ABCC9 p.Leu1524Lys
| ClinVar: |
c.4570T>A
,
p.Leu1524Ile
N
, Likely benign
c.4571T>A , p.Leu1524* N , Likely benign |
| Predicted by SNAP2: | A: N (53%), C: N (72%), D: D (75%), E: D (71%), F: D (53%), G: D (66%), H: D (66%), I: N (97%), K: D (71%), M: N (87%), N: D (66%), P: D (71%), Q: D (63%), R: D (71%), S: D (59%), T: D (53%), V: N (97%), W: D (66%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, V: N, W: D, Y: D, |
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[hide] ABCC9 is a novel Brugada and early repolarization ... Int J Cardiol. 2014 Feb 15;171(3):431-42. doi: 10.1016/j.ijcard.2013.12.084. Epub 2014 Jan 4. Hu D, Barajas-Martinez H, Terzic A, Park S, Pfeiffer R, Burashnikov E, Wu Y, Borggrefe M, Veltmann C, Schimpf R, Cai JJ, Nam GB, Deshmukh P, Scheinman M, Preminger M, Steinberg J, Lopez-Izquierdo A, Ponce-Balbuena D, Wolpert C, Haissaguerre M, Sanchez-Chapula JA, Antzelevitch C
ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.
Int J Cardiol. 2014 Feb 15;171(3):431-42. doi: 10.1016/j.ijcard.2013.12.084. Epub 2014 Jan 4., [PMID:24439875]
Abstract [show]
BACKGROUND: Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K(+) channel (I(K-ATP)), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis that genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS. METHODS AND RESULTS: Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC(5)(0) that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC(5)(0) from 8.5 +/- 2 mM to 13.4 +/- 5 muM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by -18.0 mV (p<0.01) and increased late I(Na) from 0.14% to 2.01% of peak I(Na) (p<0.01). CONCLUSION: Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in I(K-ATP) when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
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No. Sentence Comment
119 Age for Dx (y/o) Gender Dx VT/VF FH a Syncope SCD Other b Name SIFT score Polyphen score Exon Change in amino acid Global MAF (1000 genome) Global MAF (ESP) 1 27 M ERS3 Y Y Y - Y - - R663C 0.02 0.99 14 c.1987C N T 0 0.000154 2 38 M ERS3 - - Y Y - - - A665T 0.57 0.002 14 c.1993G N A 0.001 N/A 3 63 M BrS + CAD - Y - Y Y ICD - N733D 0.05 0.069 16 c.2197A N G 0 0 4 20 M ERS3 + bradycardia - Y Y - Y - - V734I 0.43 0.002 17 c.2200G N A 0.005 0.009236 5 20 M ERS3 + bradycardia Y Y Y Y Y ICD, quinidine - 6 40 M ERS3 + AVB + bradycardia Y - Y Y - ICD SCN5A 7 20 M ERS2 + bradycardia - - Y - - - CACNA1C 8 25 M ERS2 - - - Y - - SCN10A V1137I 0.76 0.005 27 c.3409G N A 0.0041 0.0082 9 65 M BrS + SQTS Y - Y Y - ICD SCN10A, CACNA1C R1197C 0.05 0.999 29 c.3589C N T 0 0 10 18 M BrS + SAB - Y Y - Y - SCN5A S1402C 0 0.996 34 c.4205C N G 0 0.000077 11 39 M BrS Y - Y Y Y ICD - L1524K fs*5 N/A N/A 38 4570-4572 delTTA InsAAAT 0 0 -: No; Dx: diagnosis; VT/VF: ventricular tachycardia/ventricular fibrillation; SCD: sudden cardiac death; MAF: the minor-allele frequency; 1000 genome: the 1000 Human Genome Project Database; ESP: exome sequencing project; ERS3: early repolarization syndrome type 3; BrS: Brugada syndrome; CAD: coronary artery disease; ICD: implantable cardioverter defibrillator; AVB: atrioventricular block; ERS2: ERS type 2; SQTS: short QT syndrome; SAB: sinoatrial block.
X
ABCC9 p.Leu1524Lys 24439875:119:868
status: NEW