Paralogue Annotation for KCNH2 residue 628

Residue details

Gene: KCNH2
Reference Sequences: LRG: LRG_288, Ensembl variant: ENST00000262186 / ENSP00000262186
Amino Acid Position: 628
Reference Amino Acid: G - Glycine
Protein Domain: Transmembrane/Linker/Pore

Paralogue Variants mapped to KCNH2 residue 628

ParalogueVariantAssociated DiseaseMapping QualityConsensusPubmed
HCN4G482RBradycardia & left ventricular noncompaction cardiHigh8 25145517, 25145517, 25145518, 25145518
HCN4G482RSinus bradycardia & myocardial noncompactionHigh8 26206080

To assess whether the paralogue annotation here confidently predicts that variation at this residue is pathogenic, it is important to check the reports in the Pubmed links above to ascertain that the mutations in these paralogues have been proved likely to be disease-causing. It is also important to check that the direction of effect of the variant in the paralogue is compatible with your observed phenotype in KCNH2.

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See full Alignment of Paralogues

Known Variants in KCNH2

ProteinCDSDisease ClassificationDiseasedbSNP linksEffect Prediction
p.G628Ac.1883G>C Inherited ArrhythmiaLQTSSIFT: deleterious
Polyphen: probably damaging
ReportsInherited ArrhythmiaLQTS Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan. Circ Arrhythm Electrophysiol. 2010 3(1):10-7. 19996378
p.G628Sc.1882G>A Inherited ArrhythmiaLQTSSIFT: deleterious
Polyphen: probably damaging
ReportsInherited ArrhythmiaLQTS A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995 80(5):795-803. 7889573
Inherited ArrhythmiaLQTS Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 102(10):1178-85. 10973849
Inherited ArrhythmiaLQTS Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002 105(7):794-9. 11854117
Other Cardiac Phenotype Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations. J Am Coll Cardiol. 2004 43(5):826-30. 14998624
Inherited ArrhythmiaLQTS Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 2(5):507-17. 15840476
Inherited ArrhythmiaLQTS Gene sequencing in neonates and infants with the long QT syndrome. Genet Test. 2005 9(4):281-4. 16379539
Inherited ArrhythmiaLQTS Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006 113(3):365-73. 16432067
Inherited ArrhythmiaLQTS Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006 70(3):214-27. 16922724
Inherited ArrhythmiaLQTS Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome. Circ J. 2008 72(5):694-9. 18441445
Inherited ArrhythmiaLQTS Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. J Clin Invest. 2008 118(6):2246-59. 18464931
Inherited ArrhythmiaLQTS Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 6(9):1297-303. 19716085
Inherited ArrhythmiaLQTS Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 120(18):1752-60. 19841300
Inherited ArrhythmiaLQTS Pore mutants of HERG and KvLQT1 downregulate the reciprocal currents in stable cell lines. Am J Physiol Heart Circ Physiol. 2010 299(5):H1525-34. 20833965
Inherited ArrhythmiaLQTS Blockade of permeation by potassium but normal gating of the G628S nonconducting hERG channel mutant. Biophys J. 2011 101(3):662-70. 21806934
Inherited ArrhythmiaLQTS HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998 273(33):21061-6. 9694858
Inherited ArrhythmiaLQTS Isoform-specific dominant-negative effects associated with hERG1 G628S mutation in long QT syndrome. PLoS One. 2012 7(8):e42552. 22876326
Inherited ArrhythmiaLQTS Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation. 2005 111(3):264-70. 15642761
Inherited ArrhythmiaLQTS Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. 22949429
Inherited ArrhythmiaLQTS An in vivo cardiac assay to determine the functional consequences of putative long QT syndrome mutations. Circ Res. 2013 112(5):826-30. doi: 10.1161/CIRCRESAHA.112.300664. 23303164
p.G628Vc.1883G>T Inherited ArrhythmiaLQTSSIFT: deleterious
Polyphen: probably damaging
ReportsInherited ArrhythmiaLQTS Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 2(5):507-17. 15840476
Inherited ArrhythmiaLQTS Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Nat Commun. 2014 5:5535. doi: 10.1038/ncomms6535. 25417810
p.G628Rc.1882G>C Inherited ArrhythmiaLQTSSIFT:
ReportsInherited ArrhythmiaLQTS Genetic characteristics of children and adolescents with long-QT syndrome diagnosed by school-based electrocardiographic screening programs. Circ Arrhythm Electrophysiol. 2014 7(1):107-12. doi: 10.1161/CIRCEP.113.000426. 24363352
p.G628Dc.1883G>A Inherited ArrhythmiaLQTSSIFT:
ReportsInherited ArrhythmiaLQTS Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench. J Cardiovasc Electrophysiol. 2014 25(1):66-73. doi: 10.1111/jce.12270. 24112685