ABCMdb

PMID: 15858154

Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A
Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.
J Mol Diagn. 2005 May;7(2):289-99., [PubMed]

Sentences

No. Mutations Sentence Comment

26 ABCC7 p.Ile506Val Fourteen novel amino acid changing variants were identified in a total of 183 CFTR sequence changes (excluding the common M470V and I506V polymorphism and 5T/7T/9T variants in intron 8). Login to comment 74 ABCC7 p.Arg334Trp ⌬F508 was observed in homozygosity 6 times (11%), but with another ACMG/ ACOG defined common mutation only (R334W) once (2%). Login to comment 76 ABCC7 p.Leu206Trp ABCC7 p.Ile1027Thr ABCC7 p.Trp1204* Other than ⌬F508 itself and I1027T, typically occurring in cis-, only two individual mutations, W1204X and L206W, were observed with ⌬F508 more than once (twice each) in this study. Login to comment 78 ABCC7 p.Glu588Val Of these additional 82 mutations 15 were novel, but one of these occurred twice (E588V). Login to comment 81 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Gly542* G542X, which is a common allele of European origin, occurred a total of 7 times (1%), including once in homozygosity, while R334W and R553X occurred twice each. Login to comment 82 ABCC7 p.Trp1204* In contrast, among the 78 non-ACMG/ACOG mutations observed in our study group, 24 were noted two or more times, including six instances of the splice site mutation 406-1GϾA, and four instances of W1204X. Login to comment 83 ABCC7 p.Gly542* ABCC7 p.Val232Asp ABCC7 p.Arg75* ABCC7 p.Trp1204* ABCC7 p.Glu116Lys ABCC7 p.Thr501Ala While ⌬F508 was homozygous in six subjects, seven other less common alleles (G542X, W1204X, R75X, V232D, E116K, T501A, 3272-26 AϾG) were also seen in the homozygous state. Login to comment 85 ABCC7 p.Gly542* 1429del7bp A one-year-old Hispanic female has a novel 1429del7bp in combination with the well-established G542X mutation (exon 11). Login to comment 89 ABCC7 p.Ser573Cys This would result in premature termination of translation, which is known to result in CF, presumably as a result of nonsense-mediated mRNA decay or dysfunctionally shortened protein products.20 Promising effects of gentamicin treatment on CFTR expression may enhance targeted treatment in patients with these mutations.21 S573C A 9-year-old boy with pancreatitis has a CϾG transversion at nucleotide position 1850. Login to comment 91 ABCC7 p.Ser573Cys This mutation in exon 12 substitutes a cysteine for serine at amino acid position 573. Login to comment 94 ABCC7 p.Pro574His ABCC7 p.Asp572Asn D572N was identified in a Russian patient22 and P574H was identified in two patients with pancreatic sufficiency.23 The serine residue at position 573 is highly conserved across species, as are at least seven residues on either side in mammals, and two in amphibians and fish.24 A second mutation in this subject was not identified. Login to comment 95 ABCC7 p.Tyr913* ABCC7 p.Tyr913* Y913X A male newborn of European/Brazilian ancestry, with meconium ileus at birth and severe pancreatic insufficiency was found to have ⌬F508 and two additional mutations, including the novel Y913X in exon 15. Login to comment 97 ABCC7 p.Tyr913* The novel Y913X results in a premature termination codon resulting from a TϾA change at nucleotide 2872, while the third mutation is a known Table 1. Login to comment 98 ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Asp1270Asn ABCC7 p.Glu831* ABCC7 p.Pro205Ser ABCC7 p.Glu585* ABCC7 p.Leu206Trp ABCC7 p.Arg1066Cys ABCC7 p.His199Tyr ABCC7 p.Asp1152His ABCC7 p.Gly576Ala ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Gln890* ABCC7 p.Asp1445Asn ABCC7 p.Arg1066His ABCC7 p.Leu967Ser ABCC7 p.Phe693Leu ABCC7 p.Glu116Lys ABCC7 p.Asp836Tyr ABCC7 p.Ala559Thr ABCC7 p.Gln98Arg ABCC7 p.Phe311Leu ABCC7 p.Ala1009Thr ABCC7 p.Leu320Val ABCC7 p.Gln1313* Spectrum of CFTR Sequence Variants in 257 Hispanic Patients Who Underwent Diagnostic DNA Testing for CF Mutations in 257 patients Allele counts of each mutation % of variant alleles (183) % of all alleles tested (514) ACMG/ACOG recommended 25 mutation panel* DeltaF508 53 28.96 10.31 G542X 7 3.83 1.36 R334W 2 1.09 0.39 R553X 2 1.09 0.39 DeltaI507 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 3120 ϩ 1 GϾA 1 0.55 0.19 7 different mutations 67 36.61 13.04 All mutations included ACMG/ACOG 1248 ϩ 1 GϾA 1 0.55 0.19 1249 - 29delAT 1 0.55 0.19 1288insTA1288insTA 1 0.55 0.19 1341 ϩ 80 GϾA1341 ϩ 80 GϾA 1 0.55 0.19 1429del71429del7 1 0.55 0.19 1525 - 42 GϾA1525 - 42 GϾA 1 0.55 0.19 1717 - 1 GϾA 1 0.55 0.19 1717 - 8 GϾA 2 1.09 0.39 1811 ϩ 1 GϾA1811 ϩ 1 GϾA 1 0.55 0.19 2055del9-ϾA 3 1.64 0.58 2105-2117del13insAGAAA 1 0.55 0.19 2215insG 1 0.55 0.19 2585delT2585delT 1 0.55 0.19 2752 - 6 TϾC 1 0.55 0.19 296 ϩ 28 AϾG 1 0.55 0.19 3120 ϩ 1 GϾ A 1 0.55 0.19 3271 ϩ 8 AϾG3271 ϩ 8 AϾG 1 0.55 0.19 3271delGG 1 0.55 0.19 3272 - 26 AϾG 2 1.09 0.39 3876delA 2 1.09 0.39 4016insT 1 0.55 0.19 406 - 1 GϾA 6 3.28 1.17 406 - 6 TϾC 1 0.55 0.19 4374 ϩ 13 A ϾG 1 0.55 0.19 663delT 1 0.55 0.19 874insTACA874insTACA 1 0.55 0.19 A1009T 2 1.09 0.39 A559T 1 0.55 0.19 D1152H 1 0.55 0.19 D1270N 3 1.64 0.58 D1445N 2 1.09 0.39 D836Y 1 0.55 0.19 DeltaF311 1 0.55 0.19 DeltaF508 53 28.96 10.31 DeltaI507 1 0.55 0.19 E116K 2 1.09 0.39 E585X 1 0.55 0.19 E588VE588V 2 1.09 0.39 E831X 1 0.55 0.19 F311L 1 0.55 0.19 F693L 1 0.55 0.19 G1244E 1 0.55 0.19 G542X 7 3.83 1.36 G576A 1 0.55 0.19 H199Y 3 1.64 0.58 I1027T 3 1.64 0.58 I285FI285F 1 0.55 0.19 L206W 3 1.64 0.58 L320V 1 0.55 0.19 L967S 1 0.55 0.19 L997F 3 1.64 0.58 P1372LP1372L 1 0.55 0.19 P205S 1 0.55 0.19 P439SP439S 1 0.55 0.19 Q1313X 1 0.55 0.19 Q890X 2 1.09 0.39 Q98R 1 0.55 0.19 R1066C 1 0.55 0.19 R1066H 1 0.55 0.19 (Table continues) missense variant, I1027T (3212TϾC), in exon 17a.25 Family studies have not been performed to identify which allele carries two mutations. Login to comment 99 ABCC7 p.Ile1027Thr However, I1027T has been reported in cis with the ⌬F508 mutation in the Human Gene Mutation Database26 and has been observed in this phase in several family studies at Ambry, as well. Login to comment 100 ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Tyr913* Moreover, if I1027T is in cis with ⌬F508, little additional effect would be expected as ⌬F508 is a "severe" allele, whereas if it is in cis with the novel Y913X, the premature termination of translation would occur before reaching I1027T, and no additional effect might result. Login to comment 101 ABCC7 p.Glu588Val E588V A 5-month-old female of Northwestern European and Hispanic ancestry with a positive newborn screening by Table 2. Login to comment 102 ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg668Cys ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Ile285Phe ABCC7 p.Ser573Cys ABCC7 p.Pro439Ser ABCC7 p.Pro439Ser ABCC7 p.Tyr913* ABCC7 p.Arg1438Trp ABCC7 p.Arg1438Trp ABCC7 p.Glu588Val ABCC7 p.Glu588Val ABCC7 p.Pro1372Leu ABCC7 p.Thr604Ser Novel Variants Detected in 257 Hispanic Patients Patient Novel variant 1 Other variants Age and symptoms 1 1429del7bp G542X Newborn with intestinal blockage 2 S573C None 9 years old, pancreatitis, limited clinical history 3 Y913X deltaF508/I1027T 1 month old, vomiting, weight loss, diarrhea 4 E588V deltaF508/R1438W Identified one time in a family, family studies revealed deltaF508 and R1438W are in cis 5 E588V G542X Newborn with pneumonia and sweat chloride of 59 mmol/L 6 P439S R668C 10 years old with mild CF symptoms; another patient with CBAVD has P439S/R334W 7 T604S deltaF508 1 month old 8 874insTACA deltaF508 Newborn with meconium ileus and IUGR 9 2585delT deltaF508/I1027T 13 years old with CF 10 1811 ϩ 1 G to A None 44 years old with positive sweat chloride; also seen in 5-year-old CF patient with 3821delT mutation 11 I285F None 1 year old with chronic respiratory problems, also carries a silent mutation at A455 12 P1372L None 1 month old, rule out CF 13 3271 ϩ 8 A to G None 16 years old, borderline sweat test 14 1341 ϩ 80 G to A None Recurrent sinusitis 15 1525 - 42 G to A None Two patients, one 9 years old with FTT, and one 18 months old with chronic lung disease, pulmonary hypotension, hypoxia CBAVD, congenital bilateral absence of the vas deference; IUGR, intrauterine growth retardation. Login to comment 103 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg74Trp ABCC7 p.Ser549Asn ABCC7 p.Arg1158* ABCC7 p.Ser1235Arg ABCC7 p.Ser945Leu ABCC7 p.Arg668Cys ABCC7 p.Tyr563Asn ABCC7 p.Val232Asp ABCC7 p.Trp1089* ABCC7 p.Trp1098Cys ABCC7 p.Arg75* ABCC7 p.Trp1204* ABCC7 p.Arg1070Trp ABCC7 p.Ser492Phe ABCC7 p.Val11Ile ABCC7 p.Arg352Trp ABCC7 p.Thr351Ser ABCC7 p.Arg1438Trp ABCC7 p.Thr501Ala Table 1. Continued Mutations in 257 patients Allele counts of each mutation % of variant alleles (183) % of all alleles tested (514) R1070W 1 0.55 0.19 R1158X 1 0.55 0.19 R1438W 1 0.55 0.19 R334W 2 1.09 0.39 R352W 1 0.55 0.19 R553X 2 1.09 0.39 R668C 2 1.09 0.39 R74W 3 1.64 0.58 R75X 3 1.64 0.58 S1235R 2 1.09 0.39 S492F 2 1.09 0.39 S549N 1 0.55 0.19 S573CS573C 1 0.55 0.19 S945L 1 0.55 0.19 T351S 1 0.55 0.19 T501A 2 1.09 0.39 T604ST604S 1 0.55 0.19 V11I 1 0.55 0.19 V201 mol/L 1 0.55 0.19 V232D 2 1.09 0.39 V754 mol/L 1 0.55 0.19 W1089X 2 1.09 0.39 W1098C 1 0.55 0.19 W1204X 4 2.19 0.78 Y563N 1 0.55 0.19 Y913XY913X 1 0.55 0.19 85 different mutations 183 100.00 35.60 Novel variants are in boldface, mutations on the ACMG/ACOG panel are italicized. Login to comment 109 ABCC7 p.Arg1438Trp One of these is novel, whereas the other has very recently been reported in the CF mutation database.10 R1438W is caused by a CϾT nucleotide substitution in position 4444 in the final exon (#24) of the CFTR gene. Login to comment 111 ABCC7 p.Arg1438Trp Although the change from a charged polar residue to a bulky non-polar amino acid appears drastic, functional changes cannot be determined without expression studies. The results of family studies confirm that the ⌬F508 mutation and R1438W sequence variant are in cis-in our study subject. Login to comment 112 ABCC7 p.Ser977Phe ABCC7 p.Glu588Val In the CF mutation database, this variant also occurred in combination with other sequence variants: S977F in cis, and ⌬F508 in trans.10 The E588V variant, which is in trans in our subject, is caused by an AϾT nucleotide substitution in position 1895 in exon 12. Login to comment 114 ABCC7 p.Gly542* This was a newborn with pneumonia and a borderline sweat chloride result of 59 mmol/L, who also carried a G542X mutation. Login to comment 115 ABCC7 p.Pro439Ser ABCC7 p.Pro439Ser P439S A 10-year-old Hispanic boy with somewhat atypical features of CF has a novel mutation, P439S (1447CϾT), in exon 9. Login to comment 119 ABCC7 p.Arg668Cys The other mutation in this child is R668C in exon 13. Login to comment 121 ABCC7 p.Thr604Ser T604S A male newborn identified as affected at a large CF center has a novel CϾG substitution at nucleotide position 1943. Login to comment 122 ABCC7 p.Thr604Ser This changes a conserved threonine to a serine (T604S) within exon 13 of the CFTR gene. Login to comment 130 ABCC7 p.Ile1027Thr This patient carries two additional mutations including a ⌬F508 mutation and I1027T. Login to comment 135 ABCC7 p.Ile285Phe I285F A 1-year-old male of Hispanic and African American ancestry with chronic respiratory problems had a novel AϾT nucleotide substitution at position 985. Login to comment 141 ABCC7 p.Pro1372Leu P1372L A newborn female referred to "rule out CF" had a novel CϾT substitution at nucleotide position 4247, which changes a proline to a leucine within exon 22. Login to comment 152 ABCC7 p.Trp1204* W1204X* A boy with classic CF, has a W1204X mutation in exon 19, as well as a ⌬F508 mutation as the other allele. Login to comment 164 ABCC7 p.Ile148Thr This is lower than the ϳ65% relative mutation frequency in Caucasian individuals.11 In addition, the mutations that were identified in this control group were largely rare, and only 13/61 (including I148T) different mutations are included in the 25 mutation screening panel recommended by ACMG/ACOG. Login to comment 165 ABCC7 p.Pro67Leu ABCC7 p.Ser1235Arg ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Ile1027Thr ABCC7 p.Glu60* Due to ascertainment bias, six mutations not included in the recommended panel occurred with a relative frequency greater than 1%: E60X, G576A, I1027T, P67L, R668C, and S1235R. Login to comment 170 ABCC7 p.Gly542* Mutations G542X and 406-1GϾA accounted for 3.8% and 2.5% respectively, and 3849 ϩ 10kbCϾT was present at 1.6%. Login to comment 171 ABCC7 p.Arg334Trp ABCC7 p.Ser549Asn ABCC7 p.Arg75* ABCC7 p.Trp1204* Mutations R75X, 935delA, S549N, W1204X, and R334W were present at a relative frequency of 1.3%, and 12 additional mutations were each represented at a frequency of 1% of detected mutations (Table 3). Login to comment 173 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Of the 22 mutations present at a relative frequency of 1% or more, only eight are currently included in the standard 25 mutation panel recommended (I148T, R334W, ⌬F508, G542X, R553X, 1717-1GϾA, 3120 ϩ 1GϾA, and 3849 ϩ 10kbCϾT), although a recent ACMG revision will remove variant I148T.13 The California Department of Health Services is also tracking Hispanic mutations.15 However, these may duplicate some of those described in the other reports and therefore are not included in this analysis. Login to comment 176 ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser549Arg In comprehensive non-U.S. studies from Brazil, Colombia, and Spain, 420 mutations were identified (231, 117, and 72, respectively).33-35 Only seven occurred with a relative frequency Ͼ1%: ⌬F508 (67.4%), G542X (9%), N1303K (2.4%), R1162X (2.4%), R334W (2.1%), W1282X (1.2%), and S549R (1%). Login to comment 177 ABCC7 p.Ser549Arg Interestingly, all but one of these (S549R) are part of the 25 mutation screening panel, which may reflect a greater Caucasian admixture. Login to comment 186 ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Arg1162* ABCC7 p.Glu831* ABCC7 p.Glu585* ABCC7 p.Arg1158* ABCC7 p.Tyr1092* ABCC7 p.Ser945Leu ABCC7 p.Asp1152His ABCC7 p.Trp1098Cys ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His ABCC7 p.Leu967Ser ABCC7 p.Phe693Leu ABCC7 p.Asp836Tyr ABCC7 p.Ser573Cys ABCC7 p.Gln1313* ABCC7 p.Tyr913* ABCC7 p.Arg1438Trp ABCC7 p.Pro1372Leu ABCC7 p.Thr604Ser Table 3. Continued CFTR mutations Alleles Relative mutation frequency (%) (of 317) G567A 1 Ͻ1 S573C 1 Ͻ1 E585X 1 Ͻ1 T604S 1 Ͻ1 F693L 1 Ͻ1 V754 mol/L 1 Ͻ1 2108delA 1 Ͻ1 2184delA 1 Ͻ1 2215insG 1 Ͻ1 2585delT 1 Ͻ1 2752 - 6TϾC 1 Ͻ1 E831X 1 Ͻ1 D836Y 1 Ͻ1 Y913X 1 Ͻ1 S945L 1 Ͻ1 L967S 1 Ͻ1 3171delC 1 Ͻ1 3199del6 1 Ͻ1 3271 ϩ 8AϾG 1 Ͻ1 R1066H 1 Ͻ1 R1070W 1 Ͻ1 Y1092X 1 Ͻ1 W1098C 1 Ͻ1 3500 - 2AϾT 1 Ͻ1 4016insT 1 Ͻ1 4374 ϩ 13AϾG 1 Ͻ1 D1152H 1 Ͻ1 R1158X 1 Ͻ1 R1162X 1 Ͻ1 W1282X 1 Ͻ1 N1303K 1 Ͻ1 Q1313X 1 Ͻ1 P1372L 1 Ͻ1 R1438W 1 Ͻ1 Total 317 100 Table 3. Login to comment 187 ABCC7 p.Gly551Asp ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Arg334Trp ABCC7 p.Gly542* ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Pro205Ser ABCC7 p.Ile148Thr ABCC7 p.Leu206Trp ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Ser1235Arg ABCC7 p.Arg1066Cys ABCC7 p.His199Tyr ABCC7 p.Arg668Cys ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Tyr563Asn ABCC7 p.Gln890* ABCC7 p.Val232Asp ABCC7 p.Trp1089* ABCC7 p.Arg75* ABCC7 p.Trp1204* ABCC7 p.Asp1445Asn ABCC7 p.Ser492Phe ABCC7 p.Glu116Lys ABCC7 p.Val11Ile ABCC7 p.Ala559Thr ABCC7 p.Gln179Lys ABCC7 p.Gln98Arg ABCC7 p.Phe311Leu ABCC7 p.Ala1009Thr ABCC7 p.Arg352Trp ABCC7 p.Ile285Phe ABCC7 p.Leu320Val ABCC7 p.Pro439Ser ABCC7 p.Thr351Ser ABCC7 p.Glu588Val ABCC7 p.Thr501Ala CFTR Sequence Variants Identified in Five Comprehensive CFTR Studies in US Hispanics CFTR mutations Alleles Relative mutation frequency (%) (of 317) deltaF508 123 38.80 3876delA 15 4.70 G542X 12 3.80 406 - 1GϾA 8 2.50 3849 ϩ 10kbCϾT 5 1.60 R75X 4 1.30 935delA 4 1.30 S549N 4 1.30 W1204X 4 1.30 R334W 4 1.30 2055del9ϾA 3 1 R74W 3 1 H199Y 3 1 L206W 3 1 663delT 3 1 3120 ϩ 1GϾA 3 1 L997F 3 1 I1027T 3 1 R1066C 3 1 W1089X 3 1 D1270N 3 1 2105del13insAGAAA 3 1 Q98R 2 Ͻ1 E116K 2 Ͻ1 I148T 2 Ͻ1 R668C 2 Ͻ1 P205S 2 Ͻ1 V232D 2 Ͻ1 S492F 2 Ͻ1 T501A 2 Ͻ1 1949del84 2 Ͻ1 Q890X 2 Ͻ1 3271delGG 2 Ͻ1 3272 - 26AϾG 2 Ͻ1 G1244E 2 Ͻ1 D1445N 2 Ͻ1 R553X 2 Ͻ1 E588V 2 Ͻ1 1717 - 8GϾA 2 Ͻ1 A1009T 2 Ͻ1 S1235R 2 Ͻ1 G85E 1 Ͻ1 296 ϩ 28AϾG 1 Ͻ1 406 - 6TϾC 1 Ͻ1 V11I 1 Ͻ1 Q179K 1 Ͻ1 V201 mol/L 1 Ͻ1 874insTACA 1 Ͻ1 I285F 1 Ͻ1 deltaF311 1 Ͻ1 F311L 1 Ͻ1 L320V 1 Ͻ1 T351S 1 Ͻ1 R352W 1 Ͻ1 1248 ϩ 1GϾA 1 Ͻ1 1249 - 29delAT 1 Ͻ1 1288insTA 1 Ͻ1 1341 ϩ 80GϾA 1 Ͻ1 1429del7 1 Ͻ1 1525 - 42GϾA 1 Ͻ1 P439S 1 Ͻ1 1717 - 1GϾA 1 Ͻ1 1811 ϩ 1GϾA 1 Ͻ1 deltaI507 1 Ͻ1 G551D 1 Ͻ1 A559T 1 Ͻ1 Y563N 1 Ͻ1 (Table continues) In this study, we used temporal temperature gradient gel electrophoresis (TTGE) and direct DNA sequencing to increase the sensitivity of mutation detection in U.S. Hispanics, and to determine whether additional mutations are recurrent. Login to comment 199 ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Ser549Asn ABCC7 p.Arg75* ABCC7 p.Trp1204* The pooled data set demonstrates that the most frequently seen mutations are: ⌬F508, G542X, 406-1GϾA, W1204X, R75X, 2055del9ϾA, 3876delA, ⌬I507, S549N, I148T, N1303K, 935delA, and 3849 ϩ 10kbCϾT. Login to comment 201 ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Ile148Thr ABCC7 p.Leu206Trp ABCC7 p.Ser549Asn ABCC7 p.Ser1235Arg ABCC7 p.His199Tyr ABCC7 p.Arg668Cys ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Gln890* ABCC7 p.Val232Asp ABCC7 p.Trp1089* ABCC7 p.Arg75* ABCC7 p.Trp1204* ABCC7 p.Ile506Thr ABCC7 p.Asp1445Asn ABCC7 p.Ser492Phe ABCC7 p.Glu116Lys ABCC7 p.Ala1009Thr ABCC7 p.Glu588Val ABCC7 p.Thr501Ala Comparison of Relative Frequencies of CFTR Sequence Variants in Comprehensive CFTR Studies in US and Mexican Hispanics This study % Orozco 2000 % US/ Mexican % deltaF508 28.96 54.48 43.72 G542X 3.83 8.28 5.19 406 - 1GϾA 3.28 2.07 2.38 W1204X 2.19 Ͻ1 1.08 R74W 1.64 Ͻ1 R75X 1.64 2.07 1.51 H199Y 1.64 Ͻ1 Ͻ1 L206W 1.64 Ͻ1 L997F 1.64 Ͻ1 I1027T 1.64 Ͻ1 2055del9ϾA 1.64 1.38 1.27 D1270N 1.64 Ͻ1 E116K 1.09 Ͻ1 V232D 1.09 Ͻ1 R334W 1.09 Ͻ1 S492F 1.09 Ͻ1 T501A 1.09 Ͻ1 R553X 1.09 Ͻ1 Ͻ1 E588V 1.09 Ͻ1 R668C 1.09 Ͻ1 Q890X 1.09 Ͻ1 W1089X 1.09 Ͻ1 S1235R 1.09 Ͻ1 D1445N 1.09 Ͻ1 3876delA 1.09 3.24 1717 - 8GϾA 1.09 Ͻ1 3272 - 26AϾG 1.09 Ͻ1 A1009T 1.09 Ͻ1 deltaI507 Ͻ1 3.45 1.30 S549N Ͻ1 3.45 1.95 G567A Ͻ1 Ͻ1 I148T 2.07 1.08 I506T 1.38 Ͻ1 N1303K 2.76 1.08 935delA 1.38 1.30 2183AAϾG 1.38 Ͻ1 3199del6 1.38 Ͻ1 3849 ϩ 10kbCϾT Ͻ1 1.30 ACMG/ACOG italicized. Login to comment 202 ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr which occur with a relative frequency above 1% in the pooled data set, only six (⌬F508, G542X, ⌬I507, I148T, N1303K, and 3849 ϩ 10kbCϾT) were included in the ACMG/ACOG 25-mutation screening panel12 and in the recent revision exclusion of I148T has been recommended.13 The most frequently seen mutations in the U.S. and Mexican studies combined (n ϭ 462 identified mutations) include the 10 most frequent mutations observed in the Mexican study.36 They also include all but one mutation (R334W) occurring with a relative frequency above 1% in the five combined studies performed in the U.S. In that group, only ⌬I507, N1303K and I148T were present at a relative frequency below 1%. Login to comment 204 ABCC7 p.Ser549Asn ABCC7 p.Arg75* ABCC7 p.Trp1204* Some of the disparity in mutation detection between Caucasians and Hispanics could be alleviated by adding at least seven additional mutations to the currently recommended ACOG/ACMG panel of 25 mutations: 406-1GϾA, W1204X, R75X, 2055del9ϾA, 3876delA, S549N, and 935delA (Table 4). Login to comment 214 ABCC7 p.Tyr913* Four of the novel mutations (1429del7bp,Y913X, 874insTACA, and 2585delT) result in premature termination codons. Login to comment 221 ABCC7 p.Ser549Asn ABCC7 p.Arg75* ABCC7 p.Trp1204* For carrier screening of Hispanic patients, inclusion of additional mutations with significant frequency in the Hispanic CF population (especially 406-1GϾA, W1204X, R75X, 2055del9ϾA, 3876delA, S549N, and 935delA) may be helpful to supplement the ACMG/ACOG panel. Login to comment