ABCC7 p.Pro1290Ser
| ClinVar: |
c.3870A>G
,
p.Pro1290=
N
, Benign/Likely benign
c.3868C>T , p.Pro1290Ser ? , not provided |
| CF databases: |
c.3868C>A
,
p.Pro1290Thr
(CFTR1)
?
, The mutation was detected by DGGE analysis and characterized by direct sequencing. We have seen it only twice, in over 500 control chromosomes from Italian population.
c.3868C>T , p.Pro1290Ser (CFTR1) ? , The missense mutation was detected by DGGE and identified by direct sequencing. It was found on the paternal chromosome in a CBAVD patient, with his maternal chromosome carrying 3272-26A→G. The mutation was not observed in 218 other CFTR alleles from 109 healthy fertile males, 90 chromosomes from 45 CBAVD patients, 30 chromosomes from 15 children carrying one CF mutation and 10 chromosomes from 5 CF patients. This mutation creates an EcoRV restriction site. |
| Predicted by SNAP2: | A: D (59%), C: D (53%), D: D (71%), E: D (75%), F: D (75%), G: D (71%), H: D (66%), I: D (71%), K: D (80%), L: N (72%), M: D (66%), N: N (53%), Q: D (63%), R: D (80%), S: N (53%), T: N (82%), V: D (66%), W: D (80%), Y: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Molecular characterization of the cystic fibrosis ... Genet Med. 2007 Mar;9(3):163-72. Grangeia A, Sa R, Carvalho F, Martin J, Girodon E, Silva J, Ferraz L, Barros A, Sousa M
Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens.
Genet Med. 2007 Mar;9(3):163-72., [PMID:17413420]
Abstract [show]
PURPOSE: Approximately 20% of patients with congenital absence of the vas deferens remain without two mutations identified. We applied a strategy of serial screening steps to 45 patients with congenital absence of the vas deferens and characterized cystic fibrosis transmembrane conductance regulator gene mutations in all cases. METHODS: DNA samples of 45 patients with congenital absence of the vas deferens were screened by successive different molecular genetics approaches. RESULTS: Initial screening for the 31 most frequent cystic fibrosis mutations, IVS8 poly(TG)m, poly(T)n, and M470V polymorphisms, identified 8 different mutations in 40 patients (88.9%). Extensive cystic fibrosis transmembrane conductance regulator gene analysis by denaturing gradient gel electrophoresis, denaturing high-performance liquid chromatography, and DNA sequencing detected 17 further mutations, of which three were novel. Cystic fibrosis transmembrane conductance regulator gene rearrangements were searched by semiquantitative fluorescent multiplex polymerase chain reaction, which detected a CFTRdele2,3 (21 kb) large deletion and confirmed two homozygous mutations. Overall, 42 patients (93.3%) had two mutations and 3 patients (6.7%) had one mutation detected. CONCLUSIONS: The present screening strategy allowed a higher mutation detection rate than previous studies, with at least one cystic fibrosis transmembrane conductance regulator gene mutation found in all patients with congenital absence of the vas deferens.
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No. Sentence Comment
93 DeltaF508 was the second most common mutation, representing 21 (23.3%) of total alleles, followed by R334W (6, Table 1 CFTR gene mutations and polymorphisms in patients with congenital absence of the vas deferens Mutation Location Nucleotide alteration Effect Method 1 CFTRdele2,3 Exons 2-3 Deletion of exons 2 and 3 Frameshift QFM-PCR 2 R117H Exon 4 G¡A at 482 AA substitution 31 mutation panel 3 P205S Exon 6a C¡T at 745 AA substitution DGGE/dHPLC 4 L206W Exon 6a T¡G at 749 AA substitution DGGE/dHPLC 5 R258G Exon 6b A¡G at 904 AA substitution DGGE/dHPLC 6 R334W Exon 7 C¡T at 1132 AA substitution 31 mutation panel 7 T5 allele Intron 8 Deletion of 2T at 1342-12 to -6 Aberrant splicing DGGE/DNA sequencing 8 P439S Exon 9 C¡T at 1447 AA substitution DGGE/dHPLC 9 D443Ya Exon 9 G¡T at 1459 AA substitution DGGE/dHPLC 10 I507del Exon 10 Deletion of 3 bp at 1648-1653 AA deletion 31 mutation panel 11 DeltaF508 Exon 10 Deletion of 3 bp at 1652-1655 AA deletion 31 mutation panel 12 G542X Exon 11 G¡T at 1756 Truncation 31 mutation panel 13 V562I Exon 12 G¡A at 1816 AA substitution DGGE/dHPLC 14 G576Aa Exon 12 G¡C at 1859 Aberrant splicing DGGE/dHPLC 15 D614G Exon 13 A¡G at 1973 AA substitution DGGE/dHPLC 16 R688Ca Exon 13 C¡T at 2134 AA substitution DGGE/dHPLC 17 V754M Exon 13 G¡A at 2392 AA substitution DGGE/dHPLC 18 E831X Exon 14a G¡T at 2623 Truncation DGGE/dHPLC 19 3272-26AϾG Intron 17a A¡G at 3272-26 Aberrant splicing DGGE/dHPLC 20 2789ϩ5G¡A Intron 14b G¡A at 2789ϩ5 Aberrant splicing 31 mutation panel 21 V1108L Exon 17b G¡C at 3454 AA substitution DGGE/dHPLC 22 L1227S Exon 19 T¡C at 3812 AA substitution DGGE/dHPLC 23 S1235R Exon 19 T¡G at 3837 AA substitution DGGE/dHPLC 24 P1290S Exon 20 C¡T at 4000 AA substitution DGGE/dHPLC 25 N1303K Exon 21 C¡G at 4041 AA substitution 31 mutation panel 26 E1401K Exon 23 G¡A at 4333 AA substitution DGGE/dHPLC Polymorphisms 1 TG repeats Intron 8 9-13 copies at 1342-12 to -35 Sequence variation DGGE/DNA sequencing 2 M470V Exon 10 A or G at 1540 Sequence variation DNA sequencing 3 125G/C Exon 1 G¡C at 125 Sequence variation DGGE/dHPLC 4 1001ϩ11T/C Intron 6b C¡4T at 1001ϩ11 Sequence variation DGGE/dHPLC 5 1716G/A Exon 10 G¡A at 1716 Sequence variation DGGE/dHPLC 6 1899-136T/G Intron 12 T¡G at 1899-136 Sequence variation DGGE/dHPLC 7 T854T Exon 14a T¡G at 2694 Sequence variation DGGE/dHPLC 8 3601-65C/A Intron 18 C¡A at 3601-65 Sequence variation DGGE/dHPLC 9 4521G/A Exon 24 G¡A at 4521 Sequence variation DGGE/dHPLC QFM-PCR, semiquantitative fluorescent multiplex polymerase chain reaction; bp, base pair; DGGE, denaturing gradient gel electrophoresis; dHPLC, denaturing high-performance liquid chromatography.
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ABCC7 p.Pro1290Ser 17413420:93:1809
status: NEW101 The missense M470V polymorphism was evaluated in all 45 pa- tientswithCAVD(Table2).TheallelicfrequencyoftheM470variant Table 2 CFTR genotypes identified in patients with congenital absence of the vas deferens CFTR mutation genotypes [(TG)mTn] genotype M470V Patients N % DeltaF508 (TG)10T9 (TG)12T5 M V 11 24.4 DeltaF508 (TG)10T9 (TG)11T5 M M 1 2.2 DeltaF508 R117H (TG)10T9 (TG)10T7 M M 2 4.4 G542X (TG)10T9 (TG)12T5 M V 2a 4.4 DeltaF508 R334W (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 D443Y-G576A-R668C (TG)10T9 (TG)10T7 M M 1 2.2 DeltaF508 D614G (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 E831X (TG)10T9 (TG)11T7 M V 1 2.2 DeltaF508 L1227S (TG)10T9 (TG)11T7 M M 1 2.2 DeltaF508 E1401K (TG)10T9 (TG)11T7 M V 1 2.2 I507del D614G (TG)11T7 (TG)10T7 M V 1 2.2 N1303K L206W (TG)10T9 (TG)9T9 M M 1 2.2 R117H P205S (TG)11T7 (TG)10T7 M V 1 2.2 R117H R334W (TG)10T7 (TG)11T7 M V 1 2.2 R334W P439S (TG)11T7 (TG)11T7 M V 1 2.2 R334W R334Wb (TG)11T7 (TG)11T7 V V 1 2.2 R334W V562I (TG)11T7 (TG)11T5 V M 1 2.2 D443Y-G576A-R668C 3272-26A¡G (TG)10T7 (TG)10T7 M M 1 2.2 G576A-R668C V754Mb (TG)10T7 (TG)11T7 M M 1 2.2 S1235R S1235Rb (TG)13T5 (TG)13T5 M M 1 2.2 2789ϩ5G¡A S1235Rb (TG)10T7 (TG)13T5 M M 1 2.2 3272-26A¡G P1290S (TG)11T7 (TG)10T7 M V 1 2.2 P205S (TG)11T7 (TG)12T5 V V 1 2.2 G576A-R668C b (TG)10T7 (TG)11T5 M M 1 2.2 V1108L b (TG)11T7 (TG)11T5 V M 1 2.2 N1303K (TG)10T9 (TG)12T5 M V 1 2.2 3272-26A¡G b (TG)10T7 (TG)12T5 M V 1 2.2 CFTRdele2,3 b (TG)11T7 (TG)13T5 V M 1 2.2 b (TG)11T5 (TG)12T5 M V 1 2.2 b (TG)13T5 (TG)12T5 M V 1 2.2 DeltaF508 - (TG)10T9 (TG)11T7 M V 1a 2.2 L206W -b (TG)9T9 (TG)11T7 M V 1 2.2 R258G -b (TG)11T7 (TG)11T7 V V 1 2.2 a CUAVD.
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ABCC7 p.Pro1290Ser 17413420:101:1214
status: NEW110 Large Table 3 Allelic frequencies of CFTR mutations in patients with congenital absence of the vas deferens CBAVD CUAVD Total Patients 42 3 45 Alleles 84 6 90 Mutations N % N % N % 1 T5 allele 26a 31 2 33.3 28 31.1 2 DeltaF508 20 23.8 1 16.7 21 23.3 3 R334W 6a 7.1 0 0 6 6.7 4 R117H 4 4.8 0 0 4 4.4 5 G576A 4b 4.8 0 0 4 4.4 6 R688C 4b 4.8 0 0 4 4.4 7 S1235R 3a 3.6 0 0 3 3.3 8 3272-26A¡G 3 3.6 0 0 3 3.3 9 P205S 2 2.4 0 0 2 2.2 10 L206W 2 2.4 0 0 2 2.2 11 D443Y 2b 2.4 0 0 2 2.2 13 D614G 2 2.4 0 0 2 2.2 14 N1303K 2 2.4 0 0 2 2.2 12 G542X 0 0 2 33.3 2 2.2 15 R258G 1 1.2 0 0 1 1.1 16 P439S 1 1.2 0 0 1 1.1 17 I507del 1 1.2 0 0 1 1.1 18 V562I 1 1.2 0 0 1 1.1 19 V754M 1 1.2 0 0 1 1.1 20 E831X 1 1.2 0 0 1 1.1 21 2789ϩ5G¡A 1 1.2 0 0 1 1.1 22 V1108L 1 1.2 0 0 1 1.1 23 L1227S 1 1.2 0 0 1 1.1 24 P1290S 1 1.2 0 0 1 1.1 25 E1401K 1 1.2 0 0 1 1.1 26 CFTRdele2,3 1 1.2 0 0 1 1.1 CBAVD, congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens.
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ABCC7 p.Pro1290Ser 17413420:110:808
status: NEW[hide] Molecular and functional characterization of CBAVD... Cell Physiol Biochem. 2008;22(1-4):79-92. Epub 2008 Jul 25. Grangeia A, Barro-Soria R, Carvalho F, Damas AM, Mauricio AC, Kunzelmann K, Barros A, Sousa M
Molecular and functional characterization of CBAVD-causing mutations located in CFTR nucleotide-binding domains.
Cell Physiol Biochem. 2008;22(1-4):79-92. Epub 2008 Jul 25., [PMID:18769034]
Abstract [show]
BACKGROUND: About 98% of male affected with cystic fibrosis (CF [MIM 219700]) are infertile due to bilateral absence of vas deferens (CBAVD [MIM 277180]), which makes up 1-2 % of all cases with male infertility. A previous screening of the entire coding region of the cystic fibrosis transmembrane conductance regulator gene (CFTR [MIM 602421]) in CBAVD patients identified three novel mutations: P439S is located in the first nucleotide binding domain (NBD1) of CFTR, whereas P1290S and E1401K are located in NBD2. METHODS: We analysed the effects of these novel mutations on CFTR processing and chloride (Cl(-)) channel activity. RESULTS: Although maturation patterns were not affected, total amounts of mature P439S-CFTR and P1290S-CFTR were reduced. Confocal microscopy showed correct membrane localisation of E1401K-CFTR, whereas P439S-CFTR and P1290S-CFTR mutants were located mainly in the cytoplasm. Iodide influx assay and whole-cell patch clamp demonstrated significantly reduced cAMP-dependent anion conductances for all three mutants. CONCLUSION: Dysfunction of CFTR is caused by either defective CFTR trafficking (P439S and P1290S) or/and Cl- channel function (P1290S and E1401K). Thus reduced Cl- conductance caused by the three CFTR mutations affects normal development of vas deferens and leads to CBAVD, but the remaining function is sufficient to prevent other typical CF symptoms.
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No. Sentence Comment
2 A previous screening of the entire coding region of the cystic fibrosis transmembrane conductance regulator gene (CFTR [MIM 602421]) in CBAVD patients identified three novel mutations: P439S is located in the first nucleotide binding domain (NBD1) of CFTR, whereas P1290S and E1401K are located in NBD2.
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ABCC7 p.Pro1290Ser 18769034:2:265
status: NEW4 Results: Although maturation patterns were not affected, total amounts of mature P439S-CFTR and P1290S-CFTR were reduced.
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ABCC7 p.Pro1290Ser 18769034:4:96
status: NEW5 Confocal microscopy showed correct membrane localisation of E1401K-CFTR, whereas P439S-CFTR and P1290S-CFTR mutants were located mainly in the cytoplasm.
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ABCC7 p.Pro1290Ser 18769034:5:96
status: NEW7 Conclusion: Dysfunction of CFTR is caused by either defective CFTR trafficking (P439S and P1290S) or/and Cl-channel function (P1290S and E1401K).
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ABCC7 p.Pro1290Ser 18769034:7:90
status: NEWX
ABCC7 p.Pro1290Ser 18769034:7:126
status: NEW59 Plasmids, cell culture, transient transfection CFTR mutations (P439S, P1290S and E1401K) were generated (QuikChange site-directed mutagenesis kit, Stratagene, La Jolla, CA) in the eukaryotic expression vector pCMVCFTRNot6.2, according to the manufacturer`s instructions.
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ABCC7 p.Pro1290Ser 18769034:59:70
status: NEW103 P1290S (NBD2) was identified in a 45 year old patient heterozygous for the Table 1.
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ABCC7 p.Pro1290Ser 18769034:103:0
status: NEW112 Multiple alignments of CFTR amino acid sequences from different species and localization of NBD1, NBD2 and three novel CFTR mutations (P439S, P1290S, E1401K).
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ABCC7 p.Pro1290Ser 18769034:112:142
status: NEW126 Biosynthesis of CFTR mutants Maturation patterns of wild-type (wt) CFTR and mutant CFTR (F508del-CFTR, P439S-CFTR, P1290S-CFTR and E1401K-CFTR) were compared by Western blotting.
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ABCC7 p.Pro1290Ser 18769034:126:115
status: NEW130 However, total amounts of mature P439S-CFTR and P1290S-CFTR were significantly reduced compared to wtCFTR, as indicated by densitometric analysis (Fig. 2B).
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ABCC7 p.Pro1290Ser 18769034:130:48
status: NEW137 The mutants P439S-CFTR and P1290S-CFTR were mainly expressed in the cytoplasm with little membrane expression, while E1401K-CFTR was clearly present in the cell membrane, similar to wtCFTR (Fig. 3A-B).
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ABCC7 p.Pro1290Ser 18769034:137:27
status: NEW143 P439S-CFTR and P1290S-CFTR are detected predominantly in the cytoplasm but to some degree also in the plasma membrane.
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ABCC7 p.Pro1290Ser 18769034:143:15
status: NEW159 Intracellular cAMP was enhanced by stimulation of the cells with 2 µM FSK and 100 µM IBMX, which largely increased the rate of I- influx in HEK293 cells expressing wtCFTR, while non-transfected cells or F508del-CFTR expressing cellsdidnotrespondtostimulation(Fig.4A-B).Expression of all three mutants P439S-CFTR, P1290S-CFTR and E1401K-CFTR allowed for cAMP-induced increase in I- influx, although the rate of I- influx was significantly lower than that for wtCFTR (Fig. 4A-B).
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ABCC7 p.Pro1290Ser 18769034:159:323
status: NEW160 Reduced I- influx seems to be in accordance with the reduced levels of protein expression for two mutants P439S-CFTR, P1290S-CFTR.Although E1401K did not interfere with Fig. 5.
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ABCC7 p.Pro1290Ser 18769034:160:118
status: NEW165 GFP = green fluorescence protein, wt = wtCFTR, F508del = F508del-CFTR, P439S = P439S-CFTR, P1290S = P1290S-CFTR, E1401K = E1401K-CFTR.
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ABCC7 p.Pro1290Ser 18769034:165:91
status: NEWX
ABCC7 p.Pro1290Ser 18769034:165:100
status: NEW168 C) Effect of IBMX (100 µM) and forskolin (2 µM) on whole-cell currents of non-transfected cells and in cells expressing wtCFTR, F508del-CFTR and P1290S-CFTR.
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ABCC7 p.Pro1290Ser 18769034:168:155
status: NEW169 Current-voltage curves where mean whole-cell currents (in nA) were plotted against the Vc values (in mV), in non-transfected (black trace) and wtCFTR (red trace) expressing cells (left panel), and in cells expressing F508del-CFTR (black trace) or P1290S-CFTR (blue trace) (right panel).
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ABCC7 p.Pro1290Ser 18769034:169:247
status: NEW178 Similar to the results from I- uptake studies, CFTR mutants P439S-CFTR, P1290S-CFTR and E1401K-CFTR showed a reduced but significant current increase and activation of whole cell conductance.
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ABCC7 p.Pro1290Ser 18769034:178:72
status: NEW180 Figure 5C represents current-voltage (IV) curves, where mean whole-cell currents (in nA) were plotted against the Vc values (in mV), in non-transfected cells and HEK293 cells expressing wtCFTR (left panel), and in HEK293 cells expressing F508del-CFTR and P1290S-CFTR (right panel).
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ABCC7 p.Pro1290Ser 18769034:180:255
status: NEW188 Highlights of the possible location of E1401K and P1290S mutations refer to the SAV1866 model.
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ABCC7 p.Pro1290Ser 18769034:188:50
status: NEW198 While P439S and E1401K are close toATP binding sites and therefore likely to affect NBD-dimerization andATP binding, respectively, P1290S is located near the interface NBD/MSD, and may interfere with side-chain contacts within the membrane spanning subunit.
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ABCC7 p.Pro1290Ser 18769034:198:131
status: NEW200 In the present study, we report biochemical and functional data on three CFTR missense mutations located in NBD1 (P439S) and in NBD2 (P1290S, E1401K).
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ABCC7 p.Pro1290Ser 18769034:200:134
status: NEW212 P1290S was detected in a patient with additional 3272-26A→G mild mutation on the other chromosome.
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ABCC7 p.Pro1290Ser 18769034:212:0
status: NEW220 Densitometric analysis showed that the ratio of mature fully-glycosylated to immature core-glycosylated bands detected for P439S-CFTR and P1290S-CFTR was lower than those obtained for wtCFTR, indicating that P439S and P1290S mutations cause dysfunction of CFTR by decreasing total amounts of mature protein.
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ABCC7 p.Pro1290Ser 18769034:220:138
status: NEWX
ABCC7 p.Pro1290Ser 18769034:220:218
status: NEW221 Sub-cellular localization of the three CFTR mutants in HEK293 cells indicated dramatically reduced membrane staining for P439S-CFTR and P1290S-CFTR and suggests biosynthetic arrest of CFTR maturation similar to F508del-CFTR [43, 47].
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ABCC7 p.Pro1290Ser 18769034:221:136
status: NEW224 Thus E1401K probably reduces the activity of CFTR Cl- chan- nels while P439S-CFTR and P1290S-CFTR reduce the number of CFTR channels in the membrane.
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ABCC7 p.Pro1290Ser 18769034:224:86
status: NEW225 Further studies using single channel patch clamp will assess if E1401K reduces whole cell conductance by affecting channel open probability or single channel conductance, and if P439S and P1290S also affect CFTR channel pore/gating mechanism.
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ABCC7 p.Pro1290Ser 18769034:225:188
status: NEW228 P1290S (proline → serine) is located just before the Q-loop glutamine residue, near the interface between NBD and MSD (Figs.
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ABCC7 p.Pro1290Ser 18769034:228:0
status: NEW247 Polyphen analysis indicated that while E1401K (PSIC 1.609) is "possibly damaging", P439S (PSIC 2.396) and P1290S (PSIC 2.108) are "probably damaging" (deleterious) to protein function.
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ABCC7 p.Pro1290Ser 18769034:247:106
status: NEW250 Although, data obtained with the available bioinformatic tools must be interpreted with caution, these results confirmed experimental data, suggesting that P439S, P1290S and E1401K interfere with protein function.
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ABCC7 p.Pro1290Ser 18769034:250:163
status: NEW253 The other two missense mutations, P439S and P1290S, cause a decrease in the total amounts of the mature protein that might be attributed to a defective processing or an increased protein turnover.
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ABCC7 p.Pro1290Ser 18769034:253:44
status: NEW255 Conversely, P1290S appears to affect the NBD1-MSD interaction and thus the overall folding of the entire protein.
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ABCC7 p.Pro1290Ser 18769034:255:12
status: NEW256 Based on present data and in what has been established for the classification of different CFTR mutations, P439S and P1290S might be classified as class V mutations, associated with reduced levels of normally functioning CFTR.
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ABCC7 p.Pro1290Ser 18769034:256:117
status: NEW258 In addition, P1290S is also likely to cause a defective CFTR activity by affecting signalling with the MSD, and therefore P1290S might also be classified as a class III mutation.
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ABCC7 p.Pro1290Ser 18769034:258:13
status: NEWX
ABCC7 p.Pro1290Ser 18769034:258:122
status: NEW259 This observation might explain the lower whole-cell Cl- currents determined for P1290S-CFTR when compared with P439S-CFTR and E1401K-CFTR.
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ABCC7 p.Pro1290Ser 18769034:259:80
status: NEW264 Although P439S, P1290S and E1401K might not lead to a typical CF phenotpye, the knowledge of the mechanism by which they affect CFTR, improve the ability to interpret and predict the clinical phenotype in patients carrying the studied mutations and may give important insights about the molecular consequences of similar sequence alterations that have been, or remain to be characterized.
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ABCC7 p.Pro1290Ser 18769034:264:16
status: NEW[hide] Do common in silico tools predict the clinical con... Clin Genet. 2010 May;77(5):464-73. Epub 2009 Jan 6. Dorfman R, Nalpathamkalam T, Taylor C, Gonska T, Keenan K, Yuan XW, Corey M, Tsui LC, Zielenski J, Durie P
Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?
Clin Genet. 2010 May;77(5):464-73. Epub 2009 Jan 6., [PMID:20059485]
Abstract [show]
Computational methods are used to predict the molecular consequences of amino-acid substitutions on the basis of evolutionary conservation or protein structure, but their utility in clinical diagnosis or prediction of disease outcome has not been well validated. We evaluated three popular computer programs, namely, PANTHER, SIFT and PolyPhen, by comparing the predicted clinical outcomes for a group of known CFTR missense mutations against the diagnosis of cystic fibrosis (CF) and clinical manifestations in cohorts of subjects with CF-disease and CFTR-related disorders carrying these mutations. Owing to poor specificity, none of tools reliably distinguished between individual mutations that confer CF disease from mutations found in subjects with a CFTR-related disorder or no disease. Prediction scores for CFTR mutations derived from PANTHER showed a significant overall statistical correlation with the spectrum of disease severity associated with mutations in the CFTR gene. In contrast, PolyPhen- and SIFT-derived scores only showed significant differences between CF-causing and non-CF variants. Current computational methods are not recommended for establishing or excluding a CF diagnosis, notably as a newborn screening strategy or in patients with equivocal test results.
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No. Sentence Comment
64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure).
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ABCC7 p.Pro1290Ser 20059485:64:314
status: NEW[hide] The CFTR polymorphisms poly-T, TG-repeats and M470... Asian J Androl. 2012 Sep;14(5):687-90. doi: 10.1038/aja.2012.43. Epub 2012 Jul 30. Ni WH, Jiang L, Fei QJ, Jin JY, Yang X, Huang XF
The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens.
Asian J Androl. 2012 Sep;14(5):687-90. doi: 10.1038/aja.2012.43. Epub 2012 Jul 30., [PMID:22842702]
Abstract [show]
Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia, and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have also been frequently identified in patients with CBAVD. However, the distribution of the CFTR polymorphisms M470V, poly-T, TG-repeats and F508del mutation in the Chinese CBAVD population with presumed low cystic fibrosis (CF) frequency remains to be evaluated. Samples obtained from 109 Chinese infertile males with CBAVD and 104 normal controls were analyzed for the presence of CFTR (TG)m(T)n, M470V and F508del by PCR amplification followed by direct sequencing. Our study showed that the F508del mutation was not found in our patients. The 5T mutation was present with high frequency in Chinese CBAVD patients and IVS8-5T linked to either 12 or 13 TG repeats was highly prevalent among CBAVD patients (97.22% of 72 cases and 96.91% of 97 alleles with IVS8-5T). Moreover, a statistically significant relationship between TG12-5T-V470 haplotype and CBAVD was detected. This study indicated that the CFTR polymorphisms poly-T, TG-repeats and M470V might affect the process of CBAVD in the Chinese population.
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107 N Engl J Med 1995; 332: 1475-80. 24 Grangeia A, Carvalho F, Fernandes S, Silva J, Sousa M et al. A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens.
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ABCC7 p.Pro1290Ser 22842702:107:123
status: NEW103 N Engl J Med 1995; 332: 1475-80. 24 Grangeia A, Carvalho F, Fernandes S, Silva J, Sousa M et al. A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens.
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ABCC7 p.Pro1290Ser 22842702:103:123
status: NEW[hide] A novel missense mutation P1290S at exon-20 of the... Fertil Steril. 2005 Feb;83(2):448-51. Grangeia A, Carvalho F, Fernandes S, Silva J, Sousa M, Barros A
A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens.
Fertil Steril. 2005 Feb;83(2):448-51., [PMID:15705389]
Abstract [show]
OBJECTIVE: To report a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene missense mutation in a compound heterozygote with congenital bilateral absence of the vas deferens (CBAVD). DESIGN: Descriptive, controlled study. SETTING: Tertiary academic hospital genetics laboratory and private in vitro fertilization (IVF) clinic. PATIENT(S): One 46-year-old man with CBAVD and no clinical cystic fibrosis (CF) phenotype as indicated by the advanced age at diagnosis, absence of chronic airways and gastrointestinal disease, and normal pancreatic function and sweat chloride concentration. Genomic blood DNA from the patient's parents was analyzed to perform family studies, and 109 fertile men, 32 patients with CBAVD, 15 children carriers of one CFTR mutation, and 5 patients with CF were used to rule out polymorphism. INTERVENTION(S): Clinical evaluation and treatment, genetical screenings. MAIN OUTCOME MEASURE(S): Clinical data, biochemical assays, spermiogram analysis, testicle biopsy, intracytoplasmic sperm injection (ICSI) outcome, and CFTR whole gene mutation screening and IVS8T polymorphism. RESULT(S): The DNA analysis revealed a 7T/7T homozygote at IVS8-T, with a 4000C-->T change (P1290S) in exon 20 of the CFTR gene, which was inherited from the patient's father. It was associated with a 3272-26A-->G mutation in the other allele that was inherited from his mother. CONCLUSION(S): The novel P1290S missense CFTR mutation causes an amino acid change in a highly conserved region of the CFTR protein that controls channel opening. Pathogenicity is suggested by development of CBAVD in association with a mild CFTR mutation.
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No. Sentence Comment
0 A novel missense mutation P1290S at exon-20 of the CFTR gene in a Portuguese patient with congenital bilateral absence of the vas deferens Ana Grangeia, B.Sc.,a Filipa Carvalho, Ph.D.,a Susana Fernandes, Ph.D.,a Joaquina Silva, M.D.,b Mário Sousa, M.D., Ph.D.,a,b,c and Alberto Barros, M.D., Ph.D.a,b a Department of Genetics, Faculty of Medicine, University of Porto; b Centre for Reproductive Genetics Alberto Barros; and c Lab Cell Biology, ICBAS, University of Porto, Porto, Portugal Objective: To report a novel cystic fibrosis transmembrane conductance regulator (CFTR) gene missense mutation in a compound heterozygote with congenital bilateral absence of the vas deferens (CBAVD).
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ABCC7 p.Pro1290Ser 15705389:0:26
status: NEW7 Result(s): The DNA analysis revealed a 7T/7T homozygote at IVS8-T, with a 4000C3T change (P1290S) in exon 20 of the CFTR gene, which was inherited from the patient`s father.
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ABCC7 p.Pro1290Ser 15705389:7:90
status: NEW9 Conclusion(s): The novel P1290S missense CFTR mutation causes an amino acid change in a highly conserved region of the CFTR protein that controls channel opening.
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ABCC7 p.Pro1290Ser 15705389:9:25
status: NEW58 Analysis of exon 20 in the patient revealed a novel missense mutation, with a C to T nucleotide change at position 4000 (P1290S mutation) that leads to substitution of a proline by a serine in the CFTR protein (Fig. 1A, B).
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ABCC7 p.Pro1290Ser 15705389:58:121
status: NEW60 Restriction analysis was thus used to screen and confirm the P1290S mutation as well as reveal that it was inherited from the father and not from the mother (see Fig. 1C).
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ABCC7 p.Pro1290Ser 15705389:60:61
status: NEW61 To rule out the possibility of P1290S being a polymorphism, we analyzed 218 normal chromosomes from 109 fertile and healthy Portuguese males, 64 chromosomes from 32 patients with obstructive azoospermia due to congenital absence of the vas deferens (some of them with CFTR mutations identified), 30 chromosomes from 15 children carrying one CFTR mutation, and 10 chromosomes from five patients with confirmed CF (two CFTR mutations detected).
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ABCC7 p.Pro1290Ser 15705389:61:31
status: NEW62 In all cases, absence of the P1290S mutation was confirmed as no C3T was found at position 4000 of exon 20 in the CFTR gene.
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ABCC7 p.Pro1290Ser 15705389:62:29
status: NEW64 DISCUSSION Direct sequencing and DGGE in a CBAVD heterozygote patient for the 3272-26A3G mutation identified a novel P1290S CFTR mutation.
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ABCC7 p.Pro1290Ser 15705389:64:117
status: NEW68 Several lines of evidence suggest that the present P1290S missense CFTR mutation might be pathogenic.
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ABCC7 p.Pro1290Ser 15705389:68:51
status: NEW71 Third, and although the isolated P1290S mutation had no substantial effect per se (the patient`s father is healthy and fertile), when associated with a mild CFTR mutation (P1290S/3272-26A3G) it caused a CBAVD phenotype in the present patient.
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ABCC7 p.Pro1290Ser 15705389:71:33
status: NEWX
ABCC7 p.Pro1290Ser 15705389:71:172
status: NEW74 These data thus support the present findings, where the novel P1290S CFTR mutation was diagnosed at the age of 46 in an infertile CBAVD patient who had no clinical CF phenotype.
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ABCC7 p.Pro1290Ser 15705389:74:62
status: NEW84 Novel P1290S CFTR mutation in CBAVD.
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ABCC7 p.Pro1290Ser 15705389:84:6
status: NEW87 Novel P1290S CFTR mutation in CBAVD Vol. 83, No.
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ABCC7 p.Pro1290Ser 15705389:87:6
status: NEW