ABCMdb

ABCC7 p.Ser912Leu

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Publications

PMID: 16126774 [PubMed] Morea A et al: "Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility."

No. Sentence Comment

76 This test involved nine subjects from the infertile group, revealing the occurrence of the following rare mutations: E217G, T1054A, W356X, D443Y and 3667insTC in males and L997F and R297Q in females and 29 subjects from the control, in which we found: A1009T, D110Y, E826K, G1069R, G1130A, G194V, I556V, L320F, M348K, M82V, P1290T, R117C, R352W, R74W, S42F, S660T, S911R, S912L, T1086A, T582S, V920L and Y89C. Login to comment

PMID: 16189704 [PubMed] McGinniss MJ et al: "Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples."

No. Sentence Comment

72 The two deletions Table 2 Atypical CF or nonclassic patients in whom extensive sequencing revealed two CFTR mutations Patient Genotype Phenotype Sex Age (years) Sweat chloride concentration (mmol/l) 1 p.S912L/DF508 Chronic lung and sinus disease F 52 Not done 2 p.R1070W/p.N1303K Recurrent respiratory infections F 4.5 2X intermediate 3 p.G551D/c.2789+2 InsA Pancreatic insufficiency, little lung involvement F 50 92, 96 4 c.3849+10kb C>T/p.L732X Failure to thrive, chronic cough, chronic sinusitis M 5.5 70,73 5 p.W1282X/p.R170H Chronic pancreatitis, CBVAD M 44 Borderline (c.1641 AG>T, and c.2949-2953 del TACTC) are expected to be severe disease-associated mutations, since they change the CFTR reading frame; the two patients harboring these novel deletions had a diagnosis of CF with elevated sweat chloride levels and carried a second, previously described, CF mutation. Login to comment

PMID: 19885835 [PubMed] McWilliams RR et al: "Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma."

No. Sentence Comment

95 S42F has been described in 1 Italian CF patient.25 E528E is a synonymous polymorphism involving the last base pair in exon 10 (1716 G > A), which has been reported to affect splicing, but has not been linked to severe pulmonary disease.26 S912L is thought to be a neutral variant (serine for a leucine), unless in cis position to another mutation.27 The F1052V missense mutation is a variant with a modest effect, with normal or near-normal sweat chloride tests in combination with other mild variants.28,29 N1088S is a novel mutation that substitutes asparagine for a serine amino acid, both positively charged, and its functionality is unclear. Login to comment
103 Compound Heterozygotes Among Pancreatic Cancer Cases CFTR Mutations Sex Age at Diagnosis, y Ever/Never Smoker Family History of Pancreatic Cancer Pancreatitis ‡3 Years Before Cancer Diagnosis df508/S42F M 70 Nonsmoker No No R117H/E528E (splice site) M 75 Smoker Yes No df508/S912L W 56 Smoker No No df508/N1088S W 73 Smoker No No df508/M1191I M 79 Smoker No No df508/S1235R M 73 Smoker No No df508/F1052V M 49 Smoker No No df508/5T M 60 Smoker No No Man indicates man; W, woman. Login to comment

PMID: 20167849 [PubMed] Bienvenu T et al: "Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis."

No. Sentence Comment

82 GENOTYPE AND PHENOTYPE OF PATIENTS WITH DIFFUSE BRONCHIECTASIS BEARING TWO CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MUTATIONS Patient No. Age (yr) Sex (M/F) CFTR Mutations Sweat Cl2 (mmol/L) Basal PD (mV) NPD Index Age at Onset (yr) FEV1 (% pred) Bacteria Colonization 1 55 F F508del/D1152H 19 219 1.00 54 99 Sa 2 71 F F508del/G576A-R668C 29 223 0.44 70 114 None 3 24 M G542X/3849110kbCT 52 224 1.22 10 78 Pa 4 41 F 394delTT/D1152H 19 225 0.30 41 89 Sa 5 31 M 3849110kbC.T/3849110kbC.T 35 230 0.64 2 30 Sa/Pa 6 74 F G542X/S912L 40 233 0.19 60 106 None 7 50 M W1282X/D1152H 35 236 1.00 10 32 Pa 8 42 F F508del/D1152H 13 240 0.68 30 32 Pa 9 56 F F508del/IVS8-5T 30 242 0.70 10 70 None 10 45 F 394delTT/D1152H 25 242 0.71 18 62 Sa/Pa 11 74 F W1282X/D1152H 25 244 0.66 12 56 Pa 12 23 F S1206X/D1152H 19 244 0.68 13 107 None 13 41 F R553X/R851L-T351S 31 248 0.50 35 72 Pa 14 58 M F508del/R117H-7T 46 251 0.61 45 35 Sa/Pa 15 53 F F508del/R347H 49 258 0.63 40 77 Pa Definition of abbreviations: Cl2 5 chloride; F 5 female; M 5 male; NPD index 5 nasal potential difference index 5 e(response to øCl2 and iso/response to amil); a cut off . Login to comment

PMID: 20706124 [PubMed] Lucarelli M et al: "A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation."

No. Sentence Comment

103 In vivo findings and, in some cases, in vitro functional characterizations have been reported for [F508C; S1251N],38 [R347H; D979A],39,40 [R74W; D1270N],41 [G628R; S1235R],42,43 [M470V; S1235R],42 [S912L; G1244V],44 [R117H; (TG)mTn],45-47 [R117C; (TG)mTn],46 [S1235R; (TG)mT5],48 [G576A; R668C],10,49 [V562I; A1006E],49 [R352W; P750L],49 [1198_1203del TGGGCT; 1204GϾA],49 [V754M; CFTRdele3_10,14b_16],50 and [F508del; I1027T].51 These complex alleles have been found in patients with either CF or CFTR-RD, although more often in the former. Login to comment
105 Both in vivo and in vitro studies have also highlighted cases in which there is one main mutation with the phenotypical effect that is worsened by a second mutation, which may even be a neutral variant when isolated, as occurs for F508C,38 R74W,41 S912L,44 and M470V.42 However, different effects have also been described, as in the case of the two M470 and R1235 variants, which give rise to a hyperactive CFTR when present on different alleles but have a suppressive effect when combined on the same allele.42 In addition, the finding of complex alleles in CFTR-RD seems to suggest that a second CFTR mutation may even lead to a partial reversion of the phenotype.43 Indeed, in a reduced number of complex alleles, the effect of the second mutation may partially correct the functional defect, thereby lessening the phenotypical effect, as has been demonstrated for the R553Q mutation in the [F508del; R553Q] complex allele by in vivo52 and in vitro53 studies and for the R553M mutation in the [F508del; R553M] complex allele by an in vitro study.53 A milder phenotypical effect has also been demonstrated for the [R334W; R1158X]54 and [-102T; S549R(TϾG)]55 complex alleles if compared with alleles carrying, respectively, isolated R1158X or S549R(TϾG). Login to comment

PMID: 15744523 [PubMed] Clain J et al: "A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype."

No. Sentence Comment

0 ORIGINAL INVESTIGATION Je´ roˆ me Clain Æ Jacqueline Lehmann-Che Emmanuelle Girodon Æ Joanna Lipecka Aleksander Edelman Æ Michel Goossens Pascale Fanen A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype Received: 1 September 2004 / Accepted: 12 December 2004 / Published online: 3 March 2005 Ó Springer-Verlag 2005 Abstract In order to further elucidate the contribution of complex alleles to the wide phenotypic variability of cystic fibrosis (CF), we investigated the structure-function relationships of a severe CF-associated complex allele [p.S912L;p.G1244V]. Login to comment
2 Both p.G1244V and [p.S912L;p.G1244V] mutants had normal protein processing but markedly decreased ClÀ channel activity compared with wild-type. Login to comment
4 p.S912L had normal protein processing and no detectable impact on CFTR function. Login to comment
5 In other respects, the p.S912L variation was identified in compound heterozygosity with p.R709X in a healthy fertile man. Login to comment
6 Together, these data strongly support the view that p.S912L in isolation should be considered as a neutral variant but one that might significantly impair CFTR function when inherited in cis with another CFTR mutation. Login to comment
14 The [p.S912L;p.G1244V] double-mutant allele is associated with severe CF (Savov et al. 1995). Login to comment
16 In vitro experiments and identification of a healthy fertile man bearing the [p.R709X]+[p.S912L] genotype both indicate that the p.S912L mutation should be considered to be a polymorphism. Login to comment
17 Surprisingly, the combination of p.S912L and p.G1244V decreases J. Clain Æ J. Lehmann-Che Æ E. Girodon M. Goossens Æ P. Fanen (&) Service de Biochimie et Ge´ ne´ tique, Hoˆ pital Henri Mondor, Institut National de la Sante´ et de la Recherche Me´ dicale U.468, AP-HP, 94010 Cre´ teil, France E-mail: pascale.fanen@im3.inserm.fr Tel.: +33-1-49812854 Fax: +33-1-48993345 J. Lipecka Æ A. Edelman Faculte´ de Me´ decine Necker, Institut National de la Sante´ et de la Reche0rche Me´ dicale U.467, 156 Rue de Vaugirard, 75015 Paris, France Hum Genet (2005) 116: 454-460 DOI 10.1007/s00439-004-1246-z cAMP-dependent ClÀ channel activity compared with p.G1244V, highlighting the deleterious effect exerted by polymorphisms on the phenotype when combined in cis with a mutation. Login to comment
54 The diagnosis of CF was confirmed in the fetus by the presence of two allelic mutations, 711+1G fi T, a splice mutation of intron 5 inherited from the mother, and p.R709X, a nonsense mutation of exon 13 inherited from the father; the father carried the p.S912L variant (not transmitted to the fetus) on the other chromosome. Login to comment
56 Results Processing of CFTR mutants To analyse the processing and ClÀ channel activity of p.S912L, p.G1244V and [p.S912L;p.G1244V] mutant proteins, wild-type and mutant CFTR alleles were expressed in HeLa cells. Login to comment
63 The kinetics of core-glycosylated and mature forms of mutant CFTRs were nearly identical to those of the wild-type, indicating that p.S912L, p.G1244V and [p.S912L;p.G1244V] mutations did not affect maturation of the CFTR protein. Login to comment
75 p.S912L- transfected cells displayed a similar proportion of responsive cells to wild-type cells (92% of responsive cells vs 83%; P>0.2; Fig.3), suggesting that ClÀ channel function was not affected by this mutation. Login to comment
76 Unlike p.S912L, the p.G1244V and [p.S912L; p.G1244V] CFTR transfected cells showed a marked decrease in cAMP-stimulated ClÀ conductance compared with wild-type (43% and 2.4% of responsive cells, respectively vs. Login to comment
79 Surprisingly, whereas the p.S912L mutation had no detectable impact on CFTR function, the [p.S912L;p.G1244V] complex allele showed an almost 20-fold reduction in cAMP-dependent conductive pathway compared with the p.G1244V deleterious mutant (2.4% of responsive cells vs. Login to comment
81 Discussion Clinical data suggest that the combination of p.S912L and p.G1244V mutations in cis ([p.S912L;p.G1244V] complex allele) produces a severe CF phenotype similar to that of p.F508del homozygotes. Login to comment
83 Thus, the poor ClÀ channel activity measured in vitro (2.4% of the wild-type) and the severity of the associated disease observed in vivo (pancreatic insufficiency, severe lung disease and elevated sweat electrolytes) both indicate that the [p.S912L;p.G1244V] complex allele should be considered to be a severe allele. Login to comment
85 In this study, we have Fig. 2 a-d Pulse-chase experiments showing the turnover of the immature and mature forms of wild-type and the mutant CFTR proteins (representative of two independent experiments) Table 1 Summary of MEQ fluorescence assay results from mock-transfected, wild-type and mutant cells Statistic DFstim-DFbasal Mock Wild-type p.S912L p.G1244V [p.S912L;p.G1244V] n 28 64 36 53 42 Mean 0.002 0.023 0.036 0.005 0.001 SEM 0.001 0.017 0.028 0.005 0.001 Range 0-0.005 0-0.340 0-0.140 0-0.034 0-0.006 provided functional and clinical evidence that the p.S912L mutation is not a disease-causing mutation on the basis of the following data. Login to comment
86 (1) In vitro experiments have shown that the p.S912L mutation has no detectable impact on CFTR processing and ClÀ channel function. Login to comment
89 Notably, the healthy father of a CF fetus carrying the p.S912L mutation has been identified in our laboratory in the framework of prenatal diagnosis, whereas the CF-associated p.R709X mutation (Bonizzato et al. 1995) has been detected on his other allele. Login to comment
91 Together, these data strongly support the view that the p.S912L mutation should be considered to be a neutral variant. Login to comment
96 Surprisingly, the p.G1244V and [p.S912L;p.G1244V] alleles affect in vitro ClÀ channel function in different ways. Login to comment
97 This might indicate that p.S912L and p.G1244V mutations occurring on the same allele cause severe structural alterations worsening the effect of the p.G1244V mutation on CFTR function. Login to comment
98 However, we cannot exclude the possibility that the p.S912L mutation may have a slight, but undetectable, effect on CFTR function and that a threshold is reached when these two mutations are combined in cis. Login to comment
99 An important consequence of our observation is that when a patient or an asymptomatic relative carries the p.S912L mutation, the p.G1244V mutation should be sought in order to exclude a CF allele; this is important for genetic counselling. Login to comment
100 These results have important implications for CF because they suggest that ''neutral`` missense mutations, such as p.S912L, might significantly alter CFTR function when inherited in cis with another mutation. Login to comment

PMID: 19236881 [PubMed] Enquist K et al: "Membrane-integration characteristics of two ABC transporters, CFTR and P-glycoprotein."

No. Sentence Comment

113 For CFTR, we chose mutations located in TM1CFTR (F87L, G91R), TM3CFTR (P205S, L206W), TM4CFTR (C225R), TM5CFTR (DF311, G314E), TM6CFTR (R334L/W, I336K/R/D, I340N/S, L346P, R347L/H), TM8CFTR (S909I, S912L), TM9CFTR (I1005R, A1006E), TM10CFTR (Y1032N), and TM12CFTR (M1137R, ΔM1140, M1140K), or close to the TM region of TM1CFTR (R74W, L102R/P), TMF2CFTR (R117P/L, L137P), and TM11CFTR (M1101K/R). Login to comment
109 For CFTR, we chose mutations located in TM1CFTR (F87L, G91R), TM3CFTR (P205S, L206W), TM4CFTR (C225R), TM5CFTR (DF311, G314E), TM6CFTR (R334L/W, I336K/R/D, I340N/S, L346P, R347L/H), TM8CFTR (S909I, S912L), TM9CFTR (I1005R, A1006E), TM10CFTR (Y1032N), and TM12CFTR (M1137R, ƊM1140, M1140K), or close to the TM region of TM1CFTR (R74W, L102R/P), TMF2CFTR (R117P/L, L137P), and TM11CFTR (M1101K/R). 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

107 of patients Main diagnosis Additional information Age at diagnosis Sweat test (Cl-,mmol/L) Allele 1 Allele 2 1 FBA Fetal death 20 wg NA p.[Gly576Ala;Arg668Cys] p.Ser1235Arg 1 FBA Unknown outcome p.Arg668Cys p.Phe508del 1 FBA Not CF at birth 38 wg NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] NI 1 FBA Not CF at birth 28 wg NA p.[Gly576Ala;Arg668Cys] NI 1 Healthy CF patient`s mother NA NA p.[Asp443Tyr;Gly576Ala;Arg668Cys] p.Phe508del 1 Healthy Newborn, elevated IRT but normal ST (not CF) Birth <30 p.[Gly576Ala;Arg668Cys] p.Phe508del 1 Healthy Mother of a CF fetus (p.[Phe508del]+ [phe508del]) NA NA p.[Gly576Ala;Arg668Cys] p.Phe508del 1 Healthy Mother of a fetus with FBA but not affected with CF NA NA p.[Gly576Ala;Arg668Cys] p.Phe508del 2 Healthy Mother of a fetus with FBA but not affected with CF NA NA p.[Gly576Ala;Arg668Cys] NI 1 Healthy CF patient`s mother 59 y NA p.[Gly576Ala;Arg668Cys] p.Phe508del 1 Healthy CF patient`s mother NA NA p.[Gly576Ala;Arg668Cys] p.[Ser912Leu;Asn1303Lys] 1 Healthy CF patient`s mother 32 y NA p.[Gly576Ala;Arg668Cys] p.Leu137Arg 1 Healthy CF carrier`s partner NA NA p.[Gly576Ala;Arg668Cys] c. Login to comment

PMID: 8528204 [PubMed] Savov A et al: "Double mutant alleles: are they rare?"

No. Sentence Comment

44 S912L and G1244V A C->T transition at nucleotide position 2867 in exon 15 and a G->T transversion at position 3863 in exon 20 of the CFTR gene were found in a patient who also carries G542X. Login to comment
45 The first missense mutation results in the substitution of leucine for serine (S912L) in the transmembrane region of the CFTR protein (TM8), whereas the second leads to the replacement of glycine by valine (G1244V) in the second nucleotide binding domain. Login to comment
55 The other double mutant CF allele detected in this study carries two missense mutations (S912L + G1244V) whose independent contribution to the clinical phenotype is difficult to evaluate. Login to comment
59 It is also possible that G1244V alone would result in mild CF and that S912L is the main defect in the double mutant S912L + G1244V allele. Login to comment
67 Neither S912L nor G1244V have been found to occur in isolation in any of our patients. Login to comment

PMID: 8825494 [PubMed] Zielenski J et al: "Cystic fibrosis: genotypic and phenotypic variations."

No. Sentence Comment

593 Not surprisingly, Rl17H is associated with CF only when the allele also contains Table 2 Examples of complex alleles in the CfTR gene Principal Second site mutationa Location alteration Location Reference R75X exon 3 125G --.. C promoter 57 405 + IG --.. A intron 3 3030G --.. A exon 15 57 R1l7H exon 4 129G --.. C promoter 203 RI17H exon 4 IVS8 : 5T or 7T intron 8 101 R297Q exon 7 IVS8 : 5T or 7T intron 8 60 aF508 exon 10 R553Q exon II 59 aF508 exon 10 1I027T exon I7a 57 8F508 exon 10 deletion of D7S8 500 kb 3' of 186 CfTR S549N exon II R75Q exon 3 205a L619S exon 13 1716G � A exon 10 57 G628R (G � C) exon 13 SI235R exon 19 47 2184insA exon 13 IVS:5T exon 9 J Zielenski, J Bal, 0 Markiewicz, L-C Tsui, unpublished data A800G exon 13 IVS8 : 5T or 7T intran 8 31 S912L exon 15 GI244V exon 20 149 GlO69R exon 17b L88X exon 3 149 3732deiA exon 19 Kl200E exon 19 70 3849 + IOkbC � intron 19 R668C exon 13 57 T SI251N exon 20 F508C exon 10 94 The status of principal mutation may not be clear in every case; e.g. G628R(G --> C) vs S1235R. Login to comment

PMID: 24586523 [PubMed] Zietkiewicz E et al: "CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients."

No. Sentence Comment

57 Finally, S912L (SVM +2.12), found in a single chromosome with F508del in trans, has been reported in the CFMDB as pathogenic only if in cis with c.3067-3072del6; since the latter was not found in the analyzed patient, we considered S912L a neutral polymorphism. Login to comment
101 The more recent estimates provide much lower values, ranging from 1:5000 [14], 1:6000 cited in WHO 2002 report [15] to 1:7500 for Southeastern Poland estimated for a 1-year period of Table 2. Cont. Exon / intron (legacy) Exon / intron (Ensembl) Protein change SVM value cDNA (HGVS nomenclature) gDNA (cDNA +132 bp) Number of PL CF chromosomes Reference a Mutations in trans 15 17 L967S 0.27 c.2900T.C 3032T.C 1 CFMDB; rs1800110 unknown 18 21 D1152H 0.50 c.3454G.C 3586G.C 1 CFMDB; rs75541969 F508del Sequence changes considered as lacking pathogenic effect 4 4 I148T 2.04 c.443T.U 575T.U 4 IL19e unknown 13 14 I752V 0.35 c.2254A.G 2386A.G 1 Novelf F508 15 17 S912L 2.12 c.2735C.T 2867C.T 1 CFMDBg ; rs121909034 F508 Legend: a IL19 i 17 - mutations included in the INNOLiPA tests (see below); CFMDB - non-INNOLiPA mutations present in the CTFR mutation database; novel - mutations first reported in this study; b in three chromosomes R668C with G576A in trans; c F508del, c.1585-1G.A, G542X, N1303K or c.579+3A.G; d F508del, G542X, R553X or N1303K; e not pathogenic if not in cis with c.3067-72del6 (l.n.3199del6); f not pathogenic - see explanation the text; g not pathogenic if not in cis with G1244V. 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

54 [1117-8A>G;1727G>C; 2002C>T]) and mutations G1069R (p.Gly1069Arg), D614G (p.Asp614Gly), S42F (p.Ser42Phe) and S912L (p.Ser912Leu) should also be considered as part of this extension, even if not found in CF-PI but studied up to the DEL step because they are found in genotypes with an unknown allele. Login to comment
385 [Gly576Ala;Arg668Cys] D579G c.1736A>G CF-PS varying clinical consequence p.Asp579Gly E585X c.1753G>T CF-PI CF-causing p.Glu585* H609L c.1826A>T CFTR-RD nd p.His609Leu A613T c.1837G>A CF-PS nd p.Ala613Thr D614G c.1841A>G CF-PS unknown significance p.Asp614Gly 2143delT c.2012delT CF-PS CF-causing p.Leu671* 2183AA>G c.2051_2052delAAinsG CF-PI,CF-PS CF-causing p.Lys684SerfsX38 2184insA c.2052_2053insA CF-PI CF-causing p.Gln685ThrfsX4 R709X c.2125C>T CF-PI CF-causing p.Arg709* L732X c.2195T>G CF-PI CF-causing p.Leu732* R764X c.2290C>T CF-PI CF-causing p.Arg764* Q779X c.2335C>T uncertain: CF-PI and/or CF-PS nd p.Gln779* E831X c.2491G>T CF-PS CF-causing p.Glu831* Y849X c.2547C>A CF-PI CF-causing p.Tyr849* ex14b-17bdel c.2620-674_3367+198del9858 CF-PI nd 2789+5G>A c.2657+5G>A CF-PI,CF-PS CF-causing 2790-2A>G c.2658-2A>G CF-PS nd S912L c.2735C>T uncertain: found only with an unknown allele in trans nd p.Ser912Leu S945L c.2834C>T CF-PS CF-causing p.Ser945Leu S977F c.2930C>T CFTR-RD varying clinical consequence p.Ser977Phe L997F c.2991G>C CF-PS,CFTR-RD,CBAVD non CF-causing p.Leu997Phe ex17a-18del c.2988+1173_3468+2111del8600 CF-PI nd P1013L c.3038C>T CFTR-RD nd p.Pro1013Leu Y1032C c.3095A>G CFTR-RD nd p.Tyr1032Cys 3272-26A>G c.3140-26A>G CF-PS CF-causing L1065P c.3194T>C CF-PI,CF-PS CF-causing p.Leu1065Pro L1065R c.3194T>G uncertain: CF-PI and/or CF-PS nd p.Leu1065Arg R1066C c.3196C>T CF-PI CF-causing p.Arg1066Cys R1066H c.3197G>A CF-PI CF-causing p.Arg1066His G1069R c.3205G>A uncertain: found only with an unknown allele in trans varying clinical consequence p.Gly1069Arg Continued on next page of 0.021). Login to comment