ABCMdb

ABCC7 p.Arg31Cys

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Publications

PMID: 10601093 [PubMed] Pallares-Ruiz N et al: "Complete mutational screening of the cystic fibrosis transmembrane conductance regulator gene: cystic fibrosis mutations are not involved in healthy men with reduced sperm quality."

No. Sentence Comment

63 Frequency distribution of CFTR gene variants in populations from southern France infertile men with OAT and in controls (T)n-1540A/G-(TG)n Controls OAT PVariants Allele frequency, % of chromosomes (n ϭ 50) (n ϭ 56) Controls CBAVDa OAT 9/9 A/A 10/10 1 (2) 1 (2) NS(n ϭ 100) (n ϭ 100) (n ϭ 112) 7/9 A/A 10/12 1 0 11/10 0 1223C/T (R31C) 0.01 0 0 10/10 0 3356G/A (R75Q) 0.02 0.01 0.009 Total 1 (2) 4 (7) NS1655T/G (F508C) 0 0.01 0.009 7/9 A/G 11/10 2 41716 G/A (E528E) 0 0.01 0.018 10/12 5 21859G/C (G576A)ϩ2134C/T 0.01 0.04c 0.009 7 (14) 6 (11) NS(R668C)b 7/7 A/A 12/12 0 12377C/T (L749L) 0 0.01d 0.009 11/12 1 03417A/T (T1095T) 0.01 0 0.018 10/11 3 03419T/G (L1096R) 0.01 0 0 10/10 1 44002A/G (P1290P) 0.01 0 0.018 Total 5 (10) 5 (9) NS4404C/T (T1424T) 0.01 0.01 0.018 7/7 A/G 12/12 0 2125G/C (5ЈUTR) 0.07 0.01 0.027 11/12 0 3405ϩ46G/T 0 0 0.018 11/11 5 0406-6T/C 0.01 0 0 10/11 3 3875ϩ40A/G 0.05 0.06 0.045 10/10 8 03041-71G/Cϩ4002A/Gb 0.02 0.02 0.009 Total 16 (32) 8 (14) NS3499ϩ37G/A 0 0 0.009 7/7 G/G 11/11 16 (32) 31 (55) Ͻ 0.024374ϩ13A/G 0 0 0.009 8/11 0 1 Total 16 (32) 32 (57) 0.018aGroup of CBAVD patients whose genotypes had been previously analysed 7/5 A/G 11/11 2 (4) 0 -in our laboratory. Login to comment
75 Several missense variations identified in this study (R31C, R75Q, F508C, G576A, R668C, or E528E) have previously Table IV. Login to comment

PMID: 10746558 [PubMed] Bombieri C et al: "A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals."

No. Sentence Comment

79 Out of the 20 missense mutations, three (G85E, ∆F508, and N1303K) are certainly CF-causing, and several (R31C, K68E, R75Q, I148T, V562L, G576A-R668C, L997F, F1052V, S1235R) have been described in congenital bilateral absence of the vas deferens, in disseminated bronchiectasis, in pancreatitis, or in atypical CF cases mutations as reported in the CFGAC website (). Login to comment
80 Many (13 out of 20) of the missense mutations change highly conserved (5/5 species analyzed) amino acid residues (R75Q, G85E, I148T, I506V, R668C, G622D, L997F, I1027T, F1052V, L1096R, I1131V, R1162L, N1303K); others affect amino acid residues conserved in 4/5 species (K68 E, R170H, M470V, V562L, S1235R), or in 3/5 species (R31C and G576A; Tucker et al. 1992). Login to comment
96 Moreover, 1525-61 A/G (i 9) and 3601-65 C/A (i 18) were detected by SSCA performed in the Spanish sample only (14/82 and 12/80, respectively); these mutations were not identifiable by DGGE as used in the present work The totals are: a378; b362; c380; d356 genes eCertainly a CF-causing mutations fThe most common allele at this site is (TTGA)7 gThe most common allele at this site is T7 hThe frequency shown is that of the M allele Mutation Position North-Central Southern Spain Total East Italy Italy France 82 genes 100 genes 100 genes 100 genes 382 genes % 125 G/C 5`UTR 1 2 7 3 13 3.4 R31C 2 1 1 1 0 3 0.8 K68E 3 1 0 0 0 1 0.3 R75Q 3 1 1 2 0 4 1.0 G85Ee 3 0 1 0 0 1 0.3 406-6 T/C i 3 0 0 1 0 1 0.3 I148T 4 1 0 0 0 1 0.3 621+3 A/G i 4 0 1 0 0 1 0.3 R170H 5 1 0 0 0 1 0.3 875+40 A/G i 6a 11 5 5 2 23 6.0 (TTGA)6 f i 6a 17 11 7 13 48 12.6 1341+28 C/T i 8 1 0 0 0 1 0.3 IVS8-6g T5 i 8 8 2 4 3/78 17a 4.5 IVS8-6g T9 i 8 10 7 10 11/78 38a 10.0 M470Vh 10 42 30 39 27 138 36.1 I506V 10 1 0 0 0 1 0.3 ∆F508e 10 1 0 2 0 3 0.8 1716 G/A 10 2 1 0 5 8 2.1 V562L 12 0 0 1 0 1 0.3 G576A 12 1 0/80 1 0 2b 0.6 G622D 13 0 0/80 1 0 1b 0.3 R668C 13 1 0/80 1 0 2b 0.6 2082 C/T 13 1 0/80 0 0 1b 0.3 2377 C/T 13 0 0/80 0 1 1b 0.3 2694 T/G i 14a 33 23 33 14/80 103c 27.1 2752-15 C/G i 14b 0 3 0 0 3 0.8 3041-71 G/C i 15 0 1 2 0 3 0.8 L997F 17a 0 2 0 0 2 0.5 I1027T 17a 1 0 0 0 1 0.3 F1052V 17b 1 0 0 0 1 0.3 L1096R 17b 0 0 1 0 1 0.3 3417 A/T 17b 1 0 1 0 2 0.5 I1131V 18 0 1 0 0 1 0.3 R1162L 19 0 1 0 0 1 0.3 3690 A/G 19 0 0 0 1/80 1c 0.3 S1235R 19 1 0 0 0 1 0.3 4002 A/G 20 2 3 3 3/80 11c 2.9 4005+28insA i 20 0 1 0 0 0.3 4029 A/G 21 1 0 0 0 1 0.3 N1303Ke 21 1 0 0 0 1 0.3 4404 C/T 24 1 0 1 0 2 0.5 4521 G/A 24 21 16 14/80 15/76 66d 18.5 Total 165 113 137 98 513 encountered in the present survey are possible. Login to comment
115 The density of polymorphic sites, which is essentially the proportion of sites susceptible to evolving among the total number of sites (bp) of that gene, can be estimated by counting the number n of polymorphic sites existing in 177 Table 4 A list of the 13 ED-C mutations detected in this survey Mutation q±SE q-2.5SE 125 G/C 0.0340±0.0093 0.011 875+40 A/G 0.0602±0.0122 0.030 876-5 (GATT)6 0.1257±0.0170 0.083 IVS8 T5 0.0450±0.0107 0.018 IVS8 T9 0.1005±0.0155 0.062 IVS8 (TG)10 0.2900±0.0262 0.223 IVS8 (TG)12 0.0867±0.0162 0.046 1525-61 A/Ga 0.1750±0.0420 0.070 M470V 0.3613±0.0246 0.300 2694 T/G 0.2711±0.0228 0.214 3601-65 C/Aa 0.1500±0.0399 0.050 4002 A/G 0.0289±0.0086 0.007 4521 G/A 0.1854±0.0206 0.134 aSearched by SSCA in the sample of 40 Spanish individuals only: frequency and standard error are those of that sample Table 5 Distribution in the four subsamples of mutations found a few times but not classified Total number of Subsample times the mutation has been found NE Italy Central Southern Spain Italy France Twice G576A 1 - 1 - R668C 1 - 1 - L997F - 2 - - 3417 A/T 1 - 1 - 4404 C/T 1 - 1 - Three times R31C 1 1 1 - 2752-15 C/G - 3 - - 3041-71 G/C - 1 - Four times R75Q 1 1 2 - Eight times 1716 G/Aa 2 1 - 5 aGiven its frequency and distribution, this mutant will probably turn out to be a C mutant the stretch under study of N bp and dividing n by N. Usually, the number of sites identified as polymorphic sites is merely a minimum estimate of the total number n of polymorphic sites of the N stretch, because the number of polymorphic sites of the stretch that escaped detection remains unknown. Login to comment

PMID: 12452372 [PubMed] Gaia E et al: "Germline mutations in CFTR and PSTI genes in chronic pancreatitis patients."

No. Sentence Comment

56 All mutations (W1282X, N187K, R352Q, ⌬F508, R75Q, R31C, 621ϩ2T-ϾG, I197V, K68N, R1162X) were found in heterozygotes, indicating that these patients are carriers of a single mutation. Login to comment
78 PATIENTS CARRYING THE CFTR MUTATION* Pt Sex Age (yr) Age at onset (yr) Alcohol (g/day)† Familial CFTR mutations Exocrine insufficiency Diabetes mellitus(Յ10) (10-40) (40-80) T.B. M 59 23 (Յ10) No W1282X Yes No B.G. M 40 29 (Յ10) Yes N187K No No E.P. M 40 34 (Յ10) No R352Q No Yes D.N. M 53 47 (10-40) No R75Q Yes No R.L. F 57 44 (Յ10) No R31C No No T.F. M 56 *‡ (Յ10) No 621 ϩ 2T 3 G Yes No F.G. M 54 46 (10-40) No I197V Yes No V.M. M 65 *† (10-40) No K68N Yes No B.L. F 57 56 (10-40) Yes ⌬F508 No Yes T.G. M 25 24 (Յ10) No R1162X No No *This table shows the characteristics of chronic pancreatitis patients, carriers of CFTR mutations. Login to comment
88 Four mutations were found in patients with mild forms of CF (R31C, K68N, R75Q, and R352Q). Login to comment

PMID: 14526128 [PubMed] Bernardino AL et al: "CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients."

No. Sentence Comment

68 A total of 13 changes were found: 7 in the CFTR gene (∆F508/R851L, ∆F508/R170C, ∆F508/L206W, 2 N/∆F508, N/P205S, N/R31C and N/V920M), 2 in the PRSS1 gene (E79K and N246N) and 4 in the SPINK1 gene (-253T>C, -164G>C, -7T>G, c75C>T) (Table 1). Login to comment
69 The CFTR Gene Molecular analysis showed that 8 patients (9.8%) had mutations in the CFTR gene: 3 were compound heterozygotes (∆F508/R851L, ∆F508/R170C and ∆F508/L206W) and 5 had mutations on just one allele (2 N/∆F508, N/P205S, N/R31C and N/V920M). Login to comment
72 One (∆F508/R851L) referred only bronchitis in childhood and the last two (N/∆F508 and N/V920M) had no other additional signs. Three of the 64 patients (4.7%) with alcohol-related chronic pancreatitis but with no pulmonary problems also had CFTR mutations: N/∆F508, N/R31C and compound heterozygote ∆F508/R170C. None of these 3 patients reported azoospermia. Login to comment
78 Gene Localization Mutation Polymorphism Frequency in patients' chromosomes Frequency in controls' chromosomes P value Exon 2 R31C 1/164 (0.6%) - - Exon 5 R170C 1/164 (0.6%) - - P205S 1/164 (0.6%) - -Exon 6 L206W 1/164 (0.6%) - - Exon 10 ∆F508 5/164 (3.0%) - - Exon 14a R851L 1/164 (0.6%) - - CFTR Exon 15 V920M 1/164 (0.6%) - - Exon 3 E79K 1/164 (0.6%) 1/300 (0.3%) 1.000a PRSS1 Exon 5 N246N 47/164 (28.7%) 85/300 (28.3%) 1.000b -253T>C 20/164 (12.2%) 20/400 (5.0%) 0.004b Promoter -164G>C 4/164 (2.4%) 13/400 (3.3%) 0.788a Exon 1 -7T>G 5/164 (3.0%) 8/300 (2.7%) 0.777a SPINK1 Exon 2 c75C>T 1/164 (0.6%) 3/300 (1.0%) 1.000a a Fisher's exact test b Yates' corrected chi-squared test alcohol-related chronic pancreatitis, but with no family history. Login to comment
94 Molecular analysis showed that 9.8% of the total group of patients had mutations in the CFTR gene: 3 were compound heterozygotes (∆F508/R851L, ∆F508/R170C and ∆F508/L206W) and 5 had mutations on just one allele (2 N/∆F508, N/P205S, N/R31C and N/V920M). Login to comment
98 One (∆F508/R851L) referred only bronchitis in childhood and the last two (N/∆F508 and N/V920M) had no other additional signs. Three (4.7%) of the 64 patients with alcohol-related chronic pancreatitis but with no pulmonary problems also had CFTR mutations: N/∆F508, N/R31C and compound heterozygote ∆F508/R170C. None of these 3 patients reported azoospermia. Login to comment

PMID: 15536480 [PubMed] Modiano G et al: "A large-scale study of the random variability of a coding sequence: a study on the CFTR gene."

No. Sentence Comment

33 In the Tajima`s test,19 the null hypothesis of neutrality is rejected if a statistically significant difference between p Common and rare nonsynonymous and synonymous cSNSs G Modiano et al European Journal of Human Genetics Table 1 List of the 61 cSNSsa encountered in the present survey The random samples of genes (and the technique utilized) cSNS variants found NE Italy (DGGE) Central Italy (DGGE) Southern France (DGGE) Northern France (DHPLC) Spain (SSCA) Czechia (DGGE) Hb Â 104 Exon Exon Length (bp) Ref. no. SNS SASc 1st 100d 2nd 500 1st 100d 2nde 1st 100d 2nd 500 1st 100 2nde 82d 72 Abs. Freq. Total sample size q Â 104 se Â 104 NSf Sf 1g 53 0 0 0 0 0/452 0 924 2 111 1 223C4T R31C 1 1 1/500 1 1 0 0/450 0 5 (11) 1 932 (2 432) 45.23 13.61 90 2 224G4T R31L 0 0 0/500 0 0 0 1/450 0 1 1 932 5.17 5.17 10 3 257C4T S42F 0 0 1/500 0 0 0 0/450 0 1 1 932 5.17 5.17 10 3 109 4 334A4G K68E 1 0 0 0/498 0 0 0 0/452 0 0 1 2 504 3.99 3.99 8 5 352C4T R74W 0 0 0 0/498 0 0 0 1/452 0 0 1 2 504 3.99 3.99 8 6 356G4A R75Q 1 7 1 7/498 2 9 2 9/452 0 2 40 (40) 2 504 (2 544) 157.23 24.66 310 7 386G4A G85E 0 0 1 1/498 0 0 0 0/452 0 0 2 2 504 7.99 5.65 16 4 216 8 482G4A R117H 0 0 0 0/292 0 2 0 1/456 0 0 3 2 302 13.03 7.52 26 9 528T4G I132M 0 0 0 0/292 0 0 0 1/456 0 0 1 2 302 4.34 4.34 8 10 575T4C I148T 1 2 0 1/292 0 0 0 1/456 0 1 6 2 302 26.06 10.63 52 5 90 11 640C4T R170C 0 0 0 0/6 0 0 1/448 0 1 1 436 6.96 6.96 14 12 641G4A R170H 1 1 0 0/6 0 0 2/448 0 4 (4) 1 436 (1 930) 20.73 10.35 41 6a 164 0 0 0/6 0 0 0/432 0 0 992 6b 126 0 0 0/6 0 0 0/454 0 942 7 247 0 0 0/6 0 0 0/796 0 1 284 8 93 13 1281G4A L383 0 0 0 0/6 0 0 1/456 0 0 1 1 516 6.60 6.60 13 9 183 14 1402G4A G424S 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 15 1459G4T D443Y 0 0 0/6 0 0 1/454 0 1 940 10.64 10.64 21 10 192 16 1540A4G M470Vh 42 197 30 37/96 39 199 (i) (i) 27 571(736) 1 484 (1 912) 3849.37 111.28 4 735 17 1598C4A S489X 0 0 0 0/96 0 0 0 1/796 0 1 2 374 4.21 4.21 8 18 1648A4G I506V 1 0 0 0/96 0 0 0 0/796 0 1 2 374 4.21 4.21 8 19 1655T4G F508C 0 1 0 0/96 0 0 0 1/796 0 2 2 038 8.42 5.96 17 20 1716G4A Q528 2 16 1 0/96 0 19 i I 5 43 (58) 1 478 (2 024) 286.56 37.08 557 11 95 21 1756G4T G542X 0 2 0 0/134 0 0 0/796 0 0 2 1 984 10.08 7.12 20 22 1764T4G G544 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 23 1784G4A G551D 0 0 0 0/134 0 0 1/796 0 0 1 1 984 5.04 5.04 10 12 87 24 1816G4A V562I 0 0 0 0 1 0 0/450 0 0 1 (1) 2 004 (2 504) 3.99 3.99 8 25 1816G4C V562L 0 0 0 1 0 0 1/450 0 0 2 (3) 2 004 (2 504) 11.98 6.91 24 26 1859G4C G576A 1 2 0 1 11 0 8/450 0 0 23 (27) 2 004 (2 538) 106.38 20.36 213 13 724j 449 27 1997G4A G622D 0 0 0/80 0/96 1 0 0 0/444 0 1 2 002 5.00 5.00 10 28 2082C4T F650 1 0 0/80 0/20 0 0 0 0/444 0 1 (1) 1 926 (2 412) 4.15 4.15 8 29 2134C4T R668C 1 2 0/80 0/96 1 11 0 12/444 0 27(32) 2 002 (2 558) 125.10 21.98 247 275 30 2377C4T L748 0 0 0/6 0 1 1 388 25.77 25.77 52 14a 129 31 2670G4A W846X 0 0 0/6 0 1 0/452 0/80 0 1 1 010 9.90 9.90 20 32 2694T4G T854 33 23 0/6 33 38 149/452 14/80 11 301 1 010 2980.20 143.92 4 184 33 2695G4A V855I 0 0 0/6 0 0 1/452 0/80 0 1 1 010 9.90 9.90 20 14b 38 0 0 0 0/520 0 0 0 0/446 0 2 448 15 251 34 2816G4C S895T 0 0 0/6 0 0 2/436 0 0 2 996 20.08 14.18 40 35 2831A4C N900T 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 36 2988G4C M952I 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 37 3030G4A T966 (2)k (1)k 0 6/436 0 6 (25)k 618 (1814)k 137.82 27.37 272 38 3032T4C L967S 0 0 0/6 0 0 1/436 0 0 1 996 10.04 10.04 20 16 80 0 0 0/498 0 0 0/450 0 0 1 502 17a 151 39 3123G4C L997F 0 2 2 1/494 0 7 1 4/454 0 0 17 2 502 67.95 16.42 135 40 3157G4A A1009T 0 2 0 0/494 0 0 0 0/454 0 0 2 2 502 7.99 5.65 16 41 3212T4C I1027T 1 0 0 0/494 0 0 0 0/454 0 0 1 2 502 4.00 4.00 8 17b 228 42 3286T4G F1052V 1 1 0 1/194 0 0 0 0/452 0 0 3 (3) 2 200 (2 240) 13.39 7.73 27 43 3337G4A G1069R 0 1 0 0/194 0 0 0 0/452 0 0 1 2 200 4.55 4.55 9 CommonandrarenonsynonymousandsynonymouscSNSs GModianoetal 186 EuropeanJournalofHumanGenetics 44 3345G4T Q1071H 0 0 0 0/194 0 1 0 0/452 0 0 1 2 200 4.55 4.55 9 45 3417A4T T1995 1 3 0 0/194 1 1 0 0/452 0 0 6 (8) 2 200 (2 506) 31.92 11.27 64 46 3419T4G L1096R 0 0 0 0/194 1 0 0 0/452 0 0 1 2 200 4.55 4.55 9 47 3477C4A T1115 0 0 0 0/194 0 0 0 1/452 0 0 1 2 200 4.55 4.55 9 18 101 48 3523A4G I1131V 0 0 1 0/10 0 0 0/448 0 0 1 (2) 1 512 (1 908) 10.48 7.07 21 49 3586G4C D1152H 0 0 0 0/10 0 0 1/448 0 0 1 1 512 6.61 6.61 13 19 249 50 3617G4T R1162L 0 0 1 1/494 0 0/260 0 0/454 0 0 2 2 262 8.84 6.25 18 51 3690A4G Q1186 0 0 0 0/494 0 0/260 0 0/454 1 0 1 2 262 4.42 4.42 9 52 3813A4G L1227 0 1 0 0/494 0 0/260 0 0/454 0 0 1 2 262 4.42 4.42 9 53 3837T4G S1235R 1 1 0 1/494 0 4/260 0 7/454 0 1 15 (15) 2 262 (2 310) 69.94 16.71 140 20 156 54 4002A4G P1290 2 3 0/6 3 5 18/454 3/80 2 36 1 012 357.73 58.22 690 21 90 55 4009G4A V1293I 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 56 4029A4G T1299 1 0 0/6 0 1/300 0 1/456 0 0 3 (8) 1 316 (2 330) 34.33 12.12 69 57 4041C4G N1303K 1 0 0/6 0 0/300 0 0/456 0 0 1 1 316 7.60 7.60 15 58 4085T4C V1318A 0 0 0/6 0 0/300 0 1/456 0 0 1 1 316 7.60 7.60 15 22 173 0 0 0/18 0 0 0/450 0 0 1 022 23 106 0 0 0 0/6 0 0 0/448 0 1 436 24l 198+3 59 4404C4T Y1424 1 0 0/6 1 2 5/420 0 2 11 (32) 980 (2 516) 127.19 22.34 251 60m 4521G4A Q1463 (21) (16) (3/32) (14/80) (30) (94/420) 15/76 (17) 15 (227) 76 (1052) 2142.86 131.07 3 367 61 4563T4C D1477 0 0 0/6 0 1 0/420 0 0 1 980 10.20 10.20 20 Totals 6 525 9 584 16 109 The bracketed figures include also the RFLP analysis data (see Materials and methods); the NE Italy, Central Italy, Southern and Northern France are each subdivided into two samples where the 1st is made up of 100 genes. 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PMID: 15987793 [PubMed] Weiss FU et al: "Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls."

No. Sentence Comment

237 In the group of ICP patients being heterozygous for a single CFTR mutation one severe (2184insA, this insertion causes a frame shift) and eight mild/uncommon mutations (26 S1235R, R31C, R75Q, R347P, G576A, M348V, and V754M) were identified. Login to comment
256 The reason why numbers for compound heterozygous ICP patients in these studies are diverse (4/67 = 6% in our study) may be due to differences Table 1 CFTR and SPINK1 sequence variations identified in 30 of the 67 ICP patients PatientSex CFTR mutation T allele TG repeats PSTI mutation 1 M DF508/R117H 7/7 9/10 -/- 2 W DF508/A1087P 7/9 10/11 -/- 3 M DF508/D1152H 7/9 10/10 -/- 4 M S1235R/R668C 7/7 11/12 -/- 5 M 2184insA/- 7/7 10/12 -/- 6 M R31C/- 7/7 10/11 -/- 7 M R75Q/- 7/7 11/11 -/- 8 M R347P/- 7/7 11/12 -/- 9 M S1235R/- 7/7 11/12 -/- 10 W S1235R/- 7/7 11/12 -/- 11 M G576A/- 7/7 10/10 -/- 12 W M348V/- 7/9 10/10 -/- 13 M V754M/- 7/7 10/11 -/- 14 M -/- 5/7 11/12 -/- 15 W -/- 5/7 11/12 -/- 16 M -/- 5/7 11/12 -/- 17 W -/- 5/9 11/12 -/- 18 M -/- 5/7 11/12 -/- 19 M -/- 5/7 10/10 -/- 20 W -/- 5/7 10/10 -/- 21 W -/- 5/7 11/12 N34S/- 22 W -/- 7/7 10/11 N34S/- 23 M -/- 7/9 10/11 N34S/- 24 M -/- 7/7 11/11 N34S/- 25 M -/- 7/7 11/11 N34S/- 26 W -/- 7/7 11/11 N34S/- 27 M -/- 7/7 11/11 N34S/- 28 W -/- 7/7 10/11 N34S/- 29 W -/- 7/7 11/11 P55S/- 30 W -/- 7/7 11/11 IVS3+2TC/- Table 2 CFTR sequence variations identified in 11 of 60 healthy controls Control group Number DF508/- 3 R117H/- 2 I148T/- 1 L997F/- 1 5T/12TG 1 5T/11TG 3 in patient recruitment, the catchment populations, or the stringency with which cystic fibrosis patients were excluded. Login to comment

PMID: 16251901 [PubMed] Pompei F et al: "Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations."

No. Sentence Comment

30 The T2A rate was much lower than 1 Frequencies of the CFTR variants within the M or the V alleles exon or intron VARIANT SITES in the M genes (MM subjects) in the V genes (VV subjects) A 5' UTR 125 g/c 8/144 (0.056) 3/356 (0.008) -80 1 2 R31C 5/226 (0.004) 1/576 (0.002) -56 in M genes in V genes 6 2 R75Q 1/226 (0.004) 15/576 (0.026) -51 M V (ttga)n 0.461 0.017 7 3 G85E 0/226 (0) 1/576 (0.002) -51 2.214 0.362 (tg)n 0.616 0.114 B i 3 406-6 t/c 0/226 (0) 6/576 (0.010) -29 (t)n 0.499 0.036 8 4 R117H 2/226 (0.009) 0/576 (0) -29 10 4 I148T 3/224 (0.013) 0/576 (0) -29 C i 4 621+3 a/g 1/224 (0.004) 0/576 (0) -29 12 5 R170H 1/158 (0.006) 0/402 (0) -26 D i 6a 875+40 a/g 6/36 (0.167)c 0/118 (0)c -25 i 6b (ttga)6 13/36 (0.361) 1/118 (0.008) -23 E i 6b 1001+11 c/t 5/60 (0.083) 0/166 (0) -23 F i 8 1341+28 c/t 1/152 (0.007) 0/464 (0) -18 i 8 (tg)10 39/76 (0.513) 5/218 (0.023) -11 i 8 (tg)11 21/76 (0.276) 205/218 (0.940) -11 i 8 (tg)12 16/76 (0.211) 8/218 (0.037) -11 i 8 t5 4/76 (0.053) 2/218 (0.009) -11 i 8 t7 48/76 (0.632) 214/218 (0.982) -11 i 8 t9 24/76 (0.316) 2/218 (0.009) -11 16 10 M470V H ex 10 F508del 3/226 (0.013) 0/572 (0) 0 19 10 F508C 0/226 (0) 1/572 (0.002) 0 20 10 1716g/a 15/226 (0.066) 0/572 (0) 0 21 11 G542X 1/158 (0.006) 0/400 (0) +28 24 12 V562I 1/226 (0.004) 0/576 (0) +30 25 12 V562L 1/226 (0.004) 0/576 (0) +30 26 12 G576A 3/226 (0.013) 0/576 (0) +30 28 13 2082c/t 1/104 (0.010) 0/226 (0) +32 29 13 R668C 3/224 (0.013) 0/562 (0) +32 32 14a 2694t/g 45/70 (0.643) 9/208 (0.043) +35 I i 14a 2752-15 c/g 0/226 (0) 5/576 (0.009) +44 37 15 3030g/a 1/158 (0.006) 7/402 (0.017) +44 O i 15 3041-71 g/c 5/226 (0.022) 0/576 (0) +47 39 17a L997F 1/226 (0.004) 4/576 (0.007) +51 40 17a A1009T 0/226 (0) 1/572 (0.002) +51 42 17b F1052V 1/226 (0.004) 0/572 (0) +52 43 17b G1069R 1/226 (0.004) 0/572 (0) +52 44 17b Q1071H 1/226 (0.004) 0/572 (0) +52 45 17b 3417a/t 0/226 (0) 4/572 (0.007) +52 46 17b L1096R 1/226 (0.004) 0/572 (0) +52 52 19 3813a/g 0/118 (0) 1/484 (0.002) +68 53 19 S1235R 3/100 (0.030) 0/294 (0) +68 54 20 4002a/g 5/56 (0.089) 1/168 (0.006) +83 q in the M alleles q in the V alleles 56 21 4029a/g 0/194 (0) 3/506 (0.006) +93 57 21 N1303K 1/92 (0.011) 0/272 (0) +93 59 24 4404c/t 3/226 (0.013) 14/576 (0.024) +107 60 24 4521g/a 21/56 (0.375) 2/172 (0.012) +107 "slow evolution" markers "fast evolution" markers (i.e. STRs) H is the sum of the degrees of heterozygosity of all the markers Ref.No.a ABSOLUTE AND RELATIVE FREQUENCIES distance from the M470V siteb (Kb) H associated with the…. Login to comment

PMID: 16339147 [PubMed] Jurkuvenaite A et al: "Mutations in the amino terminus of the cystic fibrosis transmembrane conductance regulator enhance endocytosis."

No. Sentence Comment

1 In the present studies, two naturally occurring cystic fibrosis mutations in the amino terminus of CFTR, R31C, and R31L were examined. Login to comment
8 Together, the results suggest that both R31C and R31L mutations compromise biogenesis and enhance internalization of CFTR. Login to comment
25 In the present studies, we examined two naturally occurring mutations, R31C and R31L, which cause mild CF.3 To determine the defects caused by these missense mutations, we expressed them in COS-7 cells and analyzed their biogenesis and trafficking. Login to comment
26 Our results indicate that both R31C and R31L have compromised biogenesis and enhanced endocytosis compared with wild-type CFTR. Login to comment
29 MATERIALS AND METHODS Construction of CFTR Mutants-The R31C and R31L mutants were prepared by PCR mutagenesis. Login to comment
32 Using the CFTR gene contained in plasmid pCDNA3.1ϩ as template, the R31L and R31C mutants were constructed by PCR-mutagenesis using a pair of internal primers for each mutant, annealing at the Arg-31 coding site, and a pair of external primers, one annealing at the Nhe-I site of the multilinker of the vector, and one annealing at the BspE-I site in the CFTR gene. Login to comment
96 EC, extracellular; IC, intracellular; L/C, R31L and R31C mutations. Login to comment
102 With the R31C and R31L mutants, however, very little processing occurredduringthefirst2hofchase(0and4.7 Ϯ 1.5%,respectively).By4h, 10.3 Ϯ 3.0% (R31C) and 11.3 Ϯ 2.1% (R31L) of CFTR was converted to the mature form, indicating that, although there is a processing defect, it does not cause complete inhibition. Login to comment
106 The results indicate that the protein half-life of the wild-type protein is 13.3 Ϯ 1.2 h, and the R31C and R31L half-lives are 12.7 Ϯ 0.6 and 14.3 Ϯ 3.1 h, respectively, indicating that, FIGURE 3. Login to comment
108 Wild-type, R31C, and R31L CFTR half-lives were determined in COS-7 cells 24 h after transfection. Login to comment
111 A, representative gels of wild-type (WT), R31C, and R31L CFTR half-lives are shown. Login to comment
115 Protein maturation of R31C and R31L CFTR is inefficient compared with wild-type CFTR. Login to comment
120 A, representative metabolic labeling experiments are shown for wild type (WT), R31C, and R31L (left panels). Login to comment
126 Maturation efficiencies of wild type, R31C, and R31L were calculated after 4 h of chase (average Ϯ S.D., n ϭ 3; *, p Ͻ 0.005; **, p Ͻ 0.001). Login to comment
127 C, R31C (C) and R31L (L) are not temperature-sensitive. Login to comment
128 WT, R31C and R31L CFTR were immunoprecipitated from COS-7 cells 48 h after transfection. Login to comment
131 A 27 °C incubation increased the amount of B band but did not influence C band production for R31C or R31L CFTR. Login to comment
133 Reduced Surface Expression of R31C and R31L-Because some mutant protein was processed correctly and the protein half-life appeared normal, the surface pool of the Arg-31 mutants was examined next. Login to comment
136 For the R31C and R31L mutants, however, staining was much more restricted to an intracellular, reticular pattern. Login to comment
138 To confirm this observation, cells expressing wild-type, R31C, and R31L CFTR were surface-biotinylated (Fig. 4B), CFTR was immunoprecipitated, and the biotinylated fraction was detected by Western blot analysis. Login to comment
139 The results indicate that the surface pool of the R31C and R31L mutants is 20.3 Ϯ 7.5 and 33.6 Ϯ 11.7% of the wild-type protein, respectively (n ϭ 4, p Ͻ 0.005, and p Ͻ 0.05, respectively. Login to comment
141 R31C and R31L Are Internalized More Rapidly than the Wild-type CFTR-Because the surface pool was smaller than predicted, we next tested whether the mutations affected CFTR clearance from the cell surface. Login to comment
145 The R31C and R31L mutants, however, have dramatically altered internalization kinetics with 54 Ϯ 4 and 55 Ϯ 13.9% of the R31C and R31L mutants, respectively (internalized during the same warm-up period). Login to comment
147 The Functional Activity of the R31C and R31L Mutants Is Severely Compromised-As a final measure of the total CFTR chloride channels at the cell surface, we tested the functional activity of the R31C and R31L mutants in two complementary functional assays, macroscopic patch clamp experiments and SPQ assays. Login to comment
152 Cells transfected with the R31L and R31C mutants exhibited two differences as compared with wild-type-transfected cells. Login to comment
157 R31C and R31L surface expression is lower than wild-type CFTR. Login to comment
158 A, wild-type, R31C, and R31L CFTR distributions were examined in COS-7 cells 48 h after transfection using indirect immunofluorescence. Login to comment
160 Arrows indicate the prominant cell surface expression of the wild-type protein CFTR and the diminished amount of surface staining in the R31C and R31L CFTR-expressing cells. Login to comment
165 Internalization of the R31C and R31L CFTR mutants is dramatically enhanced compared with the wild-type protein. Login to comment
166 A, wild-type, R31C, and R31L CFTR internalization in COS-7 cells. Login to comment
181 DISCUSSION The R31C and R31L are naturally occurring missense CF mutations that appear to have a mild phenotype (31).3 Both of these mutations are rare (identified once in 284 CF chromosomes, for the R31L mutation). Login to comment
182 The R31C mutation was found in a 45-year-old male CF patient diagnosed in childhood who was pancreatic-sufficient with moderate pulmonary symptoms and a positive sweat test. Login to comment
194 R31C and R31L mutants have diminished channel activity compared with the wild-type protein. Login to comment
195 A-C, representative current traces for wild-type (WT) and R31C and R31L mutants. Login to comment
204 Note that the data for the L and C mutants overestimate their functional activities, because unlike WT, most excised mutant patches exhibited undetectable CFTR activity and were excluded from this analysis (R31L, 4 active patches of 13 total; R31C, 4 active patches of 19 total; wild type, 4 active patches of 6 total). Login to comment
206 E, functional analysis of wild-type and R31C and R31L CFTR using SPQ fluorescence. Login to comment
207 The change in SPQ fluorescence is shown for COS-7 cells expressing wild-type, R31C, and R31L CFTR. Login to comment
232 Analysis of the ⌬F508, N287Y, and R31L and R31C indicate that alterations in the transport of CFTR at the cell surface, whether it is enhanced internalization or compromised recycling, can result in a disease phenotype. Login to comment

PMID: 17098864 [PubMed] Roxo-Rosa M et al: "Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms."

No. Sentence Comment

180 Jurkuvenaite et al. (42) recently studied R31C and R31L, two CF mutations in the N terminus of CFTR that affect the first AFT (R29QR31). Login to comment

PMID: 17575549 [PubMed] Dray X et al: "Association of pancreas divisum and recurrent acute pancreatitis with the IVS8-5T-12TG allele of the CFTR gene and CFTR dysfunction."

No. Sentence Comment

34 Genetic testing showed no mutation in the cationic trypsinogen gene and found the R31C and IVS8-5T-12TG variants in the CFTR gene. Login to comment
65 Sweat Chloride Concentrations, NPD, Respiratory Function, and CFTR mutations Test Patient 1 Patient 2 Sweat chloride concentration (mM) Test 1 11 48 Test 2 11 81 NPD (mV) Basal j21 j16 $Amil 9 3 $Clj /Amil j7 j1 $Iso/Clj 0 2 Respiratory function FVC (% pred.) 118 84 FEV1 (% pred.) 115 86 FEF25-75 (% pred.) 100 114 PaO2 (mm Hg) 104 101 PaCO2 (mm Hg) 32 39 CFTR mutations Patient R31C F508del IVS8-5T-12TG IVS8-5T-12TG Father IVS8-5T-12TG Not done IVS8-9T-10TG Mother R31C IVS8-5T-11TG IVS8-7T-11TG IVS8-5T-12TG $Amil (mV) indicates the response to superfusion with 10j4 M amiloride, a blocker of epithelial sodium channel; $Clj /Amil (mV), change in NPD after a perfusion of a low-chloride solution; FVC, forced vital capacity; FEF25-75, forced midexpiratory flow rate; FEV1, forced expiratory volume in 1 second; $Iso/Clj (mV), response to the A-adrenergic agonist isoproterenol (10j5 M) added to the low-chloride solution containing amiloride; PaO2, arterial oxygen tension at rest; PaCO2, arterial carbon dioxide tension at rest; % pred., percentage of predicted value. Login to comment

PMID: 17890437 [PubMed] Montgomery J et al: "Scanning the cystic fibrosis transmembrane conductance regulator gene using high-resolution DNA melting analysis."

No. Sentence Comment

145 2 223CϾT R31C 3 355CϾT R75X 386GϾA G85E 4 482GϾA R117H 575TϾC I148T 621 ؉ 1GϾTb 5 711 ؉ 1GϾT 7 1078delT 1132CϾT R334W 1150delA 1172GϾC R347P 8 1341 ϩ 18AϾCc 9 1496CϾA A455E 10 1651-1653del I507del 1653-1655del F508deld 11 1717 - 1GϾA 1756GϾT G542Xe 1784GϾA G551Db 1789CϾT R553Xf 1811GϾC R560T 12 1898 ؉ 1GϾA 13 2184delA 14b 2789 ؉ 5GϾAe 16 3120 ؉ 1GϾA 18 3500 - 2AϾTg 19 3616CϾT R1162X 3659delC Intron 19 3849 ؉ 10kbCϾTe 20 3978GϾA W1282X 21 4041CϾG N1303K 22 4178GϾA G1349Dc a Disease-causing variants recommended for genotyping by the ACMG (4) are in bold. Login to comment

PMID: 18306312 [PubMed] Gene GG et al: "N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel."

No. Sentence Comment

247 A recent report analyzing the natural mutations p.R31C and p.R31L, has shown that these subtle N-terminus alterations compromise biogenesis and enhance internalization of CFTR, contributing to the loss of surface expression and the associated defect in chloride conductance of the channel [Jurkuvenaite et al., 2006]. Login to comment

PMID: 18493878 [PubMed] Paranjape SM et al: "Atypical cystic fibrosis and CFTR-related diseases."

No. Sentence Comment

64 Determination of the transepithelial nasal potential difference has been beneficial in establishing a CF Table 1 Mutations, sites, and molecular consequences associated with either an atypical presentation of CF respiratory disease or pancreatic sufficiency or late-onset pancreatic insufficiency (http:// www.genet.sickkids.on.ca) Mutation Site Consequence Atypical presentation M1210I Exon 19 Met to Ile at 1210 S1455X Exon 24 Ser to Stop at 1455 1811+18G→A Intron 11 mRNA splicing defect L346P Exon 7 Leu to Pro at 346 Y161D Exon 4 Tyr to Asp at 161 R31C Exon 2 Arg to Cys at 31 I752S Exon 13 Ile to Ser at 752 2811G/T Exon 15 Sequence variation Pancreatic sufficiency or late-onset pancreatic insufficiency R600G Exon 13 Arg to Gly at 600 D1152H Exon 18 Asp to His at 1152 Y89C Exon 3 Tyr to Cys at 89 R117H Exon 4 Arg to His at 117 D110E Exon 4 Asp to Glu at 110 296 + 3insT Intron 2 mRNA splicing defect E217G Exon 6a Glu to Gly at 217 V392G Exon 8 Val to Gly at 392 N1088D Exon 17b Asn to Asp at 1088 S737F Exon 13 Missense 1716+1G→A Intron 10 mRNA splicing defect R334W Exon 7 Arg to Trp at 334 R347P Exon 7 Arg to Pro at 347 A455E Exon 9 Ala to Glu at 455 P574H Exon 12 Pro to His at 574 3850-3T→G Intron 19 mRNA splicing defect diagnosis in many atypical cases. Login to comment

PMID: 18716917 [PubMed] George Priya Doss C et al: "A novel computational and structural analysis of nsSNPs in CFTR gene."

No. Sentence Comment

125 The nsSNPs which were predicted to be Table 1 List of nsSNPs that were predicted to be deleterious by SIFT and PolyPhen SNPs ID Alleles AA change Tolerance index PSIC rs1800072 G/A V11C 1.00 0.150 rs1800073 C/T R31C 0.18 2.288 rs1800074 A/T D44V 0.01 2.532 rs1800076 G/A R75Q 0.03 1.754 rs1800078 T/C L138P 0.01 2.192 rs35516286 T/C I148T 0.41 1.743 rs1800079 G/A R170H 0.05 1.968 rs1800080 A/G S182G 0.03 1.699 rs1800086 C/G T351S 0.30 1.600 rs1800087 A/C Q353H 0.03 2.093 rs4727853 C/A N417K 1.00 0.015 rs11531593 C/A F433L 0.65 0.694 rs1800089 C/T L467F 0.15 1.568 rs213950 G/A V470M 0.17 1.432 rs1800092 C/A/G I506M 0.00 1.574 rs1801178 A/G I507V 0.38 0.314 rs1800093 T/G F508C 0.00 3.031 rs35032490 A/G K532E 1.00 1.525 rs1800097 G/A V562I 0.13 0.345 rs41290377 G/C G576A 0.33 1.262 rs766874 C/T S605F 0.03 2.147 rs1800099 A/G S654G 0.03 1.611 rs1800100 C/T R668C 0.01 2.654 rs1800101 T/C F693L 0.61 0.895 rs1800103 A/G I807M 0.01 1.554 rs1800106 T/C Y903H 0.52 0.183 rs1800107 G/T S909I 0.10 1.624 rs1800110 T/C L967S 0.07 1.683 rs1800111 G/C L997F 0.24 1.000 rs1800112 T/C I1027T 0.03 1.860 rs1800114 C/T A1067V 0.04 1.542 rs36210737 T/A M1101K 0.05 2.637 rs35813506 G/A R1102K 0.52 1.589 rs1800120 G/T R1162L 0.00 2.038 rs1800123 C/T T1220I 0.22 0.059 rs34911792 T/G S1235R 0.45 1.483 rs11971167 G/A D1270N 0.12 1.739 rs4148725 C/T R1453W 0.00 2.513 Highly deleterious by SIFT and damaging by PolyPhen are indicated as bold deleterious in causing an effect in the structure and function of the protein by SIFT, PolyPhen and Pupasuite correlated well with experimental studies (Tsui 1992; Ghanem et al. 1994; Bienvenu et al. 1998) (Table 3). Login to comment

PMID: 20021716 [PubMed] Gallati S et al: "Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners."

No. Sentence Comment

117 Based on discriminant analysis, this study predicts a high probability for the presence of CFTR mutations especially in patients with reduced ejaculate volumes (<3 ml) and structural abnormalities such as CAVD, inguinal hernia, hypotrophic testes or cryptorchidism, confirming former findings reported by Casals et al. (2000) and representing symptoms that are also frequently observed in Table 3 (continued) Couple no. Infertile male CFTR mutation Female partner CFTR mutation Offspring genotype Risk for genotype (%) 14 R31C/wt oligospermia V920M/wt R31C/V920M 25 R31C/wt 25 V920M/wt 25 wt/wt 25 15 R31C/wt azoospermia I148T/wt R31C/I148T 25 R31C/wt 25 I148T/wt 25 wt/wt 25 16 V754M/wt oligospermia V754M/wt V754M/V754M 25 V754M/wt 50 wt/wt 25 Bold = mutations associated with classic cystic fibrosis; italic = mutations associated with a mild or uncertain, unpredictable phenotype; CAVD = congenital absence of the vas deferens; wt = wildtype allele. Login to comment

PMID: 20846557 [PubMed] Sutton JM et al: "Total pancreatectomy and islet cell autotransplantation as a means of treating patients with genetically linked pancreatitis."

No. Sentence Comment

117 Patient demographics Descriptive statistics Data mean (SEM) Range Age, y 32 (3) 15-59 Weight, kg 73 (6) 39-127 Body mass index, kg/m2 24 (2) 15-35 Chronic pancreatitis, y 14 (2) 3-47 Sex Male, n = 8 Female, n = 8 Previous pancreatic operations Puestow, n =3 Whipple, n = 3 Genetic mutations and loci, n (%) CFTR 10 (62.5) R297Q 2 DF508 + R117H 1 R553X + M470V 1 DF508 1 R117H 1 P750L 1 D1152H 1 R31C 1 S1235R 1 PRSS1 4 (25) R122H 3 Unknown* 1 SPINK1 2 (12.5) N34S 2 *One patient was identified as having a PRSS1 mutation, but the specific locus mutation was unknown at the time of publication. Login to comment

PMID: 21499205 [PubMed] Lucidi V et al: "The etiology of acute recurrent pancreatitis in children: a challenge for pediatricians."

No. Sentence Comment

46 Genetic Findings Observed in Our Study Population and Related Clinical Features CFTR PRSS1 SPINK1 Clinical CharacteristicsMutations IVS8 F508del/UN 9T/9T S181G/- NEG No respiratory symptoms 3849+10KbC9T/UN 7T/7T NEG NEG No respiratory symptoms UN/UN 7T/7T NEG N34S/- UN/UN 5T/7T NEG NEG No respiratory symptoms 1899-136T/C/UN 5T/7T NEG NEG No respiratory symptoms F508del/UN 5T/9T NEG NEG No respiratory symptoms D1152H/D1152H NEG NEG No respiratory symptoms R75Q/UN 5T/7T NEG NEG No respiratory symptoms L997F/UN 7T/9T NEG NEG No respiratory symptoms UN/UN 7T/7T NEG N34S/- W1282X/I148T 7T/9T NEG NEG No respiratory symptoms NEG N34S/- R75Q/F1052V NEG NEG No respiratory symptoms F508del/D1152H NEG NEG Bronchiectasis-CF 406-6T/C/E528E 7T/7T NEG NEG No respiratory symptoms F508del/UN 7T/9T Mild respiratory symptomsYCF L967S/L997F NEG NEG No respiratory symptoms E528E/UN 5T/7T Crohn disease, food allergy 1716 G/A/UN 7T/7T NEG NEG No respiratory symptoms 1898+1G9A/UN 7T/7T No respiratory symptoms R31C/UN No respiratory symptoms R75Q/UN 7T/7T NEG NEG No respiratory symptoms N29T;V212I; D217Y NEG F508del/UN 7T/9T NEG NEG Pancreas divisum S1235R/UN 7T/9T NEG NEG Duodenal stenosis Entries in bold font undelines the detection of mutations or polymorphisms in the studied genes. Login to comment

PMID: 9921909 [PubMed] Bombieri C et al: "Complete mutational screening of the CFTR gene in 120 patients with pulmonary disease."

No. Sentence Comment

62 Five mutations (G576A, R668C, R74W, R31C, and I506V) are not thought to be the cause of CF (CFGAC website): three of them (G576A, R668C, and R74W) have been found in CBAVD patients (Anguiano et al. 1992; Chillon et al. 1995; Mercier et al. 1995; Verlingue et al. 1996), R31C was described in a DBE patient (Girodon et al. 1997), and I506V was found in the normal allele in the father of a CF child (Ghanem et al. 1994). Login to comment
64 All these mutations, except V754M and R31C, affect highly conserved residues among five species investigated: human, bovine, mouse, Xenopus, and dogfish (Tucker et al. 1992). Login to comment
88 of cases CFTR gene PolyTb status tested mutationa DBE 23 1 G576A-R668C/L997F 7/9 1 ∆F508/L997F 9/9 1 ∆F508/- 7/9 1 R1066C/- 5/7 1 3667ins4/- 5/7 1 R75Q/- 7/7 1 M1137V/- 7/7 1 -/- 5/5 3 -/- 5/7 10 -/- 7/7 2 -/- 7/9 CB 27 1 P111L/- 7/7 1 R117H/- 7/7 1 E585X/- 7/7 1 P1072L/- 7/7 1 -/- 5/7 15 -/- 7/7 6 -/- 7/9 1 -/- 9/9 E 25 1 R668C/- 7/7 6 -/- 5/7 16 -/- 7/7 6 -/- 7/9 S 8 1 E826K/- 7/7 1 ∆F508/- 7/9 1 4382delA/- 7/7 1 L997F/- 7/9 1 V754M/- 7/9 3 -/- 7/7 LC 26 1 I148T/- 5/7 1 D1270N-R74W 5/7 1 D651N/- 7/7 1 Y301C/- 7/7 1 -/- 5/7 16 -/- 7/7 5 -/- 7/9 TB 4 1 -/- 5/7 1 -/- 7/7 2 -/- 7/9 Pneumonia 5 4 -/- 7/7 1 -/- 5/7 Pnx 2 2 -/- 7/7 Controls 68 1 L997F/- 7/9 1 R31C/- 7/7 1 I506V/- 5/7 1 -/- 5/7 1 -/- 5/9 23 -/- 7/7 4 -/- 7/9 1 -/- 9/9 2 ? Login to comment
120 Three missense mutations were detected in 33 controls: L997F, which is present in two DBE and in one sarcoidosis patients; R31C, which was first described in an apparently unaffected 6-year-old child (Ghanem et al. 1994) and next in a DBE patient (Girodon et al. 1997); I506V, which was described in a healthy parent of a CF patient who bore ∆F508 on the other chromosome (Kobayashi et al. 1990). Login to comment

PMID: 22678879 [PubMed] El-Seedy A et al: "CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes."

No. Sentence Comment

105 [2002C>T;3718-2477C>T] p.Gln689X 2 CSD Nasal polyposis 14 y,16 y NA, 29 p.[Gly576Ala;Arg668Cys] NI 3 IP 35-39 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] NI 1 IP Bronchitis 49 y NA p.[Gly576Ala;Arg668Cys] p.PheF508del 1 IP 42 y NA p.[Gly576Ala;Arg668Cys] p.Arg668Cys 1 IP NA NA p.[Gly576Ala;Arg668Cys] c.1210_34TG[12]T[5] 4 IP 19-69 y NA p.[Gly576Ala;Arg668Cys] NI 1 Cholestasis 60 y NA p.[Gly576Ala;Arg668Cys] c.1584G>A 33 CBAVD 27-50 y 9-82 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Phe508del 2 CBAVD 30 y,36 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.2051_2052delAAinsG 1 CBAVD 34 y 72 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Trp1282X 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Asn1303Lys 1 CBAVD 35 y 65-66 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Ser549Asn 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.3605delA 1 CBAVD 30 y 41-69 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Gln1411X 1 CBAVD 31 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg347His 3 CBAVD 29 y, 34 y, NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Gly542X 1 CBAVD 35 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.946delT 1 CBAVD 26 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] c.4242_4242+1delGGinsT 1 CBAVD 41 y 31 p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg117His 1 CBAVD 32 y NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Thr338Ile 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Glu379Lys 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Met1137Val 1 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Thr1246Ile 2 CBAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] NI 1 CBAVD 34 NA p.[Gly576Ala;Arg668Cys] p.Asn1303Lys 8 CBAVD 30-42 y NA p.[Gly576Ala;Arg668Cys] NI 1 CBAVD 27 y NA p.Arg668Cys p.Phe508del 1 CBAVD 30 y NA p.Arg668Cys NI 1 CUAVD NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Phe508del 1 CUAVD NA NA p.[Gly576Ala;Arg668Cys] NI 1 CUAVD Renal agenesis NA NA p.[Gly576Ala;Arg668Cys] NI 1 Hypofertility (not CBAVD) CF carrier`s partner NA NA p.[Gly576Ala;Arg668Cys] p.Asp1152His 1 FBA Mild CF considered possible, 2 older brothers with the same genotype, one with a very mild phenotype, the other being asymptomatic 22 wg NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Asn1303Lys 1 FBA TOP for de novo chromosomal translocation; not CF 21 wg NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Arg31Cys 1 FBA Not CF at birth 28 wg <30 p.[Gly576Ala;Arg668Cys] p.Phe508del 1 FBA Unknown outcome 23 wg NA p.[Gly576Ala;Arg668Cys] p.Phe508del 1 FBA Not CF at birth 21 wg <30 p.[Gly576Ala;Arg668Cys] p.Trp846X (Continued) Table 1. Login to comment

PMID: 22300503 [PubMed] Barben J et al: "Retrospective analysis of stored dried blood spots from children with cystic fibrosis and matched controls to assess the performance of a proposed newborn screening protocol in Switzerland."

No. Sentence Comment

63 This child was diagnosed with atypical CF in the first week of life using molecular diagnostics (F508 del/R31C) as both parents were known heterozygous CF carriers. Login to comment
80 CFTR mutations Alleles found Percentage of total Homozygous (n) F508del a 86 68.2 30 3905insT a 4 3.2 1 G542X a 3 2.4 - R553X a 3 2.4 1 W1282X a 2 1.6 - 1717-1 GNA a 2 1.6 - N1303K a 0 0.0 - S549R 3 2.4 1 Q525X 3 2.4 - Y1092X 2 1.6 - 3120+1 GNA b 2 1.6 1 2347delG 2 1.6 - 2176insC 1 0.8 - 3659delC 1 0.8 - 3359delCTCTG 1 0.8 - W1089X 1 0.8 - 711+1 GNT 1 0.8 - D1152H 1 0.8 - G1244E 1 0.8 - R1066C 1 0.8 - R31C 1 0.8 - R347P 1 0.8 - R74W 1 0.8 - S945L 1 0.8 - T501I 1 0.8 - K68X 1 0.8 - Total 126 100.0% 34 a Seven most common CF-gene mutations in Switzerland ("Swiss panel")=79.4% (100/126) of alleles. Login to comment

PMID: 22010920 [PubMed] Shah U et al: "Case records of the Massachusetts General Hospital. Case 32-2011. A 19-year-old man with recurrent pancreatitis."

No. Sentence Comment

146 The patient was found to have two CFTR mutations - ΔF508 and R31C. Login to comment

PMID: 18687795 [PubMed] Audrezet MP et al: "Validation of high-resolution DNA melting analysis for mutation scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene."

No. Sentence Comment

51 Sequences of the Primers Used for CFTR Analysis by HRM, GC Size, Amplicon Length, Number of Positive Controls Validated for Each Exon, and Positive Controls for Routine Analysis Exon Primer Sequences GC length Amplicon length (bp) Introns Number of heterozygous- positive controls Number of homozygous- positive controls Recommended control 1 LSCFE1Fmod 5Ј-CCGCCGCCGTTGAGCGGCAGGCACC-3Ј 8 200 bp 74 4 125GϾC LSCFE1Rmod 5Ј-CCGCCGCCGGCACGTGTCTTT CCGAAGCT-3Ј 8 19 M1I 2 2i5b 5Ј-CAAATCTGTATGGAGACC-3Ј 0 194 bp 39 5 R31C 2i3Љ 5Ј-CAACTAAACAATGTACATGAAC-3Ј 0 4 296ϩ1GϾT 3 LSCFe3Fmod LSCFe3Rmod 5Ј-CGCCGTTAAGGGAAATAGGACAA CTAAAATA-3Ј 5 276 bp 44 10 2 R75Q 5Ј-CCGCCGATTCACCAGATTTCGTAGTC-3Ј 6 66 G85V 4 LSCFe4FmodC 5Ј-CCGCCGCCGCCCGTGTTGAAATT CTCAGGGT-3Ј 12 361 bp 52 14 1 R117H LSCFe4RmodC 5Ј-CCGCCGCCCACATGTACGATAC AGAATATATGTGCC-3Ј 9 26 574delA 5 LSCFE5Fmod 5Ј-CCGCCGGTTGAAATTATCTAACTTTCC-3Ј 6 201 bp 13 8 624delT LSCFE5Rmod 5Ј-CCGAACTCCGCCTTTCCAGTTGT-3Ј 3 48 711ϩ1GϾT 6a LSCF6aFmod2 5Ј-CCGCCGGGGTGGAAGAT ACAATGACACCTG-3Ј 5 317 bp 25 8 C225X LSCF6aRmod2 5Ј-CCGCCGCCGCGATGCATAGAG CAGTCCTGGTT-3Ј 11 66 L206W 6b LSCFE6bFmod 5Ј-CGCGCCGCCGGATTTAC AGAGATCAGAGAG-3Ј 10 239 bp 0 2 1 R258G LSCFE6Brmod 5Ј-CCGCCGCCGAGGTGGA GTCTACCATGA-3Ј 8 66 1001ϩ11CϾT 7 LSCFE7Fmod2 5Ј-CCGCCGCCCTCTCCCTGAATTT TATTGTTATTGTTT-3Ј 13 326 bp 7 11 1078delT LSCFE7Rmod2 5Ј-CCCGCCGCCCTATAATGCAG CATTATGGT-3Ј 10 7 1248ϩ1GϾT 8 LSCFE8Fmod 5Ј-CCGGAATGCATTAATGCTAT TCTGATTC-3Ј 4 199 bp 32 7 W401X LSCFE8Rmod 5Ј-CCCGCAGTTAGGTGTTTAG AGCAAACAA-3Ј 4 18 1249-5AϾG 9 LSCFe9Fmod2 5Ј-CCGCCGCCGGGAATTATTTGAGAA AGCAAAACA-3Ј 8 279 bp 0 3 D443Y LSCFe9Rmod2 5Ј-CCGCCGCGAAAATACCTTCCAG CACTACAAACTAGAAA-3Ј 8 57 A455E 10 LSCF10FmodD 5Ј-CGCCGTTATGGGAGAACTGG AGCCTTCAGAG-3Ј 5 275 bp 0 15 1 F508del LSCF10RmodD 5Ј-CCGCAGACTAACCGATTGAAT ATGGAGCC-3Ј 4 68 E528E 11 h11i5 5Ј-TGCCTTTCAAATTCAGATTGAGC-3Ј 0 197 bp 42 13 2 G542X 11i3ter 5Ј-ACAGCAAATGCTTGCTAGACC-3Ј 0 17 G551D 12 LSCFE12Fmod 5Ј-CGCGTCATCTACACTAGATGACCAG-3Ј 4 244 bp 43 15 G576A 1898 ϩ 1GϾALSCFE12Rmod 5Ј-CCGGAGGTAAAATGCAATCTATGATG-3Ј 3 63 13 LSCF13AFmod 5Ј-CCGCCGCCGGAGACATATTG CAATAAAGTAT-3Ј 9 38 20 I601F LSCF13ARmod 5Ј-GCCTGTCCAGGAGACAGGA GCATCTC-3Ј 2 R668C LSCF13BFmod 5Ј-CCGCCGCAATCCTAACTGAG ACCTTACACCG-3Ј 2 R668C LSCF13BRmod 5Ј-CCGCCGATCAGGTTCAGGA CAGACTGC-3Ј 3 346 bp 2184insA LSCF13CFmod 5Ј-CCGCGGTGATCAGCACTGGCCC-3Ј 6 301 bp 77 L749L LSCF13CRmod 5Ј-CCGCGCGCGCGGCCAGTTTCTTG AGATAACCTTCT-3Ј 13 259 bp V754M LSCF13DFmod 5Ј-CGTGTCACTGGCCCCTCAGGC-3Ј 1 221 bp I807M LSCF13DRmof 5Ј-CCGCCGCCGCTAATCCTATGA TTTTAGTAAAT-3Ј 9 220 bp 2622ϩ1GϾA LSCf13FFmod 5Ј-CGCGGTGCAGAAAGAAGAAAT TCAATCCTAACTG-3Ј 4 R668C LSCF13FRmod 5Ј-CCGCCGTGCCATTCATTTGT AAGGGAGTCT-3Ј 6 2184insA 14a LSCF14aFmodB 5Ј-CCGACCACAATGGTGGCAT GAAACTG-3Ј 3 239 bp 35 7 1 T854T LSCF14aRmodB 5Ј-CCGCCGACTTTAAATCCAGTAAT ACTTTACAATAGAACA-3Ј 6 7 W846X 14b LSCF14bFmod 5Ј-CCGGAGGAATAGGTGAAGAT-3Ј 2 179 bp 38 4 2752-5GϾT LSCF14bRmodb 5Ј-CCGTACATACAAACATAGTGGATT-3Ј 3 59 2789ϩ5GϾT 15 LSCFE15Fmod 5Ј-CGCGCCGTGTATTGGAAA TTCAGTAAGTAACTTTGG-3Ј 7 412 bp 33 16 T908S LSCFE15Rmod 5Ј-CCGCAGCCAGCACTGCCAT TAGAAA-3Ј 4 68 S945L (table continues) phisms that we have chosen to exclude. Login to comment
171 Results of CFTR Analysis by HRM on 136 Samples of Patients with Idiopathic Chronic Pancreatitis (ICP) Exon Number of positive samples Mutations identified Variants identified New positive controls 1 14 14 125GϾC 2 1 1 R31C 3 9 1 G85E 7 R75Q 1 R74W 4 4 1 R117G 1 I148T R117G 1 R117H 1 A120T 5 1 1 L188P L188P 6a 5 1 V201M 1 A221A A221A 3 875ϩ40 AϾG 6b 27 1 M284T 26 1001ϩ11CϾT M284T 7 1 1 L320V L320V 8 0 0 9 1 1 D443Y 10 16 8 F508del 8 E528E 11 1 1 G542X 12 6 4 G576A 1 Y577Y L568F 1 L568F 13 7 1 S737F 4 R668C S737F 1 V754M L644L 1 L644L 14a 53 52 T854T T854TϩI853I 1 T854TϩI853I 14b 0 0 15 3 1 L967S T908S 1 T908S 1 S945L 16 0 0 17a 10 7 L997F 1 3271ϩ18CϾT 3271 ϩ 3AϾG 1 3271 ϩ 3 AϾG 1 Y1014C 17b 3 1 L1096L L1096L 1 H1054DϩG1069R 1 3272-33AϾG H1054DϩG1069R 3272-33AϾG 18 2 1 D1152H E1124del 1 E1124del 19 5 5 S1235R poly 20 7 1 W1282X 5 P1290P 1 D1270N 21 2 1 N1303K 1 T1299T 22 0 0 23 1 0 4374ϩ13 AϾG 24 43 40 Q1463Q 2 Y1424Y 1 Q1463QϩY1024Y ing domain of a gene brings an excellent sensitivity for heterozygote detection that is very close to 100%. Login to comment

PMID: 17098482 [PubMed] Ameen N et al: "Endocytic trafficking of CFTR in health and disease."

No. Sentence Comment

680 R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment
683 Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment
681 R31C and R31L are CFTR mutations that also give rise to a mild clinical phenotype [71]. Login to comment
684 Expression of R31C and R31L CFTR leads to reduced macroscopic currents compared to expression of wt CFTR; however, since single channel records were not determined it is not possible to determine whether the reduced macroscopic currents are due to endocytic defects alone, or whether there are also altered gating kinetics. Login to comment

PMID: 10923036 [PubMed] Claustres M et al: "Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France."

No. Sentence Comment

66 Five sequence changes (R31C, R75Q, F508C, G576A, R1162L) were reported as ''mutations`` in the forms; however, they are listed as ''polymorphisms`` in the CFGAC (designed respectively as 223C/T, 356G/A, 1655T/G, 1859G/ C, and 3617G>T). Login to comment
109 h M1K, K14X, W19X, 211delG, G27E, R31C, 237insA, 241delAT, Q39X, 244delTA, 296+2T>C, 297-3C>T, W57X+F87L, 306delTAGA, P67L, A72D, 347delC, R75Q, 359insT, 394delT, 405+4A>G, Q98R, 457TAT>G, R117H+5T, R117H+I1027T, R117L, R117P, H139R, A141D, M152V, N186K, D192N, D192del, E193X, 711+1G>A, 711+3A>G, 712-1G>T, L206F, W216X, C225R, Q237E, G241R, 852del22, 876-14del12, 905delG, 993del5, E292K, Y304X, F311del, 1161delC, R347L, R352Q, W361R, 1215delG, S364P, S434X, D443Y, S466X, C491R, T501A, I506T, F508C, I507del+F508C, F508del+L467F, 1774delCT, R553G, 1802delC, 1806delA, A559E, Y563N, 1833delT, Y569C, Y569H, Y569X, G576X, G576A, T582I, 1898+3A>G+186-13C>G, 1918delGC, R600G, L610S, G628R, 2043delG, 2118del4, E664X, 2174insA, Q689X, K698R, K716X, L732X, 2347delG, 2372del8, R764X, 2423delG, S776X, 2634insT, 2640delT, C866Y, 2752-1G>T, W882X, Y913C, V920M, 2896insAG, H939D, H939R, D979V, D985H, D993Y, 3120G>A, I1005R, 3195del6, 3293delA, 3320ins5, W1063X, A1067T, 3359delCT, T1086I, W1089X, Y1092X+S1235R, W1098X, E1104X, R1128X, 3532AC>GTA, 3548TCAT>G, M1140del, 3600G>A, R1162L, 3667ins4, 3732delA+K1200E, S1206X, 3791delC, S1235R+5T, Q1238R, Q1238X, 3849+4A>G, T1246I, 3869insG, S1255P, R1283K, F1286S, 4005+1G>T, 4006-8T>A, 4015delA, N1303H, N1303I, 4172delGC, 4218insT, 4326delTC, Q1382X, 4375-1C>T, 4382delA, D1445N, CF40kbdel4-10, Cfdel17b. Login to comment

PMID: 7526685 [PubMed] Morral N et al: "Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene."

No. Sentence Comment

106 Slippage usually results in the addition or subtraction of one repeat unit either side Table 5 CpG Dinucleotides in CFTR Gene That Have More than One Mutational Event Position Change Mutation Reference 223 ......... CT R31C Ghanem et al. 1994 224 ......... GT R31L Zielenski et al., in press 355 ........ C- >T R75X Dork et al., in press 356 ......... G--*T R75L B. Costes, personal communication 356 ......... G-aA R75Q' Zielenski et al. 1991b 481 ......... CT R117C D6rk et al., in press 482 ......... G-oA R117H Dean etal. Login to comment

PMID: 16678503 [PubMed] Ngiam NS et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study."

No. Sentence Comment

121 The first description of I556V was made in a male French patient having atypical CF who was also compound heterozygous for another mutation, R31C in exon 2 [24]. Login to comment

PMID: 23416327 [PubMed] Montagnani M et al: "A patient with pancreas divisum, recurrent acute pancreatitis, and homozygosity for the cystic fibrosis transmembrane regulator-associated protein 5T allele."

No. Sentence Comment

37 Previously, Dray et al10 described 2 young female patients who carried the IVS8 5T-12TG variant of the CFTR gene in compound heterozygosity with different mutations (in 1 patient R31C, in the other patient F508del). Login to comment

PMID: 23974870 [PubMed] Sosnay PR et al: "Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene."

No. Sentence Comment

137 In addition to these ten variants, c.1210-12(7) (legacy name 7T) had already been reported to be non-penetrant48 and was identified as a second variant in numerous fathers, and a twelfth variant, p.Ile1027Thr, was deemed 159 variants ࣙ0.01% frequency in CFTR2 127 variants meet clinical and functional criteria Clinical and functional analysis 13 variants meet neither criteria 14 variants 5 variants 7 variants 6 variants Evidence of non-penetrance No evidence of non-penetrance 19 variants meet clinical or functional criteria 127 variants are CF causing 12 variants are non CF causing 20 variants are indeterminate p.Arg117HisߤC p.Arg75Gln p.Gly576Alaߤ p.Arg668Cys ߤ p.Met470Val C p.IIe1027Thr ߤC p.Val754Met ߤC p.IIe148Thr ߤC p.Arg31Cys C p.Ser1235Arg ߤ p.Leu997Phe ߤ p.Arg1162Leu p.Leu227Arg F p.Gln525* F p.Leu558SerC p.Asp614Gly C c.2657+2_2657+3insA C c.1418delG F c.1210-12(7) ߤ p.Arg1070Gln C p.Asp1270Asn ߤC p.[Gln359Lys; Thr360Lys] p.Gly1069Argߤ p.Asp1152His p.Phe1052Val c.1210-12(5) p.Arg74Trpߤ p.IIe1234Val ߤC p.Arg1070Trp ߤF p.Ser977Phe F p.Asp579Gly C p.Tyr569Asp F Penetrance analysis Figure 4ߒ Assignment of disease liability to the 159 most frequent CFTR variants using three criteria. Login to comment
173 The 127 variants that met both clinical and functional criteria were designated cystic fibrosis causing; however, 32 remaining -variants Table 1ߒ Variants associated with incomplete penetrance Variant Number of alleles in CFTR2 Frequency in CFTR2 (out of 70,777 known alleles) Number that occur in trans with a CF-causing variant in fathers Number reported in 2,062 fathers Frequency in fathers (out of 4,124 alleles) Allele frequency in 1000 Genomes Project Variants that met clinical criteria but did not meet functional criteria p.Arg31Cys 13 0.00018 4 4 0.00097 0.001-0.004 p.Ile148Thra 99 0.00140 4 9 0.00218 Not available p.Met470Val 41 0.00058 Not analyzed 1,412 0.34239 0.087-0.647 p.Val754Met 9 0.00013 4 7 0.00170 0-0.003 Variants that did not meet clinical or functional criteria p.Arg75Gln 28 0.00040 48 74 0.01794 0.009-0.033 p.Gly576Alab 42 0.00059 12 20 0.00485 0.004-0.009 p.Arg668Cysc 49 0.00069 16 29 0.00703 0.004-0.009 p.Leu997Phe 28 0.00040 5 9 0.00218 0.001-0.003 p.Arg1162Leu 9 0.00013 2 6 0.00145 0.001 p.Ser1235Arg 54 0.00076 15 21 0.00509 0.005-0.016 aDoes not cause cystic fibrosis unless in cis with the known deleterious variant p.Ile1023_Val1024del66. Login to comment

PMID: 24074415 [PubMed] Wilson GC et al: "Surgical outcomes after total pancreatectomy and islet cell autotransplantation in pediatric patients."

No. Sentence Comment

104 Patient demographics Patient characteristics Value Age (y), mean &#b1; SEM (range) 15.9 &#b1; 0.4 (14-18) Weight (kg), mean &#b1; SEM (range) 66.3 &#b1; 5.1 (42-116) Body mass index (kg/m2 ), mean &#b1; SEM (range) 21.8 &#b1; 1.8 (14-37) Gender (n) Male 7 Female 7 Etiology (n) Idiopathic 8 Genetic CFTR 4 DF508 2 R31C 1 L997F 1 SPINK1 1 N34S 1 PRSS1 1 N29I 1 Previous pancreatic operation (n) Pancreaticoduodenectomy 1 Puestow 1 Frey 1 Berne 1 CFTR, Cystic fibrosis transmembrane conductance regulator; PRSS1, cationic trypsinogen; SEM, standard error of the mean; SPINK1, serine protease inhibitor, Kazal type 1. Login to comment

PMID: 25033378 [PubMed] LaRusch J et al: "Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis."

No. Sentence Comment

116 CFTR variant %Cases %Uctrls OR p-value %Cases w/N34S OR w/N34S p-value w/N34S F508C 0.5 0.3 1.58 0.21 0.0 0.00 0.67 R1162L 0.5 0.5 1.13 0.29 1.8 4.03 0.17 I1027T 0.5 0.3 1.99 0.17 0.0 0.00 0.70 R31C 0.3 0.7 0.42 0.088 0.0 0.00 0.52 I148T 0.3 0.4 0.75 0.27 0.0 0.00 0.63 R297Q 0.3 0.2 1.89 0.21 0.0 0.00 0.76 R74W 0.2 0.2 0.85 0.29 0.0 0.00 0.71 F1052V 0.1 0.2 0.63 0.27 0.0 0.00 0.76 I807M 0.1 0.1 1.26 0.30 0.0 0.00 0.83 R258G 0.1 0.1 1.26 0.30 0.0 0.00 0.83 G1069R 0.1 0.0 0.13 0.0 V201M 0.0 0.1 0.17 0.0 0.00 0.83 Of the 81 CFTR mutations tested in the cohort, 43 were observed at least once in cases or controls. Login to comment
269 67 SNPs (125GtoC, 1716G.A, 1717-1G.A, 1898+1G.A, 2183AA.G, 2184delA, 2789+5G.A, 3120+1G.A, 3659delC, 3849+10kbC.T, 621+ 1G.T, 711+5G.A, A455E, D110H, D1152H, D1270N, D443Y, D579G, F1052V, F1074L, F508C, F508del, G1069R, G1244E, G1349D, G178R, G542X, G551D, G551S, I1131L/V, I148T, I336K/T, I507del, I807M, IVS8T5, K1180T, L1065P, L967S, L997F, M1V, M470V, M952I, M952T, N1303K, P67L, Q1463Q, R1070Q, R1162X, R117C, R117H, R170H, R258G, R297Q, R31C, R352Q, R553X, R668C, R74W, R75Q, S1235R, S1255P, S485R, S977F, T338I, T854T, V201M, W1282X) were multiplexed into 6 wells; 14 SNPs (S492F, S945L, R74Q, R560T, R1162L, G85E, I1027T, R334W, R347P, G576A, 711+1G.T, 1001+11C.T, P1290P, 3199del6) were ascertained separately via TaqMan Gene Expression Assays, with repeat confirmation of all positive results. Login to comment

PMID: 25492507 [PubMed] Nakano E et al: "Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis."

No. Sentence Comment

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
100 There were no significant difference for any other non-synonymous or synonymous variants detected in the exons Table 3 Comparison of the non-synonymous variant frequencies between the patients with CP and controls Amino acid change Genotype All CP (%) HGVD (%) P value (vs. HGVD) All CP Alcoholic CP Nonalcoholic CP Idiopathic CP Hereditary/ familial CP p.R31C CT 3/193 (1.6) 12/1102 (1.1) 0.48 [0.99 0.41 0.18 [0.99 p.R31H GA 1/193 (0.5) 0 - - - - - p.I125T TC 3/193 (1.6) 5/1102 (0.5) 0.11 [0.99 0.057 0.15 0.13 p.K411E AG 1/193 (0.5) 0 - - - - - p.V470M GA 97/193 (50.3) 573/1199 (47.8) 0.66 0.57 0.68 0.38 0.12 AA 25/193 (13.0) 185/1199 (15.4) p.I556V AG 10/193 (5.2) 78/1150 (6.8) 0.70 0.79 0.81 [0.99 0.45 GG 0/193 (0) 3/1150 (0.3) p.E585X GT 1/193 (0.5) 0 - - - - - p.L957fs 1/193 (0.5) 0 - - - - - p.L1156F GT 14/193 (7.3) 45/1136 (4.0) 0.04 0.06 0.07 0.11 0.30 TT 1/193 (0.5) 1/1136 (0.1) p.G1349S GA 1/193 (0.5) 4/1094 (0.4) 0.56 0.19 [0.99 [0.99 [0.99 p.Q1352H GC 20/193 (10.4) 57/1153 (4.9) 0.009 0.12 0.037 0.17 0.062 CC 0/193 (0) 1/1153 (0.1) p.R1453W CT 10/193 (5.2) 42/1144 (3.7) 0.32 0.25 0.49 0.45 [0.99 CP chronic pancreatitis, HGVB Human Genetic Variation Database P values were determined versus HGVD by the Fisher`s exact test Table 4 Synonymous variants in the exons of the CFTR gene detected in this study Exon Synonymous variant Amino acid change dbSNP135 Genotype Alcoholic CP (%) Idiopathic CP (%) Hereditary/ familial CP (%) 4 c.372C[T p.G124= - CT 0/46 (0) 1/121 (0.8) 0/26 (0) 13 c.1731C[T p.Y577= rs55928397 CT 0/46 (0) 1/121 (0.8) 0/26 (0) 15 c.2562T[G p.T854= rs1042077 TG 20/46 (43.5) 69/121 (57.0) 12/26 (46.2) GG 6/46 (13.0) 18/121 (14.9) 0/26 (0) 23 c.3723C[A p.G1241= rs185065886 CA 1/46 (2.2) 0/121 (0) 0/26 (0) 25 c.3975A[G p.R1325= - AG 0/46 (0) 1/121 (0.8) 0/26 (0) 27 c.4254G[A p.E1418= - GA 0/46 (0) 1/121 (0.8) 0/26 (0) 27 c.4389G[A p.Q1463= rs1800136 GA 1/46 (2.2) 3/121 (2.5) 0/26 (0) CP chronic pancreatitis between all patients with CP and controls (Tables 3, 5). Login to comment
114 Comprehensive analysis by targeted NGS enabled us to identify novel and Table 5 Comparison of the synonymous variant frequencies between the patients with CP and controls Synonymous variant Genotype All CP (%) HGVD (%) P value (vs. HGVD) All CP Alcoholic CP Nonalcoholic CP Idiopathic CP Hereditary/ familial CP c.C372T CT 1/193 (0.5) 0 - - - - - c.1731C[T CT 1/193 (0.5) 0 - - - - - c.2562T[G TG 101/193 (52.3) 528/1154 (45.8) 0.22 0.81 0.11 0.045 0.033 GG 24/193 (12.4) 181/1154 (15.7) c.3723C[A CA 1/193 (0.5) 3/671 (4.5) [0.99 0.23 [0.99 [0.99 [0.99 c.3975A[G AG 1/193 (0.5) 0 - - - - - c.4254G[A GA 1/193 (0.5) 0 - - - - - c.4389G[A GA 4/193 (2.1) 40/1112 (3.6) 0.48 [0.99 0.53 0.81 [0.99 AA 0/193 (0) 1/1112 (0.1) CP chronic pancreatitis, HGVD Human Genetic Variation Database P values were determined against HGVD by the Fisher`s exact test Table 6 Total CFTR sequencing results of patients carrying rare non-synonymous CFTR variants a Pancreatitis-associated mutations in the PRSS1, SPINK1, CTRC, and CPA1 genes Case# Etiology Age at onset Rare variant Additional non-synonymous variants c.1210-34TG(9_13) c.1210-12T(5_9) Mutation in other pancreatitis susceptibility genesa A1 Idiopathic 34 p.R31C/- p.R1453W/- TG11/TG11, 7T/7T - A2 Idiopathic 8 p.R31C/- - TG11/TG12, 7T/7T - A3 Idiopathic 16 p.R31C/- - TG11/TG12, 7T/7T - A4 Idiopathic 10 p.R31H/- - TG11/TG12, 7T/7T - A5 Idiopathic 16 p.I125T/- p.L1156F/- TG11/TG12, 7T/7T CTRC p.R29Q/- A6 Idiopathic 2 p.I125T/- - TG11/TG12, 7T/7T - A7 Hereditary 28 p.I125T/- p.R1453W/- TG11/TG12, 7T/7T - A8 Idiopathic 19 p.K411E/- p/L1156F/- TG11/TG12, 7T/7T - A9 Alcoholic 28 p.E585X/- p.I556V/- TG11/TG11, 7T/7T - A10 Idiopathic 21 p.L957fs/- p.Q1352H/- TG11/TG12, 7T/7T - A11 Alcoholic 40 p.G1349S/- - TG11/TG11, 7T/7T - rare variants in the CFTR gene. Login to comment

PMID: 25674778 [PubMed] Baker MW et al: "Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study."

No. Sentence Comment

32 [1075C>A;1079C>A] (Q359K/T360K) - - - Mutations that do not cause CF when combined with another CF-causing mutation c.1727G>C (G576A) c.3485G>T (R1162L) c.224G>A (R75Q) - - c.3080T>C (I1027T) c.91C>T (R31C) c.3705T>G (S1235R) - - c.2991G>C (L997F) c.2002C>T (R668C) c.2260G>A (V754M) - - Mutations/variants that were validated in this study are in bold. CF, cystic fibrosis. Table 1ߒContinued (http://www.hgvs.org/mutnomen/) and legacy mutation nomenclature (http://www.cftr2.org/browse.php). Login to comment

PMID: 25824995 [PubMed] Salinas DB et al: "Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants."

No. Sentence Comment

4 Conclusions: The outcomes in children 2-6 years of age with the L997F, G576A, R1162L, V754M, R668C, R31C, and S1235R variants are consistent with the CFTR2 non-CF-causing classification. Login to comment
95 Non-CF-causing variants from CF NBS in California cDNA name Number of patients identified from the CA CF NBS Mean [Cl-] conductance (as % WT-CFTR) b C/(B + C) (as % of WT-CFTR) in HeLa cellsc C/(B + C) (as % of WT-CFTR) in FRT cellsd CFTR protein quantity (as % WT-CFTR)e L997F c.1408A N G 34 22 97 104 100 G576Aa c.1727G N C 7 147 98 110 104 R1162L c.3485G N T 6 130 93 94 94 V754M c.2260G N A 4 140 98 107 102 R668Ca c.2002C N T 2 58 97 106 102 R31C c.91C N T 2 105 92 86 89 S1235R c.3705T N G 2 79 96 106 101 CA CF NBS = California Cystic Fibrosis Newborn Screening Program. Login to comment

PMID: 25869325 [PubMed] Chang MC et al: "Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment."

No. Sentence Comment

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
112 The identified variants included I556V in nine patients, 5T in seven, S42F in four, I125T in two, and R31C, R553X, S895N, and G1069R each in one patient (Table 1). Login to comment
140 AIP (n = 89) CFTR variants n = 26 % in AIP % with variant I556V 9 10.1% 34.6% 5 T 7 7.9% 26.9% S42F 4 4.5% 15.4% I125T 2 2.2% 7.7% R31C 1 1.1% 3.8% R553X 1 1.1% 3.8% S895T 1 1.1% 3.8% G1069R 1 1.1% 3.8% Table 2 Comparison of patients with and without CFTR variants in 89 patients with autoimmune pancreatitis. Login to comment

PMID: 25910067 [PubMed] Lucarelli M et al: "A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis."

No. Sentence Comment

363 [72G>C;164+2T>G] uncertain: CF-PI and/or CF-PS L24F nd; 296+2T>G nd R31C c.91C>T CFTR-RD non CF-causing p.Arg31Cys S42F c.125C>T uncertain: found only with an unknown allele in trans nd p.Ser42Phe E56G c.167G>A CBAVD nd p.Glu56Lys [R74W;V201M;D1270N] c. Login to comment
423 A similar good match may also be assumed for two mutations classified as non-CF-causing in CFTR2 [S1235R (p.Ser1235Arg) and R31C (p.Arg31Cys)] but as CFTR-RD-causing in our study, owing to the fact that CFTR2 is mainly aimed at classic CF and is more prone to a classification as non-causing for those mutations originating nonclassic clinical and biochemical phenotypes. Login to comment

PMID: 26014425 [PubMed] Girardet A et al: "The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus."

No. Sentence Comment

87 [Gln359Lys; Thr360Lys] L558S c.1673 T4C p.Leu558Ser Y569D c.1705 T4G p.Tyr569Asp D579G c.1736 A4G p.Asp579Gly D614G c.1841 A4G p.Asp614Gly S977F c.2930C4T p.Ser977Phe F1052V c.3154 T4G p.Phe1052Val G1069R c.3205G4A p.Gly1069Arg R1070Q c.3209G4A p.Arg1070Gln D1152H c.3454G4C p.Asp1152His I1234V c.3700 A4G p.Ile1234Val 5T c.1210 - 12[5] Examples of common not CF-causing variantsc R31C c.91C4T p.Arg31Cys R74W c.220C4T p.Arg74Trp R75Q c.224G4A p.Arg75Gln I148T c.443 T4C p.Ile148Thr M470V c.1408 A4G p.Met470Val G576A c.1727G4C p.Gly576Ala R668C c.2002C4T p.Arg668Cys V754M c.2260G4A p.Val754Met L997F c.2991G4C p.Leu997Phe I1027T c.3080 T4C p.Ile1027Thr R1070W c.3208C4T p.Arg1070Trp R1162L c.3485G4T p.Arg1162Leu Table 1 (Continued) HGVS nomenclature Legacy name cDNA nucleotide name Protein name S1235R c.3705 T4G p.Ser1235Arg D1270N c.3808G4A p.Asp1270Asn 7T c.1210-12[7] Abbreviation: HGVS, Human Genome Variation Society. Login to comment