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Table 4 Web. Most Frequently Cited Mutations – Up to 10 Per Genotypea
NUCLEOTIDE
CHANGE
AMINO ACID
CHANGE
MUTATION
TYPE
PROTEIN
DOMAIN
NO. OF
PROBANDS
/
FAMILIESb
COUNTRY
OR
REGION
PHENOTYPEc
REFERENCES
KCNQ1
G502A
G168R
Missense
S2
USA, Ne,
Fr
RWS
KCNQ1
L191
572-576del fs281X
Frameshift
S2-S3
USA,
Nor, Eng
RWS /
JLNS
KCNQ1
G760A
Missense
S4-S5
1-3 per
study
(12
overall) /
Ctrls.:
200+
indivs.,
1-400
chroms.,
>3000 ref.
alleles
2-7 per
study
(22
overall) /
Ctrls.:
50-400
chroms.,
>3000 ref.
alleles
1-2 per
study
(8 overall)
/ Ctrls.:
90 indivs.,
USA, Be
RWS
Tester et al.
2005; Beery et
al. 2003; van
Langen et al.
2003;
Jongbloed et
al. 2002;
Splawski et al.
2000, 1998;
Donger et al.
1997
Tester et al.
2005; Choi et
al. 2004;
Tyson et al.
2000, 1997;
Splawski et al.
2000;
Tranebjaerg et
al. 1999
Tester et al.
2005; Choi et
al. 2004;
Paulussen et
al. 2003;
V254M
2-400
chroms.,
>3000 ref.
alleles
KCNQ1
G940A
G314S
Missense
Pore
KCNQ1
A944G
Y315C
Missense
Pore
KCNQ1
C1022A
A341E
Missense
S6
Splawski et al.
2000; Donger
et al. 1997
1-2 per
USA, Ne,
study
Fr, Ja
(8 overall)
/ Ctrls.:
50-200+
indivs.,
2-400
chroms.,
>3000 ref.
alleles
1 per study USA, It
(6 overall)
/ Ctrls.:
1-200+
indivs.,
400
chroms.,
>3000 ref.
alleles
RWS
Tester et al.
2005;
Splawski et al.
2000, 1998;
Jongbloed et
al. 1999; Itoh
et al. 1998;
Donger et al.
1997
RWS,
aLQTS
1-3 per
study
(6 overall)
/ Ctrls.:
200+
RWS
Tester et al.
2005; Choi et
al. 2004; Chen
et al. 2003;
Napolitano et
al. 2000;
Splawski et al.
2000; Priori et
al. 1999;
Splawski et al.
1998
Westenskow
et al. 2004;
Chen et al.
2003;
Splawski et al.
USA, Fr
KCNQ1
C1022T
A341V
Missense
S6
KCNQ1
G1032A
A344A
Splicing
Mutation
S6
KCNQ1
C1552T
R518X
Nonsense
C-term
indivs.,
400
chroms.
1-3 per
study
(12
overall) /
Ctrls.:
1-400
chroms.,
>3000 ref.
alleles
2000; Berthet
et al. 1999
USA, Ne,
Fr, Ja
RWS
1-6 per
study
(18
overall) /
Ctrls.:
50 indivs.,
2-400
chroms.,
>3000 ref.
alleles
USA, Da,
Eng, Fr,
Ja
RWS
1-5 per
study (21
overall) /
Ctrls.:
USA,
Nor, Fi,
Sw, Eng
RWS /
JLNS
Tester et al.
2005; Kobori
et al. 2004;
Westenskow
et al. 2004;
Jongbloed et
al. 2002;
Splawski et al.
2000; Donger
et al. 1997
Tester et al.
2005; Choi et
al. 2004;
Overo et al.
2000;
Splawski et al.
2000;
Ackerman et
al. 1999;
Murray et al.
1999; Itoh et
al. 1998;
Kanters et al.
1998
Tester et al.
2005;
Splawski et al.
2000; Tyson et
200+
indivs.,
50-100
chroms.,
>3000 ref.
alleles
KCNQ1
G1766A
G589D
Missense
C-term
HERG
C526T
R176W
Missense
N-term
HERG
T1655C
L552S
Missense
S5
69 latest
single
study /
Ctrls.:
200+
indivs.
1-12 per
study (19
overall) /
Ctrls.:
33-201
indivs.
Fi
RWS /
JLNS
USA, Fi
RWS
1-11 per
study (14
overall) /
Ctrls.:
33-200+
indivs.,
400
chroms.,
>3000 ref.
alleles
USA, Fi
RWS,
AVB
al. 2000;
Fodstad et al.
2004; Wei et
al. 2000;
Larsen et al.
1999;
Tranebjaerg et
al. 1999
Fodstad et al.
2004; Piipo et
al. 2001, Swan
et al. 1999,
Saarinen et al.
1998
Fodstad et al.
2004;
Ackerman et
al. 2003;
Laitinen et al.
2000; Swan et
al. 1999
Tester et al.
2005; Fodstad
et al. 2004;
Lunetta et al.
2003; Piipo et
al. 2000;
Splawski et al.
2000; Swan et
al. 1999
HERG
C1682T
A561V
Missense
S5
1-2 per
study (8
overall) /
Ctrls.:
33-200
indivs.,
400
chroms.,
>3000 ref.
alleles
USA, It,
Ja
RWS
HERG
G1750A
G584S
Missense
S5-Pore
USA, Fi
RWS
HERG
G1810A
G604S
Missense
S5-Pore
1-10 per
study (12
overall) /
Ctrls.: 33201
indivs.,
400
chroms.,
>3000 ref.
alleles
1-4 per
study (8
overall) /
Ctrls.:
55 indivs.,
1-400
chroms.,
>3000 ref.
alleles
USA, Ne,
Fr
RWS
Tester et al.
2005;
Westenskow
et al. 2004;
Splawski et al.
2000; Priori et
al. 1999;
Napolitano et
al. 1997;
Tanaka et al.
1997; Curran
et al. 1995
Tester et al.
2005; Laitinen
et al. 2000;
Splawski et al.
2000; Swan et
al. 1999
Tester et al.
2005;
Lupoglazoff et
al. 2004; van
Langen et al.
2003;
Splawski et al.
2000;
Jongbloed et
HERG
C1838T
T613M
Missense
S5-Pore
1-6 per
study (15
overall) /
Ctrls.:
55-201
indivs.,
100
chroms.,
>3000 ref.
alleles
USA, Fi,
Ne, Fr
RWS,
AVB
HERG
C1841T
A614V
Missense
Pore
1-2 per
study (9
overall) /
Ctrls.:
80-200+
indivs.,
400
chroms.,
>3000 ref.
alleles
USA, It,
Ja, Tw
RWS
SCN5A
C1715A
A572D
Missense
DII-S5/S6
USA, Be
RWS
SCN5A
DelKPQ1505- Deletion
DIII-DIV
1-3 per
study (5
overall) /
Ctrls.: 90
indivs.,
>3000 ref.
alleles
1-4 per
USA
RWS
al. 1999
Tester est al.
2005; Choi et
al. 2004;
Lupoglazoff et
al. 2004; van
Langen et al.
2003;
Splawski et al.
2000;
Jongbloed et
al. 1999
Tester et al.
2005; LeeChen et al.
1999; Priori et
al. 1999;
Satler et al.
1998;
Splawski et al.
2000, 1998;
Tanaka et al.
1997
Tester et al.
2005; Choi et
al. 2004;
Paulussen et
al. 2003
Tester et al.
45114519del
1507
SCN5A
G4868A
R1623Q
Missense
DIV-S4
SCN5A
G4931A
R1644H
Missense
DIV-S4
study (5
overall) /
Ctrls.: 400
indivs.,
400
chroms.,
>3000 ref.
alleles
1 per study USA, Ja
(7 overall)
/ Ctrls.:
81-100
indivs.,
400
chroms.
1-2 per
study (5
overall) /
Ctrls.:
81-400
indivs.,
USA
2005;
Splawski et al.
2000;
Wattanasirichaigoon et al.
1999; Wang et
al. 1995a,b
RWS
RWS
Miller et al.
2004;
Westenskow
et al. 2004;
Miura et al.
2003;
Splawski et al.
2000;
WattanasiriChaigoon et
al. 1999;
Kambouris et
al. 1998;
Makita et al.
1998;
Yamagishi et
al. 1998
Tester et al.
2005;
Westenskow
et al. 2004;
Splawski et al.
2000;
>3000 ref.
alleles
SCN5A
G5349A
E1784K
Missense
DIV-S6/
C-term
1-4 per
study (8
overall) /
Ctrls.:
1-400
chroms.,
>3000 ref.
alleles
USA, Ca,
It
RWS,
BS
AnkB
A4274G
KCNE1
C221T
E1425G
Missense
C-term
Missense
Cytoplasmic
USA, Fr,
It
USA
RWS
S74L
KCNE1
G226A
D76N
Missense
Cytoplasmic
1 per study
(2 overall)
1 per study
(2 overall)
/ Ctrls.:
200 indivs.
1 per study
(4 overall)
/ Ctrls.: 1200 indivs.
KCNE2
T161C
M54T
Missense
Transmembrane
RWS
USA, Leb RWS /
JLNS
1 per study USA
(2 overall)
/ Ctrls.:
aLQTS
WattanasiriChaigoon et
al. 1999;
Wang et al.
1995b
Tester et al.
2005; Priori et
al. 2002;
Deschennes et
al. 2000;
Splawski et al.
2000;
Wei et al.
1999
Mohler et al.
2004,2003
Westenskow
et al. 2004,
Splawski et al.
1997
Bianchi et al.
1999; Duggal
et al.1998;
Schulze-Bahr
et al. 1997;
Splawski et al.
1997
Sesti et al.
2000; Abbott
et al. 1999
KCNE2
T170C
I57T
Missense
Transmembrane
KCNJ2
C199T
R67W
Missense
N-term
KCNJ2
C652T
R218W
Missense
C-term
KCNJ2
C880T
R218W
Missense
C-term
CACNA1c G406R
G1216A
Missense
DI-S6
CACNA1c
G1204A
Missense
DI-S6
G402S
1010
indivs.
1 per study
(2 overall)
/ Ctrls.:
1010
indivs.
1-2 per
study (4
overall) /
Ctrls.: 100
indivs.
1-5 per
study (6
overall) /
Ctrls.:
100 indivs.
4 per study
(4 overall)
USA
aLQTS
Sesti et al.
2000; Abbott
et al. 1999
USA
AS
USA
AS
Chun 2004;
Donaldson
2003;
Andelfinger
2002
Donaldson
2003; TristaniFirouzi 2002
Ne, Mex
AS
1-13 per
USA
study (14
overall) /
Ctrls.: 180
indivs.
1 per study USA
(2 overall)
/ Ctrls.:
182 indivs.
TS
TS
Jongsma
2001; Plaster
2001
Splawski
2005, 2004
Splawski 2005
Based on international article searches in Medline and review of tables and references in the “Gene Connection for the Heart” LQTS
mutation database, European Society of Cardiology Study Group on Molecular Basis of Arrhythmias, http://pc4.fsm.it:81/cardmoc,
and the “Long QT Syndrome Database” of the Human Genome Organisation (HUGO), www.ssi.dk/graphics/html/lqtsdb/lqtsdb.htm.
Last accessed: 6/17/05. Also see Antonarakis SE and the Nomenclature Working Group. Recommendations for a nomenclature system
for human gene mutations. Hum Mutat 1998;11:1-3. Table completed 7/15/05.
a
b
Where possible, number of original probands per study and over all studies (in parentheses) is listed; otherwise, number of unrelated
families studied. Number of controls retains original mention of control chromosomes or individuals.
”RWS” = Romano-Ward syndrome (heterozygous condition; cardiac symptoms only); “JLNS” = Jervell and Lange-Nielsen
syndrome (homozygous condition; cardiac symptoms + deafness); “BS” = Brugada syndrome; “AVB” = 2:1 atrioventricular block;
“aLQTS” = acquired LQTS; “AS” = “Andersen syndrome”; “TS”=”Timothy syndrome.” See Vincent GM. Long QT syndrome.
Cardiol Clinics 2000;18:309-325; Moric E, Herbert E, Trusz-Gluza M, et al. The implications of genetic mutations in the sodium
channel gene (SCN5A). Europace 2003;5:325-334; Donaldson MR, Yoon G, Fu YH, et al. Andersen-Tawil syndrome: a model of
clinical variability, pleiotropy, and genetic heterogeneity. Ann Med 2004;36 Suppl 1: 92-97; Splawski I, Timothy KW, Decher N, et al.
Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci 2005;102:8089-8096.
Abbreviations apply to Table 5.
c
Table 4. References
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Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G,
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Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. Severe arrhythmia disorder
caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci 2005;102:8089-8096.
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, TagerFlusberg H, Priori SG, Sanguinetti MC, Keating MT. Cav1.2 calcium channel dysfunction causes a multisystem disorder including
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Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating
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