ABCMdb

ABCC7 p.Ile444Ser

ClinVar:	c.1331T>G , p.Ile444Ser ? , not provided
CF databases:	c.1331T>C , p.Ile444Thr (CFTR1) ? , The I444T Mutation was detected by DPHLC and direct sequencing. The CFTR screening was performed on the spouse of a F508del heterozygote. We don't know yet if I444T is a polymorphism or a real mutation. We will investigate the question. c.1331T>G , p.Ile444Ser (CFTR1) ? , The mutation was detected by multiplex heteroduplex analysis on the MDE gel matrix. It was found in one CF patient (second mutation: [delta]F508).
Predicted by SNAP2:	A: D (75%), C: D (59%), D: D (91%), E: D (85%), F: D (66%), G: D (91%), H: D (85%), K: D (91%), L: N (87%), M: D (63%), N: D (85%), P: D (91%), Q: D (80%), R: D (85%), S: D (80%), T: D (80%), V: N (87%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Missense, nonsense, and neutral mutations define j... J Biol Chem. 2003 Jul 18;278(29):26580-8. Epub 2003 May 5. Pagani F, Buratti E, Stuani C, Baralle FE
Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9.
J Biol Chem. 2003 Jul 18;278(29):26580-8. Epub 2003 May 5., 2003-07-18 [PMID:12732620]

Abstract [show]
Exonic sequence variations may induce exon inclusion or exclusion from the mature mRNA by disrupting exonic regulatory elements and/or by affecting a nuclear reading frame scanning mechanism. We have carried out a systematic study of the effect on cystic fibrosis transmembrane regulator exon 9 splicing of natural and site-directed sequence mutations. We have observed that changes in the splicing pattern were not related to the creation of premature termination codons, a fact that indicates the lack of a significant nuclear check of the reading frame in this system. In addition, the splice pattern could not be predicted by available Ser/Arg protein matrices score analysis. An extensive site-directed mutagenesis of the 3' portion of the exon has identified two juxtaposed splicing enhancer and silencer elements. The study of double mutants at these regulatory elements showed a complex regulatory activity. For example, one natural mutation (146C) enhances exon inclusion and overrides all of the downstream silencing mutations except for a C to G transversion (155G). This unusual effect is explained by the creation of a specific binding site for the inhibitory splicing factor hnRNPH. In fact, on the double mutant 146C-155G, the silencing effect is dominant. These results indicate a strict dependence between the two juxtaposed enhancer and silencer sequences and show that many point mutations in these elements cause changes in splicing efficiency by different mechanisms.

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Sentences [show]
No. Sentence Comment
83 Four of the natural substitutions, C31T (Q414X), G61A (G424S), T122G (I444S), and C155A (A455E), significantly decreased exon 9 inclusion to 48, 30, 40, and 16%, respectively, whereas only a modest decrease was evident for N418S. Login to comment
221 WT sequence position AA change Nucleotide mutants Exon 9ϩ SR protein matrices above thresholds Disruption of preexisting sites New sites created by the mutations SC35 SR40 SF2 SR55 % WT 65 A 15 C 65 T 16 ⌬ 96 T 18 G 95 3.38 (13) G 19 A 52 A 20 G 80 C 31 Q414X T 50 A 43 G 62 SR40 0.28 (41) A 44 N414S G 59 46t49t 67 SR40 1.43 (41) G 61 G424S A 31 C 58 66g67a69g 68 SR40-1.01 (66) 3.21 (63) 2.24 (64) C 72 G 18 2.20 (67) A 63 2.01 (69) G 118 D443Y T 68 A 65 120g122a123g 96 2.24 (118) T 122 I444S G 40 A 144 G 55 T 40 C 145 G 85 A 87 A 146 G 92 3.02 (146) 2.66 (141) T 94 3.23 (143) Q452P C 96 3.46 (143) ⌬ 97 2.81 (142) 3.03 (141) G 147 T 97 C 98 2.70 (142) 3.00 (144) 2.53 (143) T 148 G 26 2.99 (142) 4.05 (143) C 90 2.49 (143) 2.47 (145) A 93 3.46 (145) T 149 C 82 2.99 (144) 3.53 (145) G 150 A 50 3.38 (148) C 62 T 151 A 65 C 67 3.00 (146) 3.15 (148) G 153 C 65 T 42 2.76 (153) G 154 T 18 C 20 C 155 A455E A 15 1.98 (152) G 3 T 5 G 156 T 10 3.59 (153) C 40 3.82 (153) G 157 V456F T 65 G 164ϩ ins 14 regulatory sequences derived from SR-specific score matrices, and the creation of novel enhancer and silencer controlling elements. Login to comment

[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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Sentences [show]
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). Login to comment