ABCMdb

ABCC7 p.Ile125Thr

ClinVar:	c.374T>C , p.Ile125Thr ? , not provided
CF databases:	c.374T>C , p.Ile125Thr (CFTR1) ? , The mutation was found in a Chinese woman by heteroduplex analysis. No additional information is available.
Predicted by SNAP2:	A: N (72%), C: N (61%), D: D (80%), E: D (75%), F: N (78%), G: D (71%), H: D (71%), K: D (53%), L: N (93%), M: N (82%), N: N (53%), P: D (80%), Q: D (66%), R: D (75%), S: D (66%), T: N (82%), V: N (93%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: N, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, V: N, W: N, Y: N,

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[hide] Highest heterogeneity for cystic fibrosis: 36 muta... Am J Med Genet. 2002 Dec 1;113(3):250-7. Kilinc MO, Ninis VN, Dagli E, Demirkol M, Ozkinay F, Arikan Z, Cogulu O, Huner G, Karakoc F, Tolun A
Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients.
Am J Med Genet. 2002 Dec 1;113(3):250-7., 2002-12-01 [PMID:12439892]

Abstract [show]
We analyzed the CFTR locus in 83 Turkish cystic fibrosis patients to identify mutations, haplotypes, and the carrier frequency in the population. We detected 36 different mutations in 125 (75%) of the total 166 CF chromosomes. Seven novel mutations were identified: four missense (K68E, Q493P, E608G, and V1147I), two splice-site (406 -3T > C and 3849 +5G > A), and one deletion (CFTRdele17b,18). The data showed that the Turkish population has the highest genetic heterogeneity at the CFTR locus reported so far. The results of this thorough molecular analysis at the CFTR locus of a population not of European descent shows that CF is not uncommon in all such populations. The large number of mutations present, as well as the high heterogeneity in haplotypes associated with the mutations suggests that most of the mutations have persisted for a long time in the population. Consistently, the carrier frequency is assessed to be high, indicating that the disease in the population is ancient.

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80 Haplotypes Associated With the Mutations Identified in 83 Turkish CF Patients* Mutation Total number of alleles Number of alleles Number of patients Haplotypes Homo Hetero DF508 39 (23.5) 6 7 23 M 28 13 1 0 1 6 7 23 M 30 13 1 0 1 6 9 23 M 31 13 1 0 1 6 7 23 M 31 13 11 4 3 6 7 23 M 7 17 2 0 2 6 7 16 M 31 13 3 1 1 6 7 17 M 31 13 17 5 7 6 7 17 M 32 13 3 1 1 1677delTA 12 (7.2) 7 7 16 V 30 13 12 5 2 2183AA > G 7 (4.2) 7 7 16 M 30 13 1 0 1 7 9 16 M 31 13 4 2 0 7 7 16 M 32 13 2 1 0 G542X 6 (3.6) 6 7 23 M 32 13 6 3 0 F1052V 5 (3.0) 6 7 17 M 7 13 4 1 2 7 5 17 M 7 17 1 0 1 W1282X 5 (3.0) 7 7 17 M 7 17 4 1 2 7 7 17 M 7 18 1 0 1 E92K 4 (2.4) 7 7 16 V 46 13 3 1 1 7 7 17 V 46 13 1 0 1 1525 À 1G > A 4 (2.4) 7 7 17 M 7 17 4 2 0 2789 þ 5G > A 4 (2.4) 7 9 17 M 7 17 3 1 1 7 5 17 M 7 17 1 0 1 N1303K 4 (2.4) 7 7 23 M 31 13 2 0 2 6 7 22 M 30 13 1 0 1 6 7 23 M 30 13 1 0 1 A46D 3 (1.8) 6 9 23 M 31 13 1 0 1 6 7 23 M 31 13 2 1 0 2184insA 3 (1.8) 7 5 17 V 30 13 1 0 1 7 7 16 V 30 13 2 0 2 R1070Q 3 (1.8) 7 7 16 M 31 13 1 0 1 7 7 17 M 31 13 2 0 2 Q493Pa 2 (1.2) 6/7 5 16 M 46 13 2 1 0 3849 þ 5G > Aa 2 (1.2) 7 7 16 M 31 13 2 1 0 CFTRdele17b,18a 2 (1.2) 6 9 16 V - - 2 1 0 K68Ea 1 (0.6) 6 9 17 M 7 13 1 0 1 R74W 1 (0.6) 6 7 16 M 32 16 1 0 1 306delTAGA 1 (0.6) 7 7 16 M 7 17 1 0 1 D110H 1 (0.6) 7 9 16 V 30 13 1 0 1 I125T 1 (0.6) 6 7 23 V 7 16 1 0 1 406 À 3T > Ca 1 (0.6) 7 7 16 V 33 17 1 0 1 I148T 1 (0.6) 6/7 7 16/17 M 7 17/23 1 0 1 621 þ 1G > T 1 (0.6) 6 7 21 V 31 13 1 0 1 R347P 1 (0.6) 7 9 17 V 30 13 1 0 1 S466X 1 (0.6) 7 7 23 M 33 13 1 0 1 L571S 1 (0.6) 7 7 16 V 29 13 1 0 1 1717 À 1G > A 1 (0.6) 7 9 17 M 7 16 1 0 1 E608Ga 1 (0.6) 7 9 16 M/V 29/31 13 1 0 1 2043delG 1 (0.6) 7 9 17 M 7 17 1 0 1 P1013L 1 (0.6) 6 5 16 M 21 18 1 0 1 R1066L 1 (0.6) 7 7 17 M 7 13 1 0 1 3129del4 1 (0.6) 7 7 16 V 29 13 1 0 1 V1147Ia 1 (0.6) 6 7 17 M 33 17 1 0 1 S1235R 1 (0.6) 6 7 17 M 39 13 1 0 1 CFTRdele2,3 1 (0.6) 7 7 16 V 33 13 1 0 1 Total 125 (75) 125 32 61 *The order of the polymorphisms is IVS6GATT, Tn, IVS8CA, M470V, IVS17BTA and IVS17BCA. Login to comment

[hide] A haplotype-based molecular analysis of CFTR mutat... Hum Mol Genet. 2003 Sep 15;12(18):2321-32. Lee JH, Choi JH, Namkung W, Hanrahan JW, Chang J, Song SY, Park SW, Kim DS, Yoon JH, Suh Y, Jang IJ, Nam JH, Kim SJ, Cho MO, Lee JE, Kim KH, Lee MG
A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.
Hum Mol Genet. 2003 Sep 15;12(18):2321-32., 2003-09-15 [PMID:12952861]

Abstract [show]
Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case-control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl(-) currents and HCO3(-) -transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.

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74 CFTR genetic variants analyzed in this study Variations found by TDGS Most common worldwide disease-causing mutations Reported disease-associated microsatellite À8G/C (50 UTR)a R117H (exon 4) T5-7,9 (IVS 8) (16) I125T (exon 4)b 621 þ 1G > T (intron 4) E217G (exon 6a)b F508del (exon 10) 1059C > T (exon 7, A309)a 1717-1G > A (intron 10) M470V (exon 10)b G542X (exon 11) I556V (exon 11)b G551D (exon 11) 2694T/G (exon 14a, T854)b R553X (exon 11) Q1352H (exon 22)b R1162X (exon 19) R1453W (exon 24)b W1282X (exon 20) N1303K (exon 21) Mutation names and nucleotide numbers are presented according to the Cystic Fibrosis Genetic Analysis Consortium (CFGAC; www.genet.sickkids.on.ca/). Login to comment
107 Frequency of CFTR gene variants in the Korean population Variation Genotype Group (number) Healthy control (n ¼ 117) Bronchiectasis (n ¼ 47) Pancreatitis (n ¼ 28) Diallelic -8G/C þ/þ 105 44 22 þ/Àa 12 3 6 R117H þ/þ 116 47 28 þ/À 1 0 0 I125T þ/þ 116 46 27 þ/À 1 1 1 E217G þ/þ 114 43 27 þ/À 3 4b 1 1059C > T þ/þ 117 47 27 (A309) þ/À 0 0 1 M470V þ/þ 23 3 6 þ/À 52 28 14 À/À 42 16 8 I556V þ/þ 111 45 28 þ/À 6 2 0 2694T/G þ/þ 41 16 8 (T854) þ/À 51 27 14 À/À 25 4 6 Q1352H þ/þ 116 43 24 þ/À 1 4* 4** R1453W þ/þ 115 46 28 þ/À 2 1 0 Microsatellite T5-7,9 5/7 4 6* 2 (IVS 8) 6/7 0 1 0 7/7 110 39*c 26 7/9 3 1 0 Differences between control and disease groups were analyzed by a chi-square test. When an expected cell value was less than 5, Fisher`s exact test was used. Login to comment
114 Haplotype assembly Allele ID -8G/C R117H I125T E217G 1059C/T T5-7,9 M470V I556V 2694T/G Q1352H R1453W Group a M470V-2694T/G background Control, n (%) Bronchiectasis, n (%) Pancreatitis, n (%) 1 G R I E C WTb V I T Q R 121 (51.7) 47 (50.0) 24 (42.9) 2-1 2 G R I E C WT M I G Q R 78 (33.3) 25 (26.6) 18 (32.1) 1-2 3 C R I E C WT M I G Q R 11 (4.7) 3 (3.2) 5 (8.9) 1-2 4 G R I E C WT V I T H R 1 (0.4) 4 (4.3)* 4 (7.1)** 2-1 5 G R I E C 5 V I T Q R 2 (0.9) 5 (5.4)* 1 (1.8) 2-1 6 G R I G C WT M I G Q R 3 (1.3) 4 (4.3)c 1 (1.8) 1-2 7 G R I E C WT V V T Q R 5 (2.1) 2 (2.2) 0 (0.0) 2-1 8 G R I E C WT V I G Q R 4 (1.7) 1 (1.0) 0 (0.0) 2-2 9 G R I E C 5 M I G Q R 2 (0.9) 1 (1.0) 1 (1.8) 1-2 10 G R I E C WT M I G Q W 2 (0.9) 1 (1.0) 0 (0.0) 1-2 11 G R T E C WT V I T Q R 1 (0.4) 1 (1.0) 1 (1.8) 2-1 12 G R I E C WT M I T Q R 2 (0.9) 0 (0.0) 0 (0.0) 1-1 13 C R I E C WT V I G Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-2 14 G H I E C WT V V T Q R 1 (0.4) 0 (0.0) 0 (0.0) 2-1 15 C R I E T WT M I G Q R 0 (0.0) 0 (0.0) 1 (1.8) 1-2 Total 234 (100.0) 94 (100.0) 56 (100.0) Haplotypes were assembled using a software based on the Bayesian algorithm (Haplotyper) (7). Login to comment

[hide] Spectrum of mutations and variants/haplotypes of C... Clin Genet. 2007 Jun;71(6):530-9. Chang MC, Chang YT, Wei SC, Tien YW, Liang PC, Jan IS, Su YN, Wong JM
Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis.
Clin Genet. 2007 Jun;71(6):530-9., [PMID:17539902]

Abstract [show]
Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported in patients with chronic pancreatitis. The authors examine whether the mutations and haplotypes of CFTR will increase the risk of developing idiopathic chronic pancreatitis (ICP) in Chinese and their genotype and phenotype correlations. Seventy-eight patients with ICP and 200 geographically and ethnically matched controls in Taiwan were analyzed. The entire 27 coding and intronic regions of the CFTR gene were identified using heteroduplex analytical techniques and confirmed by sequencing analysis. The presence of 125G/C, 1001+10C>T, IVSTn(TG)m, 1540A>G, c2694T>G, and c4521G>A were determined by directing sequencing. Abnormal CFTR allele was found to be thrice as frequent in ICP patients as in controls (22/156 vs 19/400, p < 0.0001). T5 allele was associated with early onset of ICP. In six-loci haplotype analysis, 13 common haplotypes were assembled in the 278 individuals tested. The 125G/1001+11C/TG12/470M/2694T/4521G haplotype was associated with risk of ICP (odds ratio 11.3; 95% confidence interval 2.3-54.6, p = 0.008) in Chinese. The mutation spectrum is different from other ethnic groups. A population-specific panel of CFTR changes should be recommended for targeted populations including ICP in Chinese. It is important to design suitable screening programs for different populations.

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97 These mutations include I556V, G to A 3849145, N287Y, I125T, E217G, S895N, G1O69R, and Q1352H that have been found in patients with CP or CBAVD (http://www.genet. Login to comment
109 (%) in ICP Controls (%) I556V Exon 11 A to G 1798 Amino acid substitution 7 (8.9) 2 (1) IVS8-5T Intron 8 deletaion of 2T between 1342-12 and 1342-6 Aberrant splicing 6 (7.7) 14 (7) G to A 3849145 Intron 19 G to A at 3849145 mRNA splicing defect 3 (3.8) 2 (1) N287Y Exon 6b A to T 991 Amino acid substitution 2 (2.6) 00 (0) I125T Exon 4 T to C 506 Amino acid substitution 1 (1.3) 00 (0) E217G Exon 6a A to G 782 Amino acid substitution 1 (1.3) 00 (0) S895N Exon 15 G to A 2816 Missense mutation 1 (1.3) 00 (0) G1O69R Exon 17b G to A 3337 Amino acid substitution 1 (1.3) 00 (0) Q1352H Exon 22 G to C at 4188 Amino acid substitution 0 (0.0) 1 (0.5) ICP, idiopathic chronic pancreatitis. Login to comment
157 All our mutations are belonging to Ômild` mutations compatible with previous studies (6), including I556V, G to A 3849145, I125T, E217G, N287Y, S895N, G1O69R, and Q1352H. Login to comment
171 I556V, I125T and Q1352H are reported to be associated chronic pulmonary disease from Singapore (35). Login to comment

[hide] Best practice guidelines for molecular genetic dia... Eur J Hum Genet. 2009 Jan;17(1):51-65. Epub 2008 Aug 6. Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, Cuppens H, des Georges M, Ferec C, Macek M, Pignatti PF, Scheffer H, Schwartz M, Witt M, Schwarz M, Girodon E
Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations.
Eur J Hum Genet. 2009 Jan;17(1):51-65. Epub 2008 Aug 6., [PMID:18685558]

Abstract [show]
The increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

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144 A (T)5 variant can either be associated with (TG)11, (TG)12, (TG)13, and rarely (TG)15 repeats.74 When (T)5 is found in diagnostic testing, for example, for CBAVD or atypical presentation, determination of Table 4 Classification of CFTR mutations with regard to their potential for causing disease Mutation group Examples CF-causing F508del Mainly nonsense, frameshift, splicing (invariant dinucleotide): G542X, R553X, W1282X, 2183AA4G, 3659delC, 1717-1G4A, 3120+1G4A Missense that severely affects CFTR synthesis or function: G551D, N1303K, R347P 2789+5G4A, 3849+10kbC4T, 3272-26A4G, L206Wa , D1152Ha , (TG)13(T)5a CFTR-related disorders associated L206Wa , D1152Ha , (TG)13(T)5a [R117H;(T)7], (TG)12(T)5, L997F, V562I, [R668C;G576A;D443Y], [R74W;D1270N] (TG)11(T)5b , S1235Rb No clinical consequences 875+40A4G, M470V (1540A4G), I506V (1648A4G), F508C (1655T4G), 1716G4A, 2694T4G, 4002A4G, 2752-15G4C (TG)11(T)5b , S1235Rb Unproven or uncertain clinical relevance Mainly missense mutations G622D, R170H, V938G, I125T Putative splice mutations: 406-6T4C, 2752-26A4G, 3601-17T4C Only a fraction of mutations and patients have been characterized in detail and, with the exception of frequent mutations, only small numbers of patients have been available for the study of most mutations. Login to comment

[hide] Association between cystic fibrosis transmembrane ... Yonsei Med J. 2010 Nov;51(6):912-7. Kim KW, Lee JH, Lee MG, Kim KH, Sohn MH, Kim KE
Association between cystic fibrosis transmembrane conductance regulator gene mutations and susceptibility for childhood asthma in Korea.
Yonsei Med J. 2010 Nov;51(6):912-7., [PMID:20879059]

Abstract [show]
PURPOSE: Classic cystic fibrosis is now known part of cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders. These include a wide spectrum, from multi-system disorders, such as cystic fibrosis, to mono-symptomatic conditions, such as chronic pancreatitis or congenital bilateral absence of the vas deferens. However, respiratory disease is considered typical for the multi system disorder, cystic fibrosis, and is the major cause of morbidity and mortality. The purpose of this study was to evaluate the potential effects of CFTR gene mutations in Korean children with asthma. MATERIALS AND METHODS: We selected 14 mutations identified in Korea and each of the 48 children with and without asthma were genotyped for the case-control study. RESULTS: No significant differences were found in genotype and allele frequencies of the 9 polymorphisms observed between the non-asthma and asthma groups. In a haplotype determination based on a Bayesian algorithm, 8 haplotypes were assembled in the 98 individuals tested. However, we also did not find any significant differences in haplotype frequencies between the non-asthma and asthma groups. CONCLUSION: We have concluded that this study did not show any evidence in support of providing that CFTR genetic variations significantly contribute to the susceptibility of asthma in Korean children.

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48 Among the 14 mutations, there are no mutant variants in Q98R, I125T, A309, Q220X, and Q1291X loci in our sample and the genotype frequencies of the remaining variants are listed in Table 3. Login to comment
53 CFTR Genetic Variations Analyzed in This Study Name Nucleotide change Exon Consequence Reference - 8G / C G to C at 125 5` UTR sequence variation 9 Q98R A to G at 425 Exon 4 Gln to Arg at 98 8 I125T T to C at 506 Exon 4 Ile to Thr at 125 9 E217G A to G at 782 Exon 6a Glu to Gly at 217 9 Q220X C to T at 790 Exon 6a Gln to Stop at 220 7, 8 A309A C or G at 1059 Exon 7 Sequence variation 9 TG repeat TG10-13 IVS 8 Splicing 9 T repeat T5-9 IVS 8 Splicing 9 M470V A or G at 1540 Exon 10 Met to Val at 470 9 I556V A to G at 1798 Exon 11 Ile to Val at 556 9 T854T T to G at 2694 Exon 14a Sequence variation 9 Q1291X C to T at 4003 Exon 20 Gln to Stop at 1291 9 Q1352H G to C at 4188 Exon 22 Gln to His at 1352 9 R1453W C to T at 4489 Exon 24 Arg to Trp at 1453 9 CFTR,cysticfibrosistransmembraneconductanceregulator. Login to comment
70 *pvalueswereobtainedbyusingtheχ2 testorFisher`sexacttest(expectedcellvalue<5)andtheQ98R,I125T,A309,Q220X,andQ1291X variantswereexcludedfromthetablebecauseofnofrequency. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... J Cyst Fibros. 2006 Aug;5(3):159-64. Epub 2006 Mar 6. Ngiam NS, Chong SS, Shek LP, Goh DL, Ong KC, Chng SY, Yeo GH, Goh DY
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study.
J Cyst Fibros. 2006 Aug;5(3):159-64. Epub 2006 Mar 6., [PMID:16678503]

Abstract [show]
BACKGROUND: Little is known about the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asian patients and severe asthma or idiopathic bronchiectasis. We investigated this potential relationship in the Singaporean Chinese. METHODS: Twenty patients with chronic pulmonary disease, 14 with severe asthma and 6 with idiopathic bronchiectasis, were screened for CFTR mutations by direct gene sequencing. The frequencies of identified putative mutations were compared against 40 unaffected controls and 96 unselected population samples. RESULTS: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. These alleles were also observed in the controls, but at a significantly lower allele frequency of 0.09 (P<0.01). Furthermore, the I125T mutation was significantly associated with the idiopathic bronchiectasis sub-group (P<0.05). CONCLUSIONS: The significantly higher frequency of CFTR mutations among patients with chronic pulmonary disease compared with unaffected controls suggests that these mutations may increase risk for disease. The association of I125T with idiopathic bronchiectasis alone suggests that different mutations predispose to different disease.

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4 Results: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. Login to comment
6 Furthermore, the I125T mutation was significantly associated with the idiopathic bronchiectasis sub-group ( P <0.05). Login to comment
8 The association of I125T with idiopathic bronchiectasis alone suggests that different mutations predispose to different disease. Login to comment
78 Three missense mutations (I125T in exon 4, I556V in exon 11, and Q1352H in exon 22) and one splice site variant (intron 8 12TG5T) were identified among the patients. Login to comment
83 On subgroup analysis, the I125T mutation was found to be significantly associated with idiopathic bronchiectasis but not severe asthma. Login to comment
84 Of the 6 patients with idiopathic bronchiectasis, 2 (33.3%) were heterozygous for I125T, compared to 1 in 40 normal controls (2.5%) and 2 in 96 unselected population samples (2.1%) (Table 1). Login to comment
85 In marked contrast, I125T was not observed in the severe asthma group. Login to comment
86 The I125T mutant allele frequency was 16.7% compared to 1.3% in the normal controls ( P <0.05) and an estimated population frequency of 1% ( P <0.02) (Table 2). Login to comment
93 Table 1 Frequency of CFTR gene variants in the Singaporean Chinese Variation Genotype Unselected population samples (n =93-96) Healthy controls (n =40) Severe asthma (n =14) Idiopathic bronchiectasis (n =6) I125T I125T/WT 2 1 0 2 WT/WT 94 39 14 4 I556V I556V/WT 12 4 3 0 WT/WT 84 36 11 6 Q1352H Q1352H/WT 4 1 2 0 WT/WT 91 39 12 6 12TG5T 12TG5T/Other 9 1 2 1 Other/Other 84 39 12 5 Table 2 CFTR gene variant allele frequency comparisons between patient and population and normal control groups Variation Allele Unselected population (n =186-192) Healthy controls (n =80) Severe asthma (n =28) P-value Idiopathic bronchiectasis (n =12) P-value I125T Variant 2 1 0 1.000a 2 0.018a,* Wild-type 190 79 28 1.000b 10 0.044b,* I556V Variant 12 4 3 0.415a 0 1.000a Wild-type 180 76 25 0.372b 12 1.000b Q1352H Variant 4 1 2 0.172a 0 1.000a Wild-type 186 79 26 0.163b 12 1.000b 12TG5T 12TG5T 9 1 2 0.640a 1 0.473a Other 177 79 26 0.164b 11 0.245b a P value for disease vs. unselected population. Login to comment
99 Our study identified four CFTR mutations in the population and patients, with only the I125T mutation showing a significant association with idiopathic bronchiectasis. Login to comment
108 Of the 4 mutations or variants that we found, only the I125T mutation was significant, showing an association with idiopathic bronchiectasis. Login to comment
109 Interestingly, the I125T mutation was first described in a Chinese woman and reported by Mittre in the CF Genetic Analysis Consortium [21]. Login to comment
148 There is a higher incidence of the I125T alleles in patients with idiopathic bronchiectasis. Login to comment

[hide] Targeted next-generation sequencing effectively an... Dig Dis Sci. 2015 May;60(5):1297-307. doi: 10.1007/s10620-014-3476-9. Epub 2014 Dec 10. Nakano E, Masamune A, Niihori T, Kume K, Hamada S, Aoki Y, Matsubara Y, Shimosegawa T
Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis.
Dig Dis Sci. 2015 May;60(5):1297-307. doi: 10.1007/s10620-014-3476-9. Epub 2014 Dec 10., [PMID:25492507]

Abstract [show]
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the development of cystic fibrosis, is known as a pancreatitis susceptibility gene. Direct DNA sequencing of PCR-amplified CFTR gene segments is a first-line method to detect unknown mutations, but it is a tedious and labor-intensive endeavor given the large size of the gene (27 exons, 1,480 amino acids). Next-generation sequencing (NGS) is becoming standardized, reducing the cost of DNA sequencing, and enabling the generation of millions of reads per run. We here report a comprehensive analysis of CFTR variants in Japanese patients with chronic pancreatitis using NGS coupling with target capture. METHODS: Exon sequences of the CFTR gene from 193 patients with chronic pancreatitis (121 idiopathic, 46 alcoholic, 17 hereditary, and nine familial) were captured by HaloPlex target enrichment technology, followed by NGS. RESULTS: The sequencing data covered 91.6 % of the coding regions of the CFTR gene by >/= 20 reads with a mean read depth of 449. We could identify 12 non-synonymous variants including three novel ones [c.A1231G (p.K411E), c.1753G>T (p.E585X) and c.2869delC (p.L957fs)] and seven synonymous variants including three novel ones in the exonic regions. The frequencies of the c.4056G>C (p.Q1352H) and the c.3468G>T (p.L1156F) variants were higher in patients with chronic pancreatitis than those in controls. CONCLUSIONS: Target sequence capture combined with NGS is an effective method for the analysis of pancreatitis susceptibility genes.

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90 On average, 90.3 % of the coding region was successfully covered by C20 reads Table 2 Non-synonymous CFTR variants detected in this study Exon Non-synonymous variant Amino acid change dbSNP135 Genotype SIFT (score) PolyPhen-2 (score) Alcoholic CP (%) Idiopathic CP (%) Hereditary/ familial CP (%) 2 c.91C[T p.R31C rs1800073 CT D (0.012) PD (0.989) 0/46 (0) 3/121 (2.5) 0/26 (0) 2 c.92G[A p.R31H rs149353983 GA T (0.183) B (0.003) 0/46 (0) 1/121 (0.8) 0/26 (0) 4 c.374T[C p.I125T rs141723617 TC D (0.005) B (0.17) 0/46 (0) 2/121 (1.6) 1/26 (3.8) 10 c.1231A[G p.K411E - AG D (0.015) B (0.233) 0/46 (0) 1/121 (0.8) 0/26 (0) 11 c.1408G[A p.V470M rs213950 GA T (1) B (0) 21/46 (45.7) 65/121 (53.7) 11/26 (42.3) AA 5/46 (10.9) 19/121 (15.7) 1/26 (3.8) 12 c.1666A[G p.I556V rs75789129 AG T (0.536) B (0.334) 2/46 (4.3) 8/121 (6.6) 0/26 (0) GG 0/46 (0) 0/121 (0) 0/26 (0) 13 c.1753G[T p.E585X - GT - - 1/46 (2.2) 0/121 (0) 0/26 (0) 17 c.2869delC p.L957fs - - - 0/46 (0) 1/121 (0.8) 0/26 (0) 21 c.3468G[T p.L1156F rs139729994 GT T (0.163) PD (0.994) 2/46 (4.3) 10/121 (8.3) 2/26 (7.7) TT 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.4045G[A p.G1349S rs201686600 GA D (0) PD (1) 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.4056G[C p.Q1352H rs113857788 GC D (0) PD (1) 5/46 (10.9) 11/121 (9.1) 4/26 (15.4) CC 0/46 (0) 0/121 (0) 0/26 (0) 27 c.4357C[T p.R1453W rs4148725 CT D (0) PD (0.999) 3/46 (6.5) 6/121 (5.0) 1/26 (3.8) B benign, CP chronic pancreatitis, D damaging, PD probably damaging, T tolerated, SIFT Sorting Intolerant From Tolerant heterozygous form (Table 6). Login to comment
122 This is also the case with the c.374T[C (p.I125T) variant. Login to comment
124 This p.I125T variant was originally reported in Chinese patients with idiopathic bronchiectasis and considered to be associated with CFTR-RD [35]. Login to comment
143 One patient was trans-heterozygous for the CTRC p.R29Q and CFTR p.I125T/p.L1156F variants. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... J Cyst Fibros. 2015 Sep;14(5):661-7. doi: 10.1016/j.jcf.2015.03.009. Epub 2015 Apr 11. Chang MC, Jan IS, Liang PC, Jeng YM, Yang CY, Tien YW, Wong JM, Chang YT
Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment.
J Cyst Fibros. 2015 Sep;14(5):661-7. doi: 10.1016/j.jcf.2015.03.009. Epub 2015 Apr 11., [PMID:25869325]

Abstract [show]
BACKGROUND: Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis. To date, the association of CFTR gene variants with AIP has not been studied. METHODS: The entire coding and intronic regions of the CFTR gene were examined using next-generation sequencing in 89 AIP patients. Clinical features, including imaging, histology, serology, steroid treatment response and extra-pancreatic involvement, were compared between AIP patients with and without CFTR gene variants. RESULTS: A total of 28.1% (25/89) of the AIP patients carried 26 CFTR variants, including nine with I556V, seven with 5T, four with S42F, two with I125T, and one each with R31C, R553X, S895N, and G1069R. The presence of CFTR variants and age was independent predictors of the response to steroid treatment, as shown by multivariate analysis. CONCLUSIONS: CFTR variants are associated with AIP. Because AIP patients with CFTR variants show slower and reduced steroid treatment responses, different treatments should be considered in AIP patients with CFTR variants.

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8 Results: A total of 28.1% (25/89) of the AIP patients carried 26 CFTR variants, including nine with I556V, seven with 5T, four with S42F, two with I125T, and one each with R31C, R553X, S895N, and G1069R. Login to comment