ABCMdb

ABCC7 p.Arg1066Ser

ClinVar:	c.3197G>A , p.Arg1066His D , Pathogenic c.3197G>T , p.Arg1066Leu ? , not provided c.3196C>A , p.Arg1066Ser ? , not provided c.3196C>T , p.Arg1066Cys D , Pathogenic
CF databases:	c.3197G>A , p.Arg1066His D , CF-causing ; CFTR1: This mutation was found on one CF chromosome, the other haplotype carries an unidentified mutation. The child is twenty years old, pancreatic sufficient, that missense mutation could be considered as a mild allele. c.3196C>T , p.Arg1066Cys D , CF-causing ; CFTR1: This mutation cannot be detected by restriction enzyme analysis, and they have been observed only once among 65 non-[delta]F508 CF chromosomes. c.3196C>G , p.Arg1066Gly (CFTR1) D , c.3196C>A , p.Arg1066Ser (CFTR1) ? , The above mutation was found by DGGE and direct sequencing in Caucasian patients. c.3197G>T , p.Arg1066Leu (CFTR1) ? , This is the third mutation describe at this codon 1066 which contains a CpG dinucleotide and appears to be a hot spot for mutations. The mutation was found once among more than 250 CF chromosomes we have analyzed in exon 17b.
Predicted by SNAP2:	A: D (95%), C: D (71%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (53%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Complete and rapid scanning of the cystic fibrosis... Hum Genet. 2001 Apr;108(4):290-8. Le Marechal C, Audrezet MP, Quere I, Raguenes O, Langonne S, Ferec C
Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling.
Hum Genet. 2001 Apr;108(4):290-8., [PMID:11379874]

Abstract [show]
More than 900 mutations and more than 200 different polymorphisms have now been reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ten years after the cloning of the CFTR gene, the complete scanning of the 27 exons to identify known and novel mutations remains challenging. Rapid accurate identification of mutated alleles is important for prenatal diagnosis, for cascade screening in families at risk of cystic fibrosis (CF) and for understanding the correlation between genotype and phenotype. In this study, we report the successful use of denaturing ion-pair reverse-phase high performance liquid chromatography (D-HPLC) to analyse rapidly the complete coding sequence of the CFTR gene. With 27 pairs of polymerase chain reaction primers, we optimised the temperature conditions required for the analysis of each amplicon and validated thetest conditions on samples from a panel of 1552 CF patients who came from France and other European countries and who had mutations and polymorphisms located in the various melting domains of the gene. D-HPLC identified 415 mutated alleles previously characterised by denaturing gradient gel electrophoresis and DNA sequencing, plus 74 novel mutations reported here. This new technique for screening DNA for sequence variation was extremely accurate (it identified 100% of the CFTR alleles tested so far) and rapid (the complete CFTR gene could be analysed in less than a week). Our approach should reduce the number of untyped CF alleles in populations and thus decrease the residual risk in couples at risk of CF. This technique may be important not only for CF,but also for many other genes with a high frequency of point mutations at a variety of sites.

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133 296 Table 2 (continued) Exon/ intron Mutant name Nucleic acid change Amino acid change Effect on amino acid sequence Patient 16 S 977 F C to Tat 3062 Ser to Phe at 977 (TCC to TTC) Missense CF patient 17a G 1003 X G to T at 3139 Gly to Stop at 1003 (GGA to TGA) Nonsense CF patient 17a Q 1042 X C to T at 3256 Gln to Stop at 1042 (CAA to TAA) Nonsense CF patient 17b L 1059 L A to G at 3309 Leu to Leu at 1059 (TTA to TTG) Silent Control 17b R 1066 S C to A at 3328 Arg to Ser at 1066 (CGT to AGT) Missense CF patient 17b T 1115 T C to A at 3477 Thr to Thr at 1115 (ACC to ACA) Silent Control 17b 3499+6 A to G A to G at 3499 Splicing CF patient 17b 3499+7 T to G T to G at 3499+7 Splicing Control 18 Delta M 1140 Deletion of 3 pb Frameshift CF patient 18 M 1140 K T to A at 3551 Met to Lys at 1140 (ATG to AAG) Missense Bronchiectasis 19 S 1159 F C to T at 3608 Ser to Phe at 1159 (TCT to TTT) Missense CF patient 19 S 1161 R C to G at 3615 Ser to Arg at 1161 (AGC to AGG) Missense CF patient 19 S 1206 X C to G at 3749 Ser to Stop at 1206 (TCA to TGA) Nonsense CF patient 20 F 1257 L T to G at 3903 Phe to Leu at 1257 (TTT to TTG) Missense CF patient 20 4005+33 A to G A to G at 4005 +33 Splicing Bronchiectasis 21 V1293I G to A at 4009 Val to Ile at 1293 Missense Control 21 4015 Del A Deletion of A at 4015 Frameshift CF patient 21 N 1303 I A to T at 4040 Asn to Ile at 1303 (AAC to ATC) Missense CF patient 21 P 1306 P C to T at 4050 Pro to Pro at 1306 (CCC to CCT) Silent CF patient 21 E 1308 X G to T at 4064 Glu to Stop at 1308 (GAA to TAA) Nonsense CF patient 22 4172 Del GC Deletion of GC at 4172 Frameshift CF patient 22 R 1358 S A to T at 4206 Arg to Ser at 1358 (AGA to AGT) Missense Control 22 I 1366 T T to C at 4229 Ile to Thr at 1366 (ATC to ACC) Missense Control 23 4374+10 T to C T to C at 4374+ 10 Splicing CF patient 24 D 1477 D T to C at 4563 Asp to Asp at 1477 (GAT to GAC) Silent Control This new tool thus greatly improves genetic counselling. Login to comment

[hide] Multimutational analysis of eleven cystic fibrosis... Clin Chem. 2004 Nov;50(11):2155-7. Farez-Vidal ME, Gomez-Llorente C, Blanco S, Morales P, Casals T, Gomez-Capilla JA
Multimutational analysis of eleven cystic fibrosis mutations common in the Mediterranean areas.
Clin Chem. 2004 Nov;50(11):2155-7., [PMID:15502086]

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51 Two multiplex reactions were designed for the analysis of 11 mutations: multiplex 1 (M1) analyzed K710X, R1066C/R1066S, 2869 insG, and Q890X polymorphisms; and multiplex 2 (M2) analyzed L206W, 1609delCA, R1066L/R1066H, R709X, and 1811 ϩ 1.6Kb polymorphisms. Login to comment

[hide] Genotyping microarray for the detection of more th... J Mol Diagn. 2005 Aug;7(3):375-87. Schrijver I, Oitmaa E, Metspalu A, Gardner P
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations.
J Mol Diagn. 2005 Aug;7(3):375-87., [PMID:16049310]

Abstract [show]
Cystic fibrosis (CF), which is due to mutations in the cystic fibrosis transmembrane conductance regulator gene, is a common life-shortening disease. Although CF occurs with the highest incidence in Caucasians, it also occurs in other ethnicities with variable frequency. Recent national guidelines suggest that all couples contemplating pregnancy should be informed of molecular screening for CF carrier status for purposes of genetic counseling. Commercially available CF carrier screening panels offer a limited panel of mutations, however, making them insufficiently sensitive for certain groups within an ethnically diverse population. This discrepancy is even more pronounced when such carrier screening panels are used for diagnostic purposes. By means of arrayed primer extension technology, we have designed a genotyping microarray with 204 probe sites for CF transmembrane conductance regulator gene mutation detection. The arrayed primer extension array, based on a platform technology for disease detection with multiple applications, is a robust, cost-effective, and easily modifiable assay suitable for CF carrier screening and disease detection.

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53 Table 1. Continued CFTR location Amino acid change Nucleotide change 141 IVS 16 Splicing defect 3120 ϩ 1GϾA 142 IVS 16 Splicing defect 3121 - 2AϾG 143 IVS 16 Splicing defect 3121 - 2AϾT 144 E 17a Frameshift 3132delTG 145 E 17a I1005R 3146TϾG 146 E 17a Frameshift 3171delC 147 E 17a Frameshift 3171insC 148 E 17a del V1022 and I1023 3199del6 149 E 17a Splicing defect 3271delGG 150 IVS 17a Possible splicing defect 3272 - 26AϾG 151 E 17b G1061R 3313GϾC 152 E 17b R1066C 3328CϾT 153 E 17b R1066S 3328CϾA 154 E 17b R1066H 3329GϾA 155 E 17b R1066L 3329GϾT 156 E 17b G1069R 3337GϾA 157 E 17b R1070Q 3341GϾA 158 E 17b R1070P 3341GϾC 159 E 17b L1077P 3362TϾC 160 E 17b W1089X 3398GϾA 161 E 17b Y1092X (TAA) 3408CϾA 162 E 17b Y1092X (TAG) 3408CϾG 163 E 17b L1093P 3410TϾC 164 E 17b W1098R 3424TϾC 165 E 17b Q1100P 3431AϾC 166 E 17b M1101K 3434TϾA 167 E 17b M1101R 3434TϾG 168 IVS 17b 3500 - 2AϾT 3500 - 2AϾT 169 IVS 17b Splicing defect 3500 - 2AϾG 170 E 18 D1152H 3586GϾC 171 E 19 R1158X 3604CϾT 172 E 19 R1162X 3616CϾT 173 E 19 Frameshift 3659delC 174 E 19 S1196X 3719CϾG 175 E 19 S1196T 3719TϾC 176 E 19 Frameshift and K1200E 3732delA and 3730AϾG 177 E 19 Frameshift 3791delC 178 E 19 Frameshift 3821delT 179 E 19 S1235R 3837TϾG 180 E 19 Q1238X 3844CϾT 181 IVS 19 Possible splicing defect 3849 ϩ 4AϾG 182 IVS 19 Splicing defect 3849 ϩ 10 kb CϾT 183 IVS 19 Splicing defect 3850 - 1GϾA 184 E 20 G1244E 3863GϾA 185 E 20 G1244V 3863GϾT 186 E 20 Frameshift 3876delA 187 E 20 G1249E 3878GϾA 188 E 20 S1251N 3884GϾA 189 E 20 T1252P 3886AϾC 190 E 20 S1255X 3896CϾA and 3739AϾG in E19 191 E 20 S1255L 3896CϾT 192 E 20 Frameshift 3905insT 193 E 20 D1270N 3940GϾA 194 E 20 W1282R 3976TϾC 195 E 20 W1282X 3978GϾA 196 E 20 W1282C 3978GϾT 197 E 20 R1283M 3980GϾT 198 E 20 R1283K 3980GϾA 199 IVS 20 Splicing defect 4005 ϩ 1GϾA 200 E 21 Frameshift 4010del4 201 E 21 Frameshift 4016insT 202 E 22 Inframe del E21 del E21 203 E 21 N1303K 4041CϾG 204 E 24 Frameshift 4382delA Genomic and Synthetic Template Samples Where possible, native genomic DNA was collected. Login to comment

[hide] Missense mutations in the cystic fibrosis gene in ... Hum Mutat. 1999;14(6):510-9. Lazaro C, de Cid R, Sunyer J, Soriano J, Gimenez J, Alvarez M, Casals T, Anto JM, Estivill X
Missense mutations in the cystic fibrosis gene in adult patients with asthma.
Hum Mutat. 1999;14(6):510-9., [PMID:10571949]

Abstract [show]
Asthma is a complex genetic disorder that affects 5% of adults and 10% of children worldwide. The complete characterization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified missense mutations in 15% of 144 unrelated adult patients with asthma, but in none of 41 subjects from the general population. The four more common mutations were analyzed in an extended sample consisting of 184 individuals from the general population and did not show a significant difference in frequency. The hyperfunctional CFTR M470 allele was detected in 90% of patients with CFTR missense mutations, but in 63% of subjects from the general population and 63% of asthma patients without CFTR mutations. None of the patients with missense mutations had the 5T allele of intron 8 of CFTR, responsible for low CFTR levels, while it was detected in 8% of asthma patients without CFTR mutations and in 9% of subjects from the general population. These findings suggest a putative role for a combination of CFTR missense mutations, including the M470 allele, in the genetic variability of asthma.

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93 Characteristics of 15 Amino Acid Variants/Mutants in the CFTR Gene Detected in 21 Patients With Asthma Other Evolutive Conservative Other mutations Mutation1 Reference2 Exon Domain3 Patients4 phenotypes5 conservation6 change7 at same position R74W Claustres et al., 1993 3 IC1 1 CF-PS/CBAVD b, m, r, s NC - R75Q Zielenski et al., 1991 3 IC2 4 CF-PS/DB/CBAVD/ b, d, m, r, s, x NC R75X (CF) CF Parents R75L (CBAVD) I148T Bozon et al., 1994 4 IC2 1 CF-PS b, d, m, r, s, x NC I148N (CF) A534Q This report 11 NBF1 1 - b, m NC A534E (CF) G576A Fanen et al., 1992 12 NBF1 3 CF-PS/CBAVD b, m, r, s NC G576X (CF) T582R Casals et al., 1997 12 NBF1 1 CF-PS b, d, m, r, s, x NC T582I (CF) R668C Fanen et al., 1992 13 R 5 DB/CF-PS/CBAVD/ b, d, m, r, s, x NC - CF Parents V855I This report 14a IC6 1 - b, r, s C - T896I This report 15 EC4 1 - b, d, m, r, s NC - L997F Fanen et al., 1992 17a TM9 3 DB/CF-PS/CBAVD/ b, d, m, r, s, x C - non-CF M1028R This report 17a TM10 1 - d NC M1028I (CF) T2066C Fanen et al., 1992 17b IC8 1 DB/CF-PI b, d, m, r, s, x NC R1066S (CF) R1066L (CF) R1066H (CF/CBAVD) T1142I This report 18 TM12 1 - b, d, m, r, s, x NC - R1162L Fanen et al., 1992 19 IC9 1 non-CF b, d, m, r, s, x NC R1162X (CF) T1220I Ghanem et al., 1994 19 NBF2 1 DB/non-CF b, d NC - 1 Mutation name according to the Cystic Fibrosis Genetic Analysis Consortium. Login to comment

[hide] Effect of cystic fibrosis-associated mutations in ... J Biol Chem. 1996 Aug 30;271(35):21279-84. Cotten JF, Ostedgaard LS, Carson MR, Welsh MJ
Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator.
J Biol Chem. 1996 Aug 30;271(35):21279-84., [PMID:8702904]

Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) contains multiple membrane spanning sequences that form a Cl- channel pore and cytosolic domains that control the opening and closing of the channel. The fourth intracellular loop (ICL4), which connects the tenth and eleventh transmembrane spans, has a primary sequence that is highly conserved across species, is the site of a preserved sequence motif in the ABC transporter family, and contains a relatively large number of missense mutations associated with cystic fibrosis (CF). To investigate the role of ICL4 in CFTR function and to learn how CF mutations in this region disrupt function, we studied several CF-associated ICL4 mutants. We found that most ICL4 mutants disrupted the biosynthetic processing of CFTR, although not as severely as the most common DeltaF508 mutation. The mutations had no discernible effect on the channel's pore properties; but some altered gating behavior, the response to increasing concentrations of ATP, and stimulation in response to pyrophosphate. These effects on activity were similar to those observed with mutations in the nucleotide-binding domains, suggesting that ICL4 might help couple activity of the nucleotide-binding domains to gating of the Cl- channel pore. The data also explain how these mutations cause a loss of CFTR function and suggest that some patients with mutations in ICL4 may have a milder clinical phenotype because they retain partial activity of CFTR at the cell membrane.

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16 Examination of the distribution of CF-associated missense mutations shows that the fourth intracellular loop (ICL4) which lies between M10 and M11 is another region that contains many missense mutations: at least 19 CF-associated missense mutations have been discovered in this loop (Fig. 1) (15-20).2 Interestingly, one residue within ICL4, R1066, has been reported to have four separate CF-associated mutations: R1066C, R1066H, R1066L, and R1066S. Login to comment
31 2 R1066S (C. Fe´rec, I. Quere, C. Verlingue, O. Raguenes, M.-P. Au- drezet, and B. Mercier, personal communication), F1074L (T. Casals, M. D. Ramos, J. Gime´nez, V. Nunes, and X. Estivill, personal communication), K1060T (T. Casals, M. Chillo´n, V. Nunes, J. Gime´nez, M. D. Ramos, and X. Estivill, personal communication), L1065R (T. Casals, M. D. Ramos, J. Gime´nez, V. Nunes, and X. Estivill, personal communication), T1086I (T. Bienvenu, S. Bousquet, C. Herbulot, C. Beldjord, and J. C. Kaplan, personal communication), and R1070W (M. Macek, S. Sedriks, S. Kiesewetter, and G. R. Cutting, personal communication). Login to comment
15 Examination of the distribution of CF-associated missense mutations shows that the fourth intracellular loop (ICL4) which lies between M10 and M11 is another region that contains many missense mutations: at least 19 CF-associated missense mutations have been discovered in this loop (Fig. 1) (15-20).2 Interestingly, one residue within ICL4, R1066, has been reported to have four separate CF-associated mutations: R1066C, R1066H, R1066L, and R1066S. Login to comment
30 2 R1066S (C. Fe &#b4;rec, I. Quere, C. Verlingue, O. Raguenes, M.-P. Login to comment