ABCMdb

ABCC7 p.His139Leu

ClinVar:	c.416A>G , p.His139Arg ? , not provided c.416A>T , p.His139Leu ? , not provided
CF databases:	c.416A>G , p.His139Arg (CFTR1) ? , A novel mutation was identified by DGGE and direct sequencing in a CF patient of Italian patient. The nucleotide change is A->G at position 548 in exon 4 leading to H139R c.416A>T , p.His139Leu (CFTR1) ? , This mutation has been identified in exon 4 as H139L (A to T at 548) in six Bahraini patients that belong to five unrelated families. The first patient is a heterozygous H139L / K1177X. The second and third patients are heterozygous siblings for 3120+1G->A. Finally the last three unrelated patients are heterozygous H139L / Unknown.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), I: D (95%), K: D (95%), L: D (91%), M: D (95%), N: D (95%), P: D (95%), Q: D (85%), R: N (57%), 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, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Geographic distribution of cystic fibrosis transme... Ann Trop Paediatr. 1999 Mar;19(1):69-73. Banjar H, Kambouris M, Meyer BF, al-Mehaidib A, Mogarri I
Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia.
Ann Trop Paediatr. 1999 Mar;19(1):69-73., [PMID:10605524]

Abstract [show]
A descriptive study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Saudi Arabian cystic fibrosis (CF) population in relation to clinical presentation and demographic and ethnic origin. During the period October 1992 to September 1997, 70 patients from 46 families were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. Twelve mutations were identified in 34 families, which constitutes 70% of the CF alleles in the study group. Pancreatic insufficiency (PI) was found in the following mutations: 1548delG in exon 10 (15%) which occurred mainly in native Saudi patients in the central province; 3120 + 1G-->A in intron 16 (10%) and H139L in exon 4 (7%), found mainly in native Saudis from the eastern province; delta F508 mutation (13%) which occurred mainly in expatriates of Middle Eastern origin from different provinces; L117X in exon 19 (2%); G115X in exon 4 (2%); 711 + 1G-->A in intron 5 (2%); N 1303K in exon 21 (2%) and 425del42 in exon 4 (1%); I1234V in exon 19 (13%) with a predominance of nasal polyps and a variable degree of PI and lung disease; R553X in exon 11 (1%), with electrolyte imbalance; and S549R in 11 (2%) with pancreatic sufficiency and minimal pulmonary disease. The clinical picture did not differ significantly between patients of different ethnic origins with the same CFTR mutation.

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4 Pancreatic insuf® ciency (PI) was found in the following mutations: 1548delG in exon 10 (15%) which occurred mainly in native Saudi patients in the central province; 3120 1 1G ® A in intron 16 (10%) and H139L in exon 4 (7%), found mainly in native Saudis from the eastern province; D F508 mutation (13%) which occurred mainly in expatriates of Middle Eastern origin from different provinces; L117X in exon 19 (2%); G115X in exon 4 (2%); 7111 1G ® A in intron 5 (2%); N 1303K in exon 21(2%) and 425del42 in exon 4 (1%); I1234V in exon 19 (13%) with a predominance of nasal polyps and a variable degree of PI and lung disease; R553X in exon 11 (1%), with electrolyte imbalance; and S549R in 11 (2%) with pancreatic suf® ciency and minimal pulmonary disease. Login to comment
29 of families/ Total % Position Genotype a group Prov alleles Frequency Phenotype Exon 4 425del42 1 Sa W 1 1 PI, PU, EL Exon 4 G115X 1 Sa W 2 2 PI, PU Exon 4 H139L 2 Sa E 4 5 PI, PU 1 Sa W 2 2 3 Total 6 Total 7 Total Intron 5 7111 1G ® A 1 Sa S 2 2 PI, PU Exon 10 1548delG/1548del G 4/1/1 Sa C/N/S 8/2/2 13 1548del G/N1303K* 1 Sa E 1 1 1548del G/? Login to comment
40 CFTR mutations identi® ed 4± 11 Severe pancreatic insuf® ciency and lung disease were found in the following CFTR mutations: 1548delG was found in eight families (15% of total alleles), all native Saudis, four families from Central Province; D F508 was found in ® ve families (10%), three of non-Saudi origin from different provinces; 3120 1 1G ® A was found in seven families (9%), three being native Saudi from Eastern Province; H139L was found in three (7%) native Saudi families mainly from Eastern Province; N1303K occurred in two (2%) families and G115X in one family, 425del42, L1177X and 711 1 1G ® A were each found in one family. Login to comment
50 The most common Saudi mutations are 1548delG, which constitutes 15% of the total alleles, and I1234V (13%), coming mainly from the Central Province, while 1G ® A (10%) and H139L (7%) were mainly from Eastern Province. Login to comment

[hide] Identification of novel mutations in Arabs with cy... Eur J Pediatr. 2000 May;159(5):303-9. Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF
Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations.
Eur J Pediatr. 2000 May;159(5):303-9., [PMID:10834512]

Abstract [show]
The cystic fibrosis transmembrane regulator (CFTR) gene in Arab patients with cystic fibrosis (CF) (sweat chloride > 60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3,849 + 10kbC --> T. Eight novel mutations were identified. These are: in exon 4: a) 425del42 (an in-frame 42 bp deletion that removes 14 amino acids and causes Gln98 --> His at the point of deletion), b) 475G --> T (Glu115 --> Stop) and c) 548A --> T (His139 --> Leu); in intron 5,711 + 1G --> A (splice site mutation); in exon 10, 1548delG (deletion of a "G" nucleotide causing a frameshift mutation that alters the amino acid sequence at residue 473 and results in translation termination at residue 526); in exon 11, a) 1729T --> C (Ph533E --> Leu) and b) 1,811 + 2 (splice site mutation) and finally in exon 19,3361A --> T (Lys1177 --> Stop). All mutations were detected by heteroduplex analysis and identified by sequencing. Of more than 850 known CFTR mutations, only 9 were encountered. The comparative frequencies of the most common mutations are: 1548delG> 1123V = deltaF508 = 3,120 + 1G --> A > H139L. Screening for these five mutations identifies 60% of the CF alleles in Arab populations. The novel mutation 1548delG is the most frequent (17%) among Arabs. CONCLUSION: Novel Arab-specific mutations were identified in the CFTR gene underlying cystic fibrosis. As a result of this study, the CFTR mutation detection rate among Arabs with cystic fibrosis is now comparable to that of other populations.

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5 The comparative frequencies of the most common mutations are: 1548delG> I123V DF508 3120 + 1G ® A > H139L. Login to comment
64 CFTR exons 4, 10, 11 from 100 normal individuals (200 chromosomes) were screened to evaluate whether the novel missense mutations found in these exons (H139L in exon 4 and F533L in exon 11) were neutral polymorphisms rather than pathogenic mutations. Login to comment
65 Neither the H139L (exon 4) nor the F533L (exon 11) mutations were detected among the normal individuals suggesting that they indeed represent pathogenic sequence changes. Login to comment
81 The last of the common Arab mutations (H139L) is a novel missense mutation that has not been seen in any other ethnic group. Login to comment
88 Two mutations resulted in amino acid substitutions (H139L and F533L). Login to comment
103 Two of the six ``common Arab'' mutations, namely 1548delG and H139L have not been observed in any Caucasian chromosomes, suggesting that they are derived from the native Arab population. Login to comment
109 1 (private mutation) 475G ® T G115X ± protein truncation 1 2 1a [I1234V] 1 Total: 2 2.5% 536C ® T A141D 1 2 (private mutation) 548A ® T H139L 3 6 1a [S549R] 1 Total: 4 6% Exon 5 711 + 1G ® A Splice site 1 2 1a [?] Login to comment
114 1 (private mutation) 1779T ® G S549R 1 2 1a [H139L] 1 Total: 2 2.5% 1789C ® T R553X ± protein truncation 1a [3120 + 1G ® A] 1 (private mutation) 1811 + 2T ® C Splice site 1a [1548delG] 1 (private mutation) Exon 16 3120 + 1G ® A Splice site 5 10 1a [R533X] 1 1a [N1303K] 1 1a [?] Login to comment
117 aa amino acids CFTR position Mutation Consequence Exon 4 425del42 In-frame 42 bp deletion [426-467] that predicts the removal of 14 aa [99-112] from the CFTR protein and a Gln ® His substitution at aa residue 98 [deletion point] 475G ® T [G115X] G ® T transversion at nucleotide 475 that results in Glu ® Stop codon at aa 115 548A ® T[H139L] A ® T transition at nucleotide 548 that results in a His ® Leu substitution at aa 139 Exon 5 711 + 1G ® A G ® A transition at nucleotide 711 + 1 causing a splice site defect Exon 10 1548delG Deletion of a ``G'' at nucleotide1548 which predicts a frameshift mutation that alters the aa sequence starting at residue 473 and results in translation termination at residue 526 Exon 11 1729T ® C [F533L] T ® C transition at nucleotide 1729 that results in a Phe ® Leu at aa 533 1811 + 2T ® C T ® C transversion at nucleotide 1811 + 2 causing a splice site defect Exon 19 3361A ® T [L1177X] A ® T transition at nucleotide 3361 that results in a Lys ® Stop codon at aa 1177 Fig. 1 MDE heteroduplex analysis and sequencing of amplicons containing novel CFTR mutations identi®ed in Arabs. Login to comment
125 Arab CF patients carry CFTR mutations that have not been reported in other populations (1548delG and H139L). Login to comment

[hide] Cystic fibrosis: a worldwide analysis of CFTR muta... Hum Mutat. 2002 Jun;19(6):575-606. Bobadilla JL, Macek M Jr, Fine JP, Farrell PM
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.
Hum Mutat. 2002 Jun;19(6):575-606., [PMID:12007216]

Abstract [show]
Although there have been numerous reports from around the world of mutations in the gene of chromosome 7 known as CFTR (cystic fibrosis transmembrane conductance regulator), little attention has been given to integrating these mutant alleles into a global understanding of the population molecular genetics associated with cystic fibrosis (CF). We determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort designed to: 1) increase our understanding of ancestry-genotype relationships, 2) compare mutational arrays with disease incidence, and 3) gain insight for decisions regarding screening program enhancement through CFTR multi-mutational analyses. Information on all mutations that have been published since the identification and cloning of the CFTR gene's most common allele, DeltaF508 (or F508del), was reviewed and integrated into a centralized database. The data were then sorted and regional CFTR arrays were determined using mutations that appeared in a given region with a frequency of 0.5% or greater. Final analyses were based on 72,431 CF chromosomes, using data compiled from over 100 original papers, and over 80 regions from around the world, including all nations where CF has been studied using analytical molecular genetics. Initial results confirmed wide mutational heterogeneity throughout the world; however, characterization of the most common mutations across most populations was possible. We also examined CF incidence, DeltaF508 frequency, and regional mutational heterogeneity in a subset of populations. Data for these analyses were filtered for reliability and methodological strength before being incorporated into the final analysis. Statistical assessment of these variables revealed that there is a significant positive correlation between DeltaF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestry-genotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs. From comprehensive assessment of these data, we offer recommendations that multiple CFTR alleles should eventually be included to increase the sensitivity of newborn screening programs employing two-tier testing with trypsinogen and DNA analysis.

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112 Jewish 1) 405+1G®A (48.0%) 3) W1282X (17.0%) - - 4 23 Kerem et al. [1995] (Tunisia) 2) DF508 (31.0%) 4) 3849+10KbC®T (4.0%) Jewish 1) G85E 4) G542X - - 6 10 Kerem et al. [1995] (Turkey) 2) DF508 5) 3849+10KbC®T 3) W1282X 6) W1089X Jewish (Yemen) None - - 0 5 Kerem et al. [1995] Lebanon 1) DF508 (35.0%) 6) 4096-28G®A (2.5%) - - 9 40 Desgeorges et al. [1997] 2) W1282X (20.0%) 7) 2789+5G®A (2.5%) 3) 4010del4 (10.0%) 8) M952I (2.5%) 4) N1303K (10.0%) 9) E672del (2.5%) 5) S4X (5.0%) Reunion ∆F508 (52.0%) 1717-1G→A (0.7%) 90.4 81.7 9 138 Cartault et al. [1996] Island Y122X (24.0%) G542X (0.7%) 3120+1G→A (8.0%) A309G (0.7%) A455E (2.2%) 2789+5G→A (0.7%) G551D (1.4%) Saudi North: 3) H139L - - North 1 49 families El-Harith et al. [1997]; Arabia 1) 1548delG 4) L1177X Central 3 Kambouris et al. [1997]; Central: 5) DF508 South 4 Banjar et al. [1999] 1)I1234V 6) 3120+1G®A West 9 2)1548delG 7) 425del42 East 6 3)DF508 8) R553X South: 9) N1303K 1) I1234V East: 2) 1548delG 1) 3120+1G®A 3) 711+1G®T 2) H139L 4) 3120+1G®A 3) 1548delG West: 4) DF508 1) I1234V 5) S549R 2) G115X 6) N1303K Tunisia ∆F508 (17.6%) G85E (2.6%) 58.7 34.5 11 78 Messaoud et al. [1996] G542X (8.9%) W1282X (2.6%) 711+1G→T (7.7%) Y122X (1.3%) N1303K (6.4%) T665S (1.3%) 2766del8NT (6.4%) R47W+D1270N (1.3%) R1066C (2.6%) Turkeye ∆F508 (24.5%) 1066L (1.3%) 80.6 65.0 36 1067/670 Yilmaz et al. [1995]; Estivill et al. 1677delTA (4.1%) E822X (1.3%) [1997]; Onay et al. [1998]; 2789+5G→A (3.9%) 2183+5G→A+2184insA (1.3%) Macek et al. [2002] 2181delA (3.8%) D110H (0.8%) R347H (3.6%) P1013L (0.8%) N1303K (2.9%) 3172delAC (0.8%) 621+1G→T (2.6%) 1259insA (0.8%) G542X (2.6%) M1028I (0.8%) TABLE 1. Continued. Estimated Projected detection of Number of Number of Country/ allele two CFTR mutations chromosomes Region Mutation array detectiona mutationsb includedc (max/min)d Reference WORLDWIDEANALYSISOFCFTRMUTATIONS587 E92K (2.6%) 4005+1G→A (0.7%) A96E (2.6%) W1282X (0.7%) M152V (2.6%) I148T (0.6%) 2183AA→G (2.5%) R1162X (0.6%) 296+9A→T (1.6%) D1152H (0.6%) 2043delG (1.4%) W1098X (0.6%) E92X (1.4%) E831X (0.6%) K68N (1.4%) W496X (0.6%) G85E (1.3%) F1052V (0.5%) R1158X (1.3%) L571S (0.5%) United Arab S549R (61.5%) ∆F508 (26.9%) 88.4 78.1 2 86/52 Frossard et al. [1988]; Emirates Frossard et al. [1999] North/Central/South Americas Argentina ∆F508 (58.6%) N1303K (1.8%) 69.1 47.7 5 326/228 CFGAC [1994]; Chertkoff et al. W1282X (3.9%) 1717-1G→A (0.9%) [1997] G542X (3.9%) Brazilf ∆F508 (47.7%) W1282X (1.3%) 66.8 44.6 10 820/500 CFGAC [1994]; Cabello et al. (total) G542X (7.2%) G85E (1.3%) [1999]; Raskin et al. [1999]; R1162X (2.5%) R553X (0.7%) Bernardino et al. [2000] R334W (2.5%) L206W (0.6%) N1303K (2.4%) 2347delG (0.6%) South East: >∆F508, G542X South: >N1303K Brazil ∆F508 (31.7%) N1303K (2.5%) 42.5 18.1 3 120 Parizotto and Bertuzzo [1997] (Sao Paulo) G542X (8.3%) Canada ∆F508 (59.0%) G542X (0.5%) 98.5 97.0 13 381/200 Rozen et al. [1992]; (Lac St. Jean) 621+1G→T (24.3%) N1303K (0.5%) De Braekeleer et al. [1998] A445E (8.2%) Q890X (0.5%) Y1092X (1.2%) S489X (0.5) 711+1G→T (1.0%) R117C (0.5%) I148T (1.0%) R1158 (0.5%) G85E (0.8%) Canada ∆F508 (71.4%) ∆I507 (1.3%) 90.9 82.6 7 77 Rozen et al. [1992] (Quebec City) 711+1G→T (9.1%) Y1092X (1.3%) 621+1G→T (5.2%) N1303K (1.3%) A455E (1.3%) Canada ∆F508 (70.9%) W1282X (0.9%) 82.0 67.2 10 632 Kristidis et al. [1992] (Toronto) G551D (3.1%) R117H (0.9%) G542X (2.2%) 1717-1G→A (0.6%) 621+1G→T (1.3%) R560T (0.6%) N1303K (0.9%) ∆I507 (0.6%) Chile ∆F508 (29.2%) R553X (4.2%) 33.4 11.2 2 72 Rios et al. [1994] Columbia 1) DF508 (35.4%) 3) N1303K (2.1%) - - 4 48 Restrepo et al. [2000] 2) G542X (6.3%) 4) W1282X (2.1%) Ecuador 1) DF508 (25%) - - 1 20 Paz-y-Mino et al. [1999] (Continued) BOBADILLAETAL. Login to comment

[hide] Mutational spectrum of cystic fibrosis in the Leba... J Cyst Fibros. 2010 Dec;9(6):406-10. Epub 2010 Aug 25. Farra C, Menassa R, Awwad J, Morel Y, Salameh P, Yazbeck N, Majdalani M, Wakim R, Yunis K, Mroueh S, Cabet F
Mutational spectrum of cystic fibrosis in the Lebanese population.
J Cyst Fibros. 2010 Dec;9(6):406-10. Epub 2010 Aug 25., [PMID:20797923]

Abstract [show]
BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians; it is however, considered to be rare in the Arab populations. Reports of the cystic fibrosis transmembrane regulator (CFTR) mutations from Arabs, especially from the Lebanese population, are limited. METHODS: Twenty-two unrelated Lebanese families, with at least one child with CF, were studied. DNA extracts from blood samples of patients and parents were screened for CFTR gene mutations. RESULTS: Eleven different mutations were identified. Of the 44 alleles studied, the most common mutations were: F508del (34%), N1303K (27%), W1282X (7%), and S4X (7%). Five mutations - not previously reported in the Lebanese population - were identified; these are: S549N, G542X, 2043delG, 4016insG, and R117H-7T. CONCLUSIONS: The most common CFTR mutations in addition to five mutations not previously described in the Lebanese population were identified. Identification of CFTR mutations in the Lebanese population is important for molecular investigations and genetic counseling.

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63 In populations from Saudi Arabia, United Arab Emirates, Oman, Qatar, Kuwait, and Jordan the most commonly reported mutations were 1548delG, I123V, F508del, 3120+1G→A, and H139L; while F508del (7.4%-15%) and N1303K (1.5%-14%) are not common, and the mutation W1282X is absent from these populations (Table 2) [1,3,24-26]. Login to comment
66 Interestingly, the two common Arab mutations 1548delG and H139L, which were not found in any Caucasian chromosomes and were suggested to originate from the native Arab population, were absent from our study [15,28]. Login to comment

[hide] Cystic fibrosis: a new mutation in the Lebanese po... J Cyst Fibros. 2008 Sep;7(5):429-32. Epub 2008 May 2. Farra C, Medawar R, Mroueh S, Souaid M, Cabet F, Awwad J
Cystic fibrosis: a new mutation in the Lebanese population.
J Cyst Fibros. 2008 Sep;7(5):429-32. Epub 2008 May 2., [PMID:18455968]

Abstract [show]
BACKGROUND: Cystic fibrosis is the most common autosomal recessive disorder in Caucasians. Little has been reported on its occurrence in Arab and Lebanese populations where mutation distribution seems to differ from that of Europeans. We report on the occurrence of a frameshift mutation 4016insG in two Lebanese Muslim siblings, products of consanguineous parents. This mutation generates a stop codon instead of Arginine-1301 and has never been reported before. METHODS: Both probands manifested early onset of severe respiratory and pancreatic involvement. DNA analysis was performed by PCR and sequencing for exons 1, 4, 10, 11, 20, 21 of the CFTR gene. RESULTS: Both probands were found to be homozygous for the 4016insG. Their parents were both heterozygous for the same mutation. CONCLUSION: The frameshift mutation reported in this article is being described for the first time.

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46 Recently, a panel of 11 common mutations accounting overall for 70% of all Arab CF chromosomes have been reported : ΔF508del, 3120+1G"A, N1303K, W1282X, G115X, 711+1G"A, S549R, I1234V, 1548delG , H139L and 4010del4 [9]. Login to comment