra RD, An P, Zhang Q, Nogee LM, Cole FS, Hamvas A
Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.
Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19., [PMID:23166334]
Abstract [show]
BACKGROUND AND OBJECTIVE: Neonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability. METHODS: Using next-generation, pooled sequencing of race-stratified DNA samples from infants >/=34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk. RESULTS: Single ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B. CONCLUSIONS: In contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants >/=34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.
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74 TABLE 4 Rare Mutations Identified Among Infants of African Descent Gene Mutations RDS (n = 44) Non-RDS (n = 196) Missouri Population (n = 195) ESP (n = 1869) ABCA3 R20W 2 V129M 12 F245L 1 R280C 1 R280H 2 R288K 7 (0.4%)a E292V 4 (0.2%)a F353L 3 N555S 5 G571R 1 T574I 1 2 P585S 1 L707F 14 G739A 2 15 V968M 1 1 F1164V 1 N1418S 1 R1474W 1 1 A1660V 1 Infants with variant 2 (4.5%)a 3 (1.5%)a 3 (1.5%)a 72 (3.9%)a SFTPC R35C 1 V39M 1 G57S 1 R81C 1 SFTPC allele (carrier) frequency 4 (0.2%)a CHPT1 G70R 2 T87M 1 G115A 1 Y365H 3 CHPT1 allele (carrier) frequency 7 (0.4%)a LPCAT1 A194V 6 L255Q 2 D392H 1 R526W 1 LPCAT1 allele (carrier) frequency 10 (0.5%)a PCYT1B G199D 1 (0.05%)a Identified mutations are predicted to be damaging according to both SIFT and PolyPhen (accessed March 2012) or previous association with pediatric respiratory disease. Blank boxes indicate the mutations were not observed in that specific cohort.
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ABCA3 p.Asn1418Ser 23166334:74:317
status: NEW