ABCMdb

PMID: 20059485

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., [PubMed]

Sentences

No. Mutations Sentence Comment

34 ABCC7 p.Gly551Asp Within this cohort, we identified subjects who carried common CFTR missense mutations in trans to the p.F508del mutation, p.G551D or Class I mutations (large deletions and nonsense mutations), because they are known to be disease causing and were functionally validated to abolish CFTR function. Login to comment 57 ABCC7 p.Gly551Asp ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Pro67Leu ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys PI prevalence and in silico prediction scores for 13 most frequent missense mutations identified in Canadian CF patients Mutation Total PI Total (PI + PS) PI prevalence Class PANTHER scorea POLYPHENa SIFTa p.R334W 1 9 0.11 CF-PS -7.4419 Possibly damaging 0.01 p.P67L 2 14 0.14 CF-PS -4.1736 Probably damaging 0 p.R347P 2 12 0.17 CF-PS -7.5259 Possibly damaging 0.01 p.R347H 1 5 0.20 CF-PS -6.8327 Possibly damaging 0 p.A455E 8 39 0.21 CF-PS -8.8641 Probably damaging 0 p.L206W 4 19 0.21 CF-PS -8.5817 Possibly damaging 0 p.P574H 4 7 0.57 CF-PI/PSb -8.1252 Probably damaging 0 p.G85E 15 24 0.63 CF-PI/PSb -7.3194 Possibly damaging 0 p.M1101K 22 33 0.67 CF-PI/PSb -5.8849 Probably damaging 0.01 p.R1066C 7 8 0.88 CF-PI -7.7424 Probably damaging 0 p.G551D 56 59 0.95 CF-PI -9.5654 Probably damaging 0 p.N1303K 47 49 0.96 CF-PI -9.7687 Probably damaging 0 p.V520F 7 7 1.00 CF-PI -7.1652 Benign 0 aPANTHER scores range from zero to negative values (maximum -12). Login to comment 64 ABCC7 p.Gly551Asp ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Ser1251Asn ABCC7 p.Arg352Gln ABCC7 p.Ile148Thr ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg560Thr ABCC7 p.Arg75Gln ABCC7 p.Pro67Leu ABCC7 p.Thr338Ile ABCC7 p.Met1101Lys ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Gly27Glu ABCC7 p.Arg668Cys ABCC7 p.Asp443Tyr ABCC7 p.Ile1027Thr ABCC7 p.Arg170His ABCC7 p.Val938Gly ABCC7 p.Tyr563Asn ABCC7 p.Arg792Gly ABCC7 p.Ala800Gly ABCC7 p.Leu558Ser ABCC7 p.Leu1077Pro ABCC7 p.Asp110Tyr ABCC7 p.Pro1021Ser ABCC7 p.Arg766Met ABCC7 p.Gln1291His ABCC7 p.Trp1098Arg ABCC7 p.Leu375Phe ABCC7 p.Ile980Lys ABCC7 p.Arg560Lys ABCC7 p.Gly178Arg ABCC7 p.Thr908Asn ABCC7 p.Pro111Ala ABCC7 p.Ala559Thr ABCC7 p.Asp614Gly ABCC7 p.Asp579Gly ABCC7 p.Tyr1032Cys ABCC7 p.Gly458Val ABCC7 p.Thr1053Ile ABCC7 p.Ile444Ser ABCC7 p.Leu1335Pro ABCC7 p.His199Arg ABCC7 p.Asp1154Gly ABCC7 p.Pro499Ala ABCC7 p.Val920Leu ABCC7 p.Val392Gly ABCC7 p.Lys1351Glu ABCC7 p.Gly1247Arg ABCC7 p.Leu320Val ABCC7 p.Ala1364Val ABCC7 p.Leu183Ile ABCC7 p.Glu1401Lys ABCC7 p.Pro1290Ser ABCC7 p.Arg810Gly ABCC7 p.Gly85Val ABCC7 p.Pro574Ser ABCC7 p.Thr351Ser ABCC7 p.Phe1337Val ABCC7 p.Ser1118Cys ABCC7 p.Leu1414Ser ABCC7 p.Val1240Gly ABCC7 p.Leu1339Phe ABCC7 p.Ile918Met ABCC7 p.Gln151Lys ABCC7 p.Asp1305Glu ABCC7 p.Arg248Thr ABCC7 p.Pro841Arg ABCC7 p.Phe994Cys ABCC7 p.His949Arg ABCC7 p.Val392Ala ABCC7 p.Asp58Gly ABCC7 p.Arg555Gly ABCC7 p.Leu137His ABCC7 p.Glu1409Lys ABCC7 p.Ser50Tyr ABCC7 p.Ile203Met ABCC7 p.Leu1388Gln ABCC7 p.Arg933Gly ABCC7 p.Met469Val ABCC7 p.Glu528Asp ABCC7 p.Met244Lys ABCC7 p.Leu90Ser ABCC7 p.Phe200Ile ABCC7 p.Cys866Arg ABCC7 p.Gly550Arg ABCC7 p.Ser549Lys ABCC7 p.Leu973Pro ABCC7 p.Glu1401Gly ABCC7 p.Ile1234Leu 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 120 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys For example, low scores (-9.56 to -9.77) were generated for mutations (p.G551D, p.N1303K) with high PI prevalence scores (0.95-0.96). Login to comment 121 ABCC7 p.Pro67Leu ABCC7 p.Met1101Lys Intermediate prediction scores (-7.32 to -5.88) were given for p.G86E, p.M1101K mutations with intermediate PI scores (0.63 and 0.67, respectively), and a low score (-4.17) was assigned to p.P67L with a low PI score (0.14). Login to comment 122 ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Leu206Trp However, it completely misclassified other well-established mutations with low PI prevalence scores (p.L206W, p.R334W, p.R347P and p.A455E). Login to comment 124 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Asn1303Lys ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Pro67Leu SIFT-generated low (deleterious) scores for missense mutations associated both with the highest (p.N1303K, p.G551D, p.V520F) and the lowest PI prevalence scores (p.A455E, p.P67L, p.L206W). Login to comment 126 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro However, two mutations with low PI prevalence scores (p.R347P and p.R334W) were also predicted to be deleterious (Fig. S1b, supporting information online). Login to comment 127 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Asn1303Lys While PolyPhen correctly classified the PI-CF mutations p.G551D and p.N1303K as 'probably damaging`, it misclassified the mild PS mutations p.A455E and p.P65L into the same category (Fig. S1c, supporting information online). Login to comment 128 ABCC7 p.Val520Phe ABCC7 p.Met1101Lys Conversely, PolyPhen assigned the intermediate mutation p.M1101K with other PS mutations as 'possibly damaging`, and the p.V520F was misclassified as 'benign`. Login to comment 129 ABCC7 p.Arg347Pro ABCC7 p.Arg347His A disparity in prediction scores between two mild CF-PS mutations (p.R347H and p.R347P) that confer an amino acid change in the same position of the protein points to another limitation of these tools. Login to comment 151 ABCC7 p.Arg75Gln For example, the R at position 75 is highly conserved, but R75Q is known to be a very mild mutation. Login to comment 152 ABCC7 p.Val520Phe In contrast, V520 is less conserved, but V520F is a severe mutation. Login to comment 155 ABCC7 p.Arg117His Prediction tools would not be capable of predicting the variable penetrance of the p.R117H mutation, which is dependent for it`s splicing efficiency, on the length of the poly-T-tract in intron 8 (IVS8-5T, 7T and 9T) (26-28). Login to comment 156 ABCC7 p.Arg117His ABCC7 p.Arg117His While p.R117H-5T is common in CF-PS patients, p. R117H-7T is usually found in individuals with other CFTR-related disorders. Login to comment 157 ABCC7 p.Ile148Thr Also, prediction tools will fail to account for missense mutations that are found as complex alleles (29) such as I148T (30), which subsequently was shown to be a neutral mutation, which cosegregates with a bona fide disease-causing deletion 3199del6 in exon 20 (31). Login to comment