ABCB4 p.Ile367Val
| Predicted by SNAP2: | A: D (66%), C: D (53%), D: D (85%), E: D (80%), F: D (66%), G: D (75%), H: D (80%), K: D (85%), L: N (57%), M: N (66%), N: D (80%), P: D (85%), Q: D (75%), R: D (80%), S: D (75%), T: D (71%), V: N (93%), W: D (80%), Y: D (75%), |
| 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] BSEP and MDR3 haplotype structure in healthy Cauca... Hepatology. 2004 Mar;39(3):779-91. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ
BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.
Hepatology. 2004 Mar;39(3):779-91., [PMID:14999697]
Abstract [show]
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned approximately 10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC.
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No. Sentence Comment
111 Nonsynonymous changes observed as singletons in our sample set coded for the following amino acid changes: L73V, D243A, I367V, K435T, E1099G, and G1251Q.
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ABCB4 p.Ile367Val 14999697:111:120
status: NEW116 Four variant sites (T927C, A1099G 3 I367V, G1769A 3 R590Q, and A3296G 3 E1099G) were only found in the control group, 4 were specific to PBC patients (C217G 3 L73V, A728C 3 D243A, A1304C 3 K435T, and A3751C 3 K1251Q), while 1 was PSC-specific (C1633T 3 R545C).
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ABCB4 p.Ile367Val 14999697:116:36
status: NEW[hide] Genetic variability, haplotype structures, and eth... Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8. Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R
Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).
Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8., [PMID:16763017]
Abstract [show]
Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.
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No. Sentence Comment
177 Amino Acid Change Scoring Systems for Nonsynonymous Variants Grantham SIFT PolyPhen Blosum62 EC/EU MDR3 D87E 45 1.00 0.48 2 EC P95S 74 0.48 0.87 -1 EC T175A 58 0.01 0.72 -1 EC I367V 29 0.23 0.96 3 EC E450G 98 0.01 0.13 -2 EC R590Q 43 0.01 2.51 1 EC R652G 125 0.36 1.47 -2 EU E1099G 98 0.04 1.58 -2 EC BSEP I206V 29 1.00 0.23 3 EU V284A 64 0.13 0.43 -2 EC R299K 26 1.00 0.38 2 EU V444A 64 0.63 0.78 -2 EC R616G 125 0.01 3.16 -2 EC T619A 58 0.00 1.78 -1 EC M677V 21 0.29 0.82 1 EU R698H 29 0.30 0.57 0 EC A865V 64 0.02 1.12 0 EC R958Q 43 0.04 0.24 1 EU neutral mutation model (Tajima, 1989).
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ABCB4 p.Ile367Val 16763017:177:176
status: NEW63 The numbers 1 to 42 in the variant ID column indicate all variants included in haplotype analysis and linkage disequilibrium estimation. Variant ID 5Ј Sequence Genetic Variation 3Ј Sequence Region Amino Acid Change CA KO JA Total n % n % n % n % 43 TCAATGCAC g.-7676AϾT GTCTCACAA PromA 110 0.9 96 0.0 88 0.0 294 0.3 44 CTACCCTCT g.-7554TϾC CAATGCCTC PromA 110 0.9 96 0.0 88 0.0 294 0.3 45 GAGTGAAGT g.-7253GϾA TAGAAATCT PromA 106 0.0 96 1.0 94 0.0 296 0.3 46 AATTTAGAA g.-7114AϾT ACTCAATAG PromA 108 0.0 96 1.0 94 0.0 298 0.3 1 AAGAGGAAA g.-7094GϾC TTTCTTGTA PromA 108 13.0 96 30.2 94 24.5 298 22.1 47 CAAGAATTT g.-6816CϾT ATTAGGCAA PromA 102 0.0 96 1.0 92 0.0 290 0.3 48 GAGAGAGAG g.-6639AϾC GAGCTGAAT PromA 110 0.9 90 0.0 92 0.0 292 0.3 49 GAGAGAGAG g.-6637_-6636 delAG CTGAATCAG PromA 110 0.0 90 1.1 92 0.0 292 0.3 2 GTGCCTTTG g.-6588GϾT GTGTGCTGG PromA 110 2.7 88 0.0 92 2.2 290 1.7 3 AAAGAAGAA g.-6540CϾT GAAACCAAA PromA 108 14.8 86 26.7 90 27.8 284 22.5 4 TTAGTGACC g.-6325AϾG AAAGTTTGG PromA 108 17.6 90 31.1 92 26.1 290 24.5 5 ATTCTTTTT g.-6014GϾT TACAAACCC PromA 108 16.7 94 28.7 88 26.1 290 23.4 50 ACTGGTGCT g.-5941GϾA TGGGCACTA PromA 108 0.0 94 0.0 88 1.1 290 0.3 6 TGAAGTCAC g.-5859GϾA TGGCCAGAG PromA 108 16.7 94 28.7 88 26.1 290 23.4 7 ATGAGATGA g.-5717TϾC ATATATGTG PromA 110 0.0 92 1.1 86 3.5 288 1.4 8 CCTTCTTTA g.-5610TϾC ATGCCTAAA PromA 110 100.0 96 100.0 94 97.9 300 99.3 9 TAAGTGTGG g.-5570GϾC CAGCAATTA PromA 110 12.7 96 29.2 94 24.5 300 21.7 51 TACTCTCAC g.-5509GϾA GCTCTTATG PromA 110 0.0 96 1.0 94 0.0 300 0.3 10 CTCTCTTGT g.-5236CϾT TGAGTAATA PromA 108 15.7 90 27.8 94 26.6 292 22.9 52 GAGGATAAA g.-2551AϾT AAGAAAGAT PromB 126 0.0 88 0.0 90 1.1 304 0.3 11 AGCCTTACA g.-2478TϾG CAATGCATA PromB 126 4.8 88 0.0 90 2.2 304 2.6 12 GAAGGAATT g.-1921TϾC GGGTTGATT PromB/Exon -3 122 4.9 92 0.0 82 1.2 296 2.4 53 GAAGAGAAT g.-1899CϾA CTCATGGTC PromB/Exon -3 122 0.8 92 0.0 82 0.0 296 0.3 13 ATCCTAATA g.-1603AϾT CACCCTTAT PromB 128 0.0 94 2.1 86 1.2 308 1.0 14 TTTATAGAT g.-1584CϾT CAATGACTG PromB/Exon -2 118 11.0 94 29.8 74 23.0 286 20.3 54 ACACCAGGG g.-1510TϾG CCACCCAGC PromB 126 0.0 94 1.1 68 0.0 288 0.3 15 CTTATACCA g.-1484TϾC GCTCTGCTT PromB 126 0.0 94 1.1 68 5.9 288 1.7 55 TTTGAAAGT g.-1146CϾT TCCGGTTTC PromB 126 0.0 92 1.1 82 0.0 300 0.3 16 TGGTAGGAG g.-1031CϾT AGAGACAAT PromB 126 11.1 92 30.4 82 24.4 300 20.7 56 GAGACAATT g.-1020CϾG AATACAGAC PromB 126 0.0 92 1.1 82 0.0 300 0.3 17 ATTCAATAC g.-1014AϾG GACAGAAGT PromB 126 13.5 92 30.4 82 24.4 300 21.7 18 GAACTGGGG g.-682AϾC TGCGGAAGC PromB/Exon -1 124 1.6 70 0.0 64 0.0 258 0.8 19 AGGCTCCAG g.-495CϾG CTGATCTCG PromB 126 17.5 86 29.1 84 28.6 296 24.0 20 GCGCCCCGG g.-414CϾT GGCAAGAGC PromB 126 4.8 86 3.5 84 6.0 296 4.7 21 GGCAGGCTG g.-395CϾG GCCCCTGGC PromB 126 13.5 86 3.5 84 6.0 296 8.4 22 GCCCGCGCC g.-378TϾC AGCCTGGGG PromB 126 26.2 86 27.9 84 20.2 296 25.0 57 GCGTTTCCC g.-292GϾT GGCCGGACG PromB 128 0.0 96 0.0 92 1.1 316 0.3 58 CCGGACGCG g.-280CϾA GTGGGGGGC PromB 126 0.8 86 0.0 84 0.0 296 0.3 59 CCCTGCCAG g.-186AϾG CACGCGCGA PromB/Exon 1 128 0.0 96 1.0 92 0.0 316 0.3 23 TGCCCCCGG g.-75GϾT CCCCGCGAC PromB 128 0.0 96 0.0 92 1.1 316 0.3 24 TTTATGTCG g.12597CϾT TGGGTACCA Exon 4 L59L 126 12.7 96 25.0 94 21.3 316 19.0 60 CAAATTTGT g.12680TϾG GATACTGCA Exon 4 V86V 126 0.0 96 0.0 94 1.1 316 0.3 61 ATTTGTTGA g.12683TϾG ACTGCAGGA Exon 4 D87E 126 0.0 96 0.0 94 1.1 316 0.3 62 TTCTCCTTT g.12705CϾT CAGGTAAGC Exon 4 P95S 126 0.0 96 0.0 94 1.1 316 0.3 63 TAGCTTTCA g.20782TϾG ACATTTAAA Intron 4 114 0.0 88 1.1 70 0.0 272 0.4 25 TTTTAAAAA g.20813CϾT CTGGCAATG Intron 4 116 3.4 90 1.1 70 0.0 276 1.8 26 TCACCTATT g.21044AϾG TTATCATTT Intron 5 122 16.4 52 15.4 46 32.6 220 19.5 27 AAAAGAAAA g.22281_22284delGAAAA AAGAAAAGA Intron 5 126 7.9 88 0.0 84 0.0 298 3.4 28 TGACATCAA g.22490CϾT GACACCACT Exon 6 N168N 126 42.9 88 37.5 90 44.4 304 47.7 29 GAACTCAAT g.22509AϾG CGCGGCTAA Exon 6 T175A 126 3.2 88 0.0 90 0.0 304 1.3 64 CTCTGCAGC g.23831CϾT GTTTGGGCA Exon 7 A232A 128 0.0 94 0.0 90 1.1 312 0.3 65 AAGGGTTGA g.25313CϾG CAGAGTGCC Intron 7 124 0.8 96 0.0 90 0.0 310 0.3 30 TGTCCAGAT g.25376AϾT CTCTCGGCA Exon 8 I237l 126 15.1 96 27.1 90 27.8 312 22.4 66 GTTAATATA g.28354TϾC GCATCATAT Exon 9 Y309Y 128 0.8 96 0.0 92 0.0 316 0.3 67 GCATATGTG g.30584AϾG TCTTTGATA Exon 10 I367V 118 0.8 92 0.0 92 0.0 302 0.3 68 TAATATTTA g.31823TϾG AGGAATTCC Intron 11 128 0.0 96 0.0 92 1.1 316 0.3 31 ACTTTTTTT g.31941delT CAAATTTCA Intron 11 128 7.0 96 3.1 94 1.1 318 4.1 69 ACCCTGATG g.32140AϾG GGGCACAGT Exon 12 E450G 128 0.0 96 1.0 94 0.0 318 0.3 70 ACAAATTTG g.32232CϾT GTGTGAATC Intron 12 128 0.0 96 1.0 94 0.0 318 0.3 32 GGCAATGCC g.32277GϾT ATGGATAAT Intron 12 124 6.5 96 3.1 94 3.2 314 4.5 33 CAGCTATTA g.35024AϾG ATGGTTAAA Intron 12 124 95.2 94 70.2 94 72.3 312 80.8 71 ACAGGTAAA g.35273GϾA CCTCTGATA Intron 13 126 0.0 96 0.0 94 1.1 316 0.3 72 AGTGTGCCA g.43862AϾG TACTGTAAC Intron 14 122 0.8 88 0.0 72 0.0 282 0.4 34 TGTGCCAAT g.43864AϾG CTGTAACCC Intron 14 124 0.0 88 1.1 72 2.8 284 1.1 73 TAGCACACC g.43938GϾA ACTGTCTAC Exon 15 R590Q 124 0.8 88 0.0 74 0.0 286 0.3 35 GCTGCCACT g.48606AϾG GAATGGCCC Exon 16 R652G 124 7.3 86 2.3 74 1.4 284 4.2 36 GCTACAATT g.48771AϾG TTGAAATTC Intron 16 114 5.3 86 2.3 70 1.4 270 3.3 37 TTGCAAACA g.51576CϾT CACATAACA Intron 17 122 95.1 70 74.3 80 71.3 272 82.7 38 TTACATAAC g.56969AϾG TGGTTTTAG Intron 20 126 6.3 60 3.3 66 1.5 252 4.4 74 ATATTTTAC g.58304TϾC GTATTAATG Intron 21 124 0.0 96 0.0 92 1.1 212 0.3 39 CTGTATTAA g.58312TϾC GTCTAGAAC Intron 21 122 4.1 96 1.0 92 1.1 310 2.3 75 AAAGGAGGC g.63395delT GAAGAGATG Intron 22 124 0.8 92 0.0 94 0.0 310 0.3 76 AATATTAAG g.63598AϾT TTATTCTAT Intron 23 124 0.0 92 1.1 94 0.0 310 0.3 40 ATGGTCAAG g.68988AϾG AGCAAAGAA Exon 26 E1099G 112 1.8 92 0.0 84 0.0 288 0.7 41 TATTTATAA g.72169TϾC TTGGTTAAC Intron 26 122 91.8 90 65.6 92 75.0 304 78.9 42 GTAACATTT g.73092TϾC CAAATTTAC Intron 27 124 7.3 94 1.1 86 1.2 304 3.6 n, number of alleles analyzed (number of subjects times 2).
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ABCB4 p.Ile367Val 16763017:63:4583
status: NEW111 Five rare missense mutations occurred once as single heterozygotes (singletons) in exon 4 (c.261TϾC and c.283CϾT), exon 10 (c.1099AϾG), exon 12 (c.1349AϾG), and exon 15 (c.1769GϾA), resulting in the amino acid changes p.I367V, p.R590Q, p.D87E, p.P95S, and p.E450G.
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ABCB4 p.Ile367Val 16763017:111:250
status: NEW