KCNE2 I57T - GET-Evidence



(KCNE2 Ile57Thr)

Short summary

Reported to cause Long QT syndrome, which can cause palpitations, fainting, and sudden death. Only a few patients have been reported carrying this variant; insufficient data has been reported to establish a statistically significant association of this variant with the disease.

Variant evidence
Computational 1

Other variants in this gene associated with Long QT syndrome

Functional 2

Gain of function effects observed

See Wu J et al. 2010 (20042375).


Insufficient observations to establish statistical significant association with disease

Familial -
Clinical importance
Severity 4
Treatability 3
Penetrance 4


High clinical importance, Uncertain pathogenic

(The "high clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • C @ chr21:35742947: 0.0% (4/10758) in EVS
  • Frequency shown in summary reports: 0.0% (4/10758)


Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999 Apr 16;97(2):175-87. PubMed PMID: 10219239.

This paper describes characterizing the gene KCNE2 as an ion channel. To test whether variants in the gene could cause disease, they screened for KCNE2 variants in 20 patients with drug-induced arrhythmia and 230 with arrhythmias and no known mutations (KVLQT1, HERG, SCN5A, or KCNE1). Three variants were found in the patient cohort that were not present in 1010 control individuals, and a fourth variant was classified as a polymorphism. One of the three was I57T, found in a Hispanic female with arrhythmia. The authors mention that she was part of a multigenerational family under evaluation, but do not describe any follow-up or data from other family members.

Although the aggregate data may be significant, the individual case here does not achieve a statistically significant difference from controls: case+: 1, case-: 249, control+: 0, control-: 1010. (p = 0.198)

Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL Jr, Goldstein SA. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10613-8. PubMed PMID: 10984545; PubMed Central PMCID: PMC27073.

From the same group as Abbott et al 1999. A screen for KCNE1 mutations in 98 patients who experienced long QT or torsade de pointes during drug treatment. This variant was seen in one patient. No additional controls are mentioned.

Wu J, Shimizu W, Ding WG, Ohno S, Toyoda F, Itoh H, Zang WJ, Miyamoto Y, Kamakura S, Matsuura H, Nademanee K, Brugada J, Brugada P, Brugada R, Vatta M, Towbin JA, Antzelevitch C, Horie M. KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. Heart Rhythm. 2010;7(2):199-205. doi: 10.1016/j.hrthm.2009.10.012. Epub 2009 Oct 12. PubMed PMID: 20042375; PubMed Central PMCID: PMC2819024.

The authors mention that they “recently identified the same missense KCNE2 variant … in three unrelated probands showing a Brugada type 1 ECG”. They don’t give a reference for this and give no further explanation of how these patients were discovered (i.e. how many patients were screened).

Their functional study of the variant concludes that the ion channel has significantly different properties (increased peak transient outward current, slowed decay, and accelerated recovery), described as gain of function.


Other external references

  • Score: 0.574 (possibly damaging)
    Web search results (65 hits -- see all)
  • KCNE2 confers background current characteristics to the ...
    The I57T substitution is another mutation found in the KCNE2 gene from patients with ... The KCNE2-Q9E and I57T mutants were constructed using a classical PCR ...
  • KCNE2 modulation of Kv4.3 current and its potential role in ...
    KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders. ... M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch ...
  • Long QT syndrome type 6 mutations
    KCNE2. KCNE2 Locus table - KCNE2 synopsis. OMIM: *603796 ; Gene id: 9992. AA numbering is ... T170C. I57T. Missense# Transmembrane. 1. RWS/aLQTS. Abbott et al. (1999) ;Sesti et al 2000 ...
  • Statens Serum Institut - R & D - Diagnostic - The long QT ...
    I57T. Missense. Arrthymia3. Hispanic. Abbott et al, 1999. 420C>T. A116V ... from the ATG start codon in the KCNE2 cDNA (GenBank accession no. NM_005136) ...
  • PIBB
    Dynamic Changes of Mineral Element in The Cell Wall of Growth Cells Detected by CSEM-EDX. LIANG Feng,WANG ... 3 by I57T and V65M, Two Kinds of LQT6 Associated Mutations in KCNE2 ...
  • Voltage-gated K Channels - IV
    mutations of KCNE2 in patients with LQT-6 syndrome impair I ... of recovery as KCNE2 WT, whereas I57T signi´Čücantly reduced "overshoot" amplitude and ...
  • Molecular Interactions Between Two Long-QT Syndrome Gene ...
    Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias ... long-QT syndrome (eg, M54T-hKCNE2 and I57T-hKCNE2).4 These conclusions can be generalized ...
  • DOI: 10.1161/hh1301.093633 2001;89;33-38; originally ...
    and KCNE2, have been linked to heritable or acquired long-QT syndrome. ... functional interactions between HERG and KCNE2 with a view to defining underlying ...
  • 2000;102;1178-1185 Circulation Michael Vincent and Mark T ...
    ... of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause ... (encoded by KCNE2, stoichiometry unknown) to form I. Kr. channels, which underlie the ...
  • Drug-Induced Torsades de Pointes and Implications for Drug: 6 ...
    6. Risk and Benefit: A review of the techniques and limitations of methods directed at drug-related phenomena, clinical trials, interpretation of ECGs, and evaluation ...

Other in silico analyses

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 5

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Gene search

"GENE" or "GENE A123C":

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