ABCMdb

ABCC7 p.Phe533Leu

ClinVar:	c.1597T>C , p.Phe533Leu ? , not provided
Predicted by SNAP2:	A: D (66%), C: D (59%), D: D (85%), E: D (80%), G: D (85%), H: D (75%), I: D (63%), K: D (85%), L: N (93%), M: N (53%), N: D (80%), P: D (91%), Q: D (75%), R: D (80%), S: D (80%), T: D (75%), V: D (66%), W: N (57%), Y: N (61%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: N,

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Publications
[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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No. Sentence 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
88 Two mutations resulted in amino acid substitutions (H139L and F533L). Login to comment
113 2 Total: 8 12% Exon 11 1729T ® C F533L 1a [?] Login to comment
115 1 Total: 8 11% Exon 19 3661A ® T K1177X ± protein truncation 1 2 (private mutation) 3832A ® G I1234V 7 14 1a [G115X] 1 Total: 8 12.5% Exon 21 4041C ® G N1303K 1a [1548delG] 1 1a [3120 + 1G ® A] 1 Total: 2 1.5% Undetected 11 22 1a [425del42] 1 1a [711 + 1G ® A] 1 2a [1548delG] 2 2a [DF508] 2 1a [F533L] 1 1a [1249 + 1G ® A] 1 1a [3120 + 1G ® A] 1 Total: 20 25% a Indicates a compound heterozygous family. 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

[hide] Cystic fibrosis genetic counseling difficulties du... J Cyst Fibros. 2012 Jul;11(4):344-8. doi: 10.1016/j.jcf.2012.01.004. Epub 2012 Feb 11. Poulou M, Fylaktou I, Fotoulaki M, Kanavakis E, Tzetis M
Cystic fibrosis genetic counseling difficulties due to the identification of novel mutations in the CFTR gene.
J Cyst Fibros. 2012 Jul;11(4):344-8. doi: 10.1016/j.jcf.2012.01.004. Epub 2012 Feb 11., [PMID:22326559]

Abstract [show]
BACKGROUND: The Cystic Fibrosis database includes amongst the 1893 gene mutations and polymorphisms a lot of missense mutations, the disease status of which still remains unproven. In populations with high rates of CFTR mutation heterogeneity, molecular diagnosis is difficult often causing counseling difficulties especially in cases of rare and/or novel mutations. METHODS: Approaches to counseling in cases of novel variants. RESULTS: Thirty-seven novel variants (4 synonymous, 24 missense, 2 frameshift and 10 intronic substitutions) were identified and evaluated with the help of in silico tools. CONCLUSIONS: In a diagnostic environment the answers have to be given within a specific timeframe, the in silico tools in combination with the phenotype offer some help but their diagnostic value is limited and cannot be used in isolation for the determination of the severity of the mutation.

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Sentences [show]
No. Sentence Comment
65 (2) Disease causing Screening 19 11 (10) c.1532CNG p.Ser511Cys Benign T 0.06 Path. (2) Disease causing Screening 20 24 (21) c.3932GNA p.Ser1311Asn Benign T 0.34 Path. (3) Disease causing Screening 21 17 (15) c.2778GNT p.Leu926Phe Benign T 0.24 Path. (5) Disease causing Screening 22 22 (21) c.3674CNT p.Ala1225Val Benign T0.21 Path. (1) Disease causing Screening 23 12 (11) c.1597TNC p.Phe533Leu Benign T0.94 Neut. Login to comment
73 Disruption of ESE motifs/creation of ESS motifs Acc increased (0.44/0.50) Acc gained 0.51 p.V1318G c.3953TNG No change New donor site (48.15/74.98) (+55.73%) if used causes reduction of exon size (-11nt) Donor increased (0.31/0.99) p.K1165T c.3494ANC No change Minor changes No change p.S977C c.2930CNG No change Minor changes No change p.I521F c.1561ANT No change Minor changes No change p.V1212F c.3634GNT No change Disruption of ESE motifs Donor gained 0.36 p.F319V c.955TNG No change Minor changes Acc increased (0.42/0.61) p.G817V c.2450GNT No change Minor changes No change p.C491S c.1472GNC No change Disruption of ESE motifs Acceptor sites created p.I336L c.1006ANC No change Disruption of ESE motifs No change p.F305V c.913TNG Increased score for SRp55 Disruption of ESS motifs Donor gained (0.99) p.S511C c.1532CNG Decreased score for SC35 Disruption of ESS motifs No change p.S1311N c.3932GNA Changes on ss scores Disruption of ESS motifs Donor increased (0.50/0.63) p.L926F c.2778GNT No change Creation of ESS motifs Changes on ss scores p.A1225V c.3674CNT No change Disruption of ESE motif/creation of ESS motif Donor increased (0.72/0.99) p.F533L c.1597TNC No change Creation of ESE motifs/disruption of ESS motifs No change p.Q1209H c.3627ANC No change Minor changes No change c.2490+3ANG No change Minor changes No change c.2909-36TNC Decrease of donor ss Disruption of ESS motifs Acc increased (0.33/0.48)/donor increased (0.74/0.94) c.2909-10TNC Change for SRp55 best hit (3.97/5.16) Disruption of ESS motifs No change c.4137-21GNT No change Disruption of ESE and creation of ESS motifs Acc increased (0.86/0.96) c.1116+4ANT No change WT donor site disrupted Marginal changes on donor ss c.2988+30TNC No change Disruption of ESE motif/creation of ESS motif No change c.1680-27GNA No change Disruption of ESS motifs No change c.2620-24CNG No change Creation of ESE motifs Donor gained 0.96 c.2620-18delT No change New donor ss/changes on ESE and ESS motifs Acc increased (0.41/0.55) c.2658-8CNG Decreased score for acc site Minor changes Marginal changes on ss p.L1227L c.3681ANG No change Changes on ESE and ESS motifs No change p.R1158R c.3472CNA No change Creation of ESE motifs/creation of ESS motifs Marginal changes on ss p.D1275D c.3825TNC No change No change Donor increased (0.56/0.87) p.L346L c.1036CNT No change No change No change Abbreviations: ESE: exonic splicing enhancer, HSF: human splicing finder, ESS: exonic splicing silencer, WT: wild type, Mut: mutant, ss: splicing site. Login to comment
75 Disruption of ESE motifs/creation of ESS motifs Acc increased (0.44/0.50) Acc gained 0.51 p.V1318G c.3953TNG No change New donor site (48.15/74.98) (+55.73%) if used causes reduction of exon size (-11nt) Donor increased (0.31/0.99) p.K1165T c.3494ANC No change Minor changes No change p.S977C c.2930CNG No change Minor changes No change p.I521F c.1561ANT No change Minor changes No change p.V1212F c.3634GNT No change Disruption of ESE motifs Donor gained 0.36 p.F319V c.955TNG No change Minor changes Acc increased (0.42/0.61) p.G817V c.2450GNT No change Minor changes No change p.C491S c.1472GNC No change Disruption of ESE motifs Acceptor sites created p.I336L c.1006ANC No change Disruption of ESE motifs No change p.F305V c.913TNG Increased score for SRp55 Disruption of ESS motifs Donor gained (0.99) p.S511C c.1532CNG Decreased score for SC35 Disruption of ESS motifs No change p.S1311N c.3932GNA Changes on ss scores Disruption of ESS motifs Donor increased (0.50/0.63) p.L926F c.2778GNT No change Creation of ESS motifs Changes on ss scores p.A1225V c.3674CNT No change Disruption of ESE motif/creation of ESS motif Donor increased (0.72/0.99) p.F533L c.1597TNC No change Creation of ESE motifs/disruption of ESS motifs No change p.Q1209H c.3627ANC No change Minor changes No change c.2490+3ANG No change Minor changes No change c.2909-36TNC Decrease of donor ss Disruption of ESS motifs Acc increased (0.33/0.48)/donor increased (0.74/0.94) c.2909-10TNC Change for SRp55 best hit (3.97/5.16) Disruption of ESS motifs No change c.4137-21GNT No change Disruption of ESE and creation of ESS motifs Acc increased (0.86/0.96) c.1116+4ANT No change WT donor site disrupted Marginal changes on donor ss c.2988+30TNC No change Disruption of ESE motif/creation of ESS motif No change c.1680-27GNA No change Disruption of ESS motifs No change c.2620-24CNG No change Creation of ESE motifs Donor gained 0.96 c.2620-18delT No change New donor ss/changes on ESE and ESS motifs Acc increased (0.41/0.55) c.2658-8CNG Decreased score for acc site Minor changes Marginal changes on ss p.L1227L c.3681ANG No change Changes on ESE and ESS motifs No change p.R1158R c.3472CNA No change Creation of ESE motifs/creation of ESS motifs Marginal changes on ss p.D1275D c.3825TNC No change No change Donor increased (0.56/0.87) p.L346L c.1036CNT No change No change No change Abbreviations: ESE: exonic splicing enhancer, HSF: human splicing finder, ESS: exonic splicing silencer, WT: wild type, Mut: mutant, ss: splicing site. Login to comment