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PMID: 11388756
Heim RA, Sugarman EA, Allitto BA
Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel.
Genet Med. 2001 May-Jun;3(3):168-76.,
[PubMed]
Sentences
No.
Mutations
Sentence
Comment
55
ABCC7 p.Phe508Cys
X
ABCC7 p.Phe508Cys 11388756:55:78
status:
NEW
view ABCC7 p.Phe508Cys details
The 70-mutation assay distinguished between the ⌬F508 mutation and the
F508C
sequence variant.
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56
ABCC7 p.Phe508Cys
X
ABCC7 p.Phe508Cys 11388756:56:58
status:
NEW
view ABCC7 p.Phe508Cys details
ABCC7 p.Ile506Val
X
ABCC7 p.Ile506Val 11388756:56:65
status:
NEW
view ABCC7 p.Ile506Val details
ABCC7 p.Ile507Val
X
ABCC7 p.Ile507Val 11388756:56:83
status:
NEW
view ABCC7 p.Ile507Val details
ABCC7 p.Ile506Met
X
ABCC7 p.Ile506Met 11388756:56:72
status:
NEW
view ABCC7 p.Ile506Met details
The 86-mutation assay distinguished ⌬F508 from the
F508C
,
I506V
,
I506M
, and
I507V
sequence variants.
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83
ABCC7 p.Trp1316*
X
ABCC7 p.Trp1316* 11388756:83:77
status:
NEW
view ABCC7 p.Trp1316* details
ABCC7 p.Tyr122*
X
ABCC7 p.Tyr122* 11388756:83:17
status:
NEW
view ABCC7 p.Tyr122* details
ABCC7 p.Trp1310*
X
ABCC7 p.Trp1310* 11388756:83:65
status:
NEW
view ABCC7 p.Trp1310* details
These mutations,
Y122X
, 556delA, 2909delT, 3358delAC, 3750delAG,
W1310X
, and
W1316X
, were subsequently excluded from the 86-mutation panel.
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85
ABCC7 p.Pro574His
X
ABCC7 p.Pro574His 11388756:85:40
status:
NEW
view ABCC7 p.Pro574His details
ABCC7 p.Tyr563Asp
X
ABCC7 p.Tyr563Asp 11388756:85:33
status:
NEW
view ABCC7 p.Tyr563Asp details
ABCC7 p.Gln1238*
X
ABCC7 p.Gln1238* 11388756:85:77
status:
NEW
view ABCC7 p.Gln1238* details
ABCC7 p.Cys524*
X
ABCC7 p.Cys524* 11388756:85:26
status:
NEW
view ABCC7 p.Cys524* details
These mutations, 574delA,
C524X
,
Y563D
,
P574H
, 2043delG, 3662delA, 3821delT,
Q1238X
, and 3849 ϩ 4AϾG, as well as the previous seven mutations, make no detectable contribution to mutation detection in the general U.S. CF population.
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87
ABCC7 p.Ser1251Asn
X
ABCC7 p.Ser1251Asn 11388756:87:148
status:
NEW
view ABCC7 p.Ser1251Asn details
ABCC7 p.Thr338Ile
X
ABCC7 p.Thr338Ile 11388756:87:41
status:
NEW
view ABCC7 p.Thr338Ile details
ABCC7 p.Ser549Ile
X
ABCC7 p.Ser549Ile 11388756:87:98
status:
NEW
view ABCC7 p.Ser549Ile details
ABCC7 p.Gln552*
X
ABCC7 p.Gln552* 11388756:87:105
status:
NEW
view ABCC7 p.Gln552* details
ABCC7 p.Arg1283Met
X
ABCC7 p.Arg1283Met 11388756:87:160
status:
NEW
view ABCC7 p.Arg1283Met details
ABCC7 p.Gly91Arg
X
ABCC7 p.Gly91Arg 11388756:87:11
status:
NEW
view ABCC7 p.Gly91Arg details
ABCC7 p.Thr360Lys
X
ABCC7 p.Thr360Lys 11388756:87:70
status:
NEW
view ABCC7 p.Thr360Lys details
ABCC7 p.Gln359Lys
X
ABCC7 p.Gln359Lys 11388756:87:64
status:
NEW
view ABCC7 p.Gln359Lys details
These were
G91R
, 711 ϩ 5GϾA,
T338I
, 712-1GϾT,
Q359K
/
T360K
, 1161delC, 1609delCA,
S549I
,
Q552X
, 1949del84, 1989 ϩ 5GϾT,
S1251N
, and
R1283M
.
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105
ABCC7 p.Thr338Ile
X
ABCC7 p.Thr338Ile 11388756:105:139
status:
NEW
view ABCC7 p.Thr338Ile details
Examples include 394delTT (identified in only two U.S. Caucasian alleles, although it has a frequency of 1.1-28.8% in Northern Eu- rope5),
T338I
(not identified in the United States, although it has a frequency of 9.9% in Sardinia and nearly 0.1% in Italy5), and 1609delCA (not identified in 434 Southern or mixed European Caucasian alleles and 74 Hispanic alleles, although it has a frequency of 4.1% in the east of Spain5).
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107
ABCC7 p.Met1101Lys
X
ABCC7 p.Met1101Lys 11388756:107:17
status:
NEW
view ABCC7 p.Met1101Lys details
Examples include
M1101K
(identified in 6/1,216 Caucasian alleles including one of Southern European origin, but originally described as specific to the Hutterite population15), and 3120 ϩ 1GϾA (identified in 4/4,634 Caucasian alleles, but reported to be specific to African Americans6).
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109
ABCC7 p.Trp1282*
X
ABCC7 p.Trp1282* 11388756:109:118
status:
NEW
view ABCC7 p.Trp1282* details
ABCC7 p.Asn1303Lys
X
ABCC7 p.Asn1303Lys 11388756:109:126
status:
NEW
view ABCC7 p.Asn1303Lys details
ABCC7 p.Gly542*
X
ABCC7 p.Gly542* 11388756:109:111
status:
NEW
view ABCC7 p.Gly542* details
More strikingly, the five mutations reported to account for 97% of Ashkenazi Jewish chromosomes (⌬F508,
G542X
,
W1282X
,
N1303K
, and 3849 ϩ 10 kbCϾT)16 accounted for only 39/48 chromosomes in this study (81.3%).
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110
ABCC7 p.Ala455Glu
X
ABCC7 p.Ala455Glu 11388756:110:298
status:
NEW
view ABCC7 p.Ala455Glu details
ABCC7 p.Arg553*
X
ABCC7 p.Arg553* 11388756:110:305
status:
NEW
view ABCC7 p.Arg553* details
ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 11388756:110:316
status:
NEW
view ABCC7 p.Asp1152His details
This difference is unlikely to be due to ascertainment, since the observed frequency of ⌬F508 (29%) is equivalent to the frequency of 30% reported by Abeliovich et al.16 In this study, the detection of an additional three mutations was required to bring the overall detection rate to 95.4% (
A455E
,
R553X
, and
D1152H
).
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116
ABCC7 p.Trp1089*
X
ABCC7 p.Trp1089* 11388756:116:12
status:
NEW
view ABCC7 p.Trp1089* details
Of the two,
W1089X
is relatively frequent (1.2%) but was originally reported in one Turkish and one Egyptian Jewish individual17 and had not been described in Hispanics until now. The other, 1078delT,18 was identified on one Hispanic chromosome and no others.
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118
ABCC7 p.Tyr1092*
X
ABCC7 p.Tyr1092* 11388756:118:181
status:
NEW
view ABCC7 p.Tyr1092* details
Examples include 711 ϩ 1GϾT (frequency of 6.9% in Tunisia5 and 9% in Quebec19), 1677delTA (originally described in a small Georgian ethnic group in the U.S.S.R.20), and
Y1092X
(originally identified in the Canadian population21 and in the homozygous state in a CF patient of Jewish Egyptian origin3).
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119
ABCC7 p.Trp1089*
X
ABCC7 p.Trp1089* 11388756:119:22
status:
NEW
view ABCC7 p.Trp1089* details
With the exception of
W1089X
, 1078delT, and 2869insG, all other mutations identified in Hispanics were also identified in Caucasians.
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124
ABCC7 p.Tyr563Asp
X
ABCC7 p.Tyr563Asp 11388756:124:295
status:
NEW
view ABCC7 p.Tyr563Asp details
ABCC7 p.Ser364Pro
X
ABCC7 p.Ser364Pro 11388756:124:288
status:
NEW
view ABCC7 p.Ser364Pro details
As expected, after ⌬F508 the most common African American mutation was 3120 ϩ 1GϾA, with a frequency (13.8%) comparable to that reported by Macek et al. (12.3%).6 Five mutations that are considered to be African American specific (405 ϩ 3AϾC, ⌬F311,
S364P
,
Y563D
, and 3662delA)6,12,22 were not observed in any African Americans included in this study, however.
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125
ABCC7 p.Gly551Asp
X
ABCC7 p.Gly551Asp 11388756:125:136
status:
NEW
view ABCC7 p.Gly551Asp details
ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 11388756:125:129
status:
NEW
view ABCC7 p.Arg117His details
ABCC7 p.Arg1158*
X
ABCC7 p.Arg1158* 11388756:125:121
status:
NEW
view ABCC7 p.Arg1158* details
ABCC7 p.Arg1066Cys
X
ABCC7 p.Arg1066Cys 11388756:125:189
status:
NEW
view ABCC7 p.Arg1066Cys details
It was unexpected that six of the next most common mutations after 3120 ϩ 1GϾA would be of Caucasian origin (
R1158X
,
R117H
,
G551D
, 1812-1GϾA, 1898 ϩ 1GϾA, and
R1066C
).
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126
ABCC7 p.Arg1158*
X
ABCC7 p.Arg1158* 11388756:126:135
status:
NEW
view ABCC7 p.Arg1158* details
ABCC7 p.Arg1158*
X
ABCC7 p.Arg1158* 11388756:126:213
status:
NEW
view ABCC7 p.Arg1158* details
ABCC7 p.Arg1066Cys
X
ABCC7 p.Arg1066Cys 11388756:126:10
status:
NEW
view ABCC7 p.Arg1066Cys details
Of these,
R1066C
has a frequency of 3.1% in Portugal,5 1812-1GϾA was originally identified in 1/50 Spanish CF chromosomes,24 and
R1158X
was originally identified in an Italian CF patient.13 Our detection of
R1158X
on four African American chromosomes (2.0%) was not anticipated.
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127
ABCC7 p.Arg553*
X
ABCC7 p.Arg553* 11388756:127:238
status:
NEW
view ABCC7 p.Arg553* details
ABCC7 p.Ser1255*
X
ABCC7 p.Ser1255* 11388756:127:301
status:
NEW
view ABCC7 p.Ser1255* details
ABCC7 p.Gly480Cys
X
ABCC7 p.Gly480Cys 11388756:127:231
status:
NEW
view ABCC7 p.Gly480Cys details
ABCC7 p.Gly330*
X
ABCC7 p.Gly330* 11388756:127:224
status:
NEW
view ABCC7 p.Gly330* details
ABCC7 p.Ala559Thr
X
ABCC7 p.Ala559Thr 11388756:127:245
status:
NEW
view ABCC7 p.Ala559Thr details
Of the 20 mutations that account for the overall detection rate in African Americans when ⌬F508 is excluded, nine that account for 23.6% of the chromosomes analyzed are considered to be "African" mutations6 (444delA,
G330X
,
G480C
,
R553X
,
A559T
, 2307insA, 3120 ϩ 1GϾA, 3791delC, and
S1255X
).
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128
ABCC7 p.Gly551Asp
X
ABCC7 p.Gly551Asp 11388756:128:338
status:
NEW
view ABCC7 p.Gly551Asp details
ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 11388756:128:293
status:
NEW
view ABCC7 p.Arg117His details
ABCC7 p.Arg334Trp
X
ABCC7 p.Arg334Trp 11388756:128:324
status:
NEW
view ABCC7 p.Arg334Trp details
ABCC7 p.Arg1162*
X
ABCC7 p.Arg1162* 11388756:128:403
status:
NEW
view ABCC7 p.Arg1162* details
ABCC7 p.Gln493*
X
ABCC7 p.Gln493* 11388756:128:331
status:
NEW
view ABCC7 p.Gln493* details
ABCC7 p.Arg1158*
X
ABCC7 p.Arg1158* 11388756:128:395
status:
NEW
view ABCC7 p.Arg1158* details
ABCC7 p.Arg1066Cys
X
ABCC7 p.Arg1066Cys 11388756:128:387
status:
NEW
view ABCC7 p.Arg1066Cys details
By comparison, eight "African" mutations accounted for a similar percentage of the chromosomes analyzed (23%) in the study by Macek et al.6 In contrast, 11 of the 20 mutations detected in this study are considered to be "Caucasian" mutations and account for 10.5% of the chromosomes analyzed (
R117H
, 621 ϩ 1GϾT,
R334W
,
Q493X
,
G551D
, 1812-1GϾA, 1898 ϩ 1GϾA,
R1066C
,
R1158X
,
R1162X
, and 3905insT).
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133
ABCC7 p.Arg1162*
X
ABCC7 p.Arg1162* 11388756:133:22
status:
NEW
view ABCC7 p.Arg1162* details
We did not detect the
R1162X
mutation, although it has a carrier frequency of 6.7% among Zuni Native Americans.25 Despite its small size, our sample set is the largest reported to date.
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