ABCMdb

PMID: 23810505

Prach L, Koepke R, Kharrazi M, Keiles S, Salinas DB, Reyes MC, Pian M, Opsimos H, Otsuka KN, Hardy KA, Milla CE, Zirbes JM, Chipps B, O'Bra S, Saeed MM, Sudhakar R, Lehto S, Nielson D, Shay GF, Seastrand M, Jhawar S, Nickerson B, Landon C, Thompson A, Nussbaum E, Chin T, Wojtczak H
Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California.
J Mol Diagn. 2013 Sep;15(5):710-22. doi: 10.1016/j.jmoldx.2013.05.006. Epub 2013 Jun 28., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Phe1107Leu ABCC7 p.Leu32Met ABCC7 p.Leu323Pro Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Login to comment 26 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Pro205Ser ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg1066Cys ABCC7 p.His199Tyr ABCC7 p.Trp1089* ABCC7 p.Arg75* ABCC7 p.Trp1204* ABCC7 p.Trp1204* ABCC7 p.Ser492Phe ABCC7 p.Gly330* ABCC7 p.Ala559Thr ABCC7 p.Gln98Arg Newborns were screened using the California method, which includes i) analysis of serum immunoreactive trypsinogen (IRT) levels using the AutoDELFIA neonatal IRT L kit (PerkinElmer, Waltham, MA) in all newborn blood spot specimens, ii) CFTR mutation panel [29-40 mutations (the mutations on the California panel were selected for the most part according to allelic frequencies found in a comprehensively genotyped group of California CF cases to achieve a 95% race/ethnicity-specific rate of CF case detection in black, white, and Hispanic individuals in California and include c.1585-1G>A, c.1680-1G>A, c.1973-1985del13insAGAAA, c.2175_2176insA, c.164 &#fe; 2T>A (removed on August 12, 2008), c.2988 &#fe; 1G>A, c.3717 &#fe; 12191C>T, c.3744delA, c.274-1G>A, c.489 &#fe; 1G>T, c.579 &#fe; 1G>T, p.A559T, p.F311del, p.F508del, p.I507del, p.G542X, p.G551D, p.G85E, p.H199Y, p.N1303K, p.R1066C, p.R1162X, p.R334W, p.R553X, p.S549N, p.W1089X, p.W1204X (c.3611G>A), p.W1282X, c.1153_1154insAT [added October 4, 2007], c.1923_1931del9insA, c.3140-26A>G, c.531delT, c.803delA, c.54-5940_273 &#fe; 10250del21kb, p.P205S, p.Q98R, p.R75X, p.S492F [added December 12, 2007], c.3659delC, p.G330X, p.W1204X [c.3612G>A] [added August 12, 2008] [Signature CF 2.0 ASR; Asuragen Inc., Austin, TX])] testing of specimens with IRT 62 ng/mL (highest 1.5%), iii) CFTR gene scanning and sequence analysis (Ambry Test: CF; Ambry Genetics, Aliso Viejo, CA) for specimens found to have only one mutation after CFTR mutation panel testing, and iv) referral to 1 of 15 pediatric CF care centers (CFCs) for sweat chloride (SC) testing and follow-up of all newborns with either two CFTR mutations detected during panel testing or one CFTR mutation detected during panel testing and one (or more) additional CFTR mutation and/or variant detected during sequencing. Login to comment 56 ABCC7 p.Tyr325Cys ABCC7 p.Phe1107Leu ABCC7 p.Leu32Met ABCC7 p.Leu323Pro ABCC7 p.His1375Asn ABCC7 p.Thr1396Pro ABCC7 p.Arg1128Gly ABCC7 p.Met1140Leu ABCC7 p.Cys76Arg ABCC7 p.Thr629Ala ABCC7 p.Phe315Ser ABCC7 p.Ser13Cys ABCC7 p.Val1198Met ABCC7 p.Asp249Tyr ABCC7 p.Thr1478Arg ABCC7 p.Val1022Met ABCC7 p.Arg811Ser ABCC7 p.Val1322Leu ABCC7 p.Gly1173Ser ABCC7 p.Asp112Gly ABCC7 p.Met837Thr ABCC7 p.Leu136Pro ABCC7 p.Pro718Arg ABCC7 p.Thr887Pro Multiplex ligation-dependent probe amplification12 (MRC-Holland, Amsterdam, The Netherlands) was used to determine gross deletions or duplications when CF was suspected but no or one CFTR mutations were detected by Table 1 Description of Novel CFTR Variants Identified in California, July 16, 2007, to July 15, 2010 CFTR region Nucleotide change Predicted amino acid change Type of mutation Promoter c.-983A>T Promoter c.-967T>C Promoter c.-837T>C Promoter c.-769A>G Promoter c.-730A>G Promoter c.-684G>A Promoter c.-635A>G Promoter c.-602A>T Promoter c.-510G>A Promoter c.-448A>G Promoter c.-288G>C Promoter c.-152G>C Exon 1 c.38C>G p.S13C Missense Exon 2 c.94C>A p.L32M Missense Intron 2 c.164 &#fe; 4T>A Exon 3 c.226T>C p.C76R Missense Exon 4 c.335A>G p.D112G Missense Exon 4 c.407T>C p.L136P Missense Exon 4 c.472_474delAAG p.K114del In-frame deletion Intron 6 c.744-15T>C Exon 7 c.745G>T p.D249Y Missense Intron 7 c.869 &#fe; 8G>T Exon 8 c.944T>C p.F315S Missense Exon 8 c.968T>C p.L323P Missense Exon 8 c.974A>G p.Y325C Missense Exon 8 c.1064C>T p.P355Ly Missense Exon 10 c.1278delC p.D426Efs*16 (stop codon at 441) Frameshift Exon 11 c.1479G>C p.Q493Hy Missense Exon 14 c.1885A>G p.T629A Missense Exon 14 c.2153C>G p.P718R Missense Exon 14 c.2433G>T p.R811S Missense Exon 14 c.2349_2350insT p.H784Sfs*21 (stop codon at 804) Frameshift Intron 13 c.1767-13T>G Intron 14 c.2490 &#fe; 14G>A Intron 14 c.2490 &#fe; 14G>T Exon 15 c.2554_2555insT p.Y852Lfs*44 (stop codon at 895) Frameshift Exon 15 c.2510T>C p.M837T Missense Exon 17 c.2659A>C p.T887P Missense Exon 17 c.2883_2886dupGTCA p.T963Vfs*13 (stop codon at 975) Frameshift Exon 17 c.2822delT p.L941Qfs*27 (stop codon at 967) Frameshift Exon 19 c.3064G>A p.V1022M Missense Exon 20 c.3319T>C p.F1107L Missense Intron 20 c.3367 &#fe; 3A>Cy Exon 21 c.3382A>G p.R1128G Missense Exon 21 c.3418A>T p.M1140L Missense Exon 22 c.3517G>A p.G1173S Missense Exon 22 c.3592G>A p.V1198M Missense Intron 22 c.3718-24G>A Intron 23 c.3963 &#fe; 6G>T Exon 25 c.3964G>C p.V1322L Missense Exon 25 c.4123C>A p.H1375N Missense Intron 25 c.4136 &#fe; 12A>G Exon 26 c.4186A>C p.T1396P Missense Intron 26 c.4243-5C>T Exon 27 c.4433C>G p.T1478R Missense y A known mutation occurs at the same nucleotide position or codon. Login to comment 59 ABCC7 p.Arg553* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Pro205Ser ABCC7 p.Pro205Ser ABCC7 p.Arg75* ABCC7 p.Ile556Val ABCC7 p.Tyr325Cys ABCC7 p.Phe1107Leu ABCC7 p.Leu32Met ABCC7 p.Arg1128Gly ABCC7 p.Met1140Leu ABCC7 p.Phe315Ser ABCC7 p.Val1198Met ABCC7 p.Asp249Tyr ABCC7 p.Thr1478Arg ABCC7 p.Arg811Ser ABCC7 p.Val1322Leu ABCC7 p.Leu136Pro ABCC7 p.Thr887Pro of parents receiving CFTR mutation testing Diagnosis/ status Study participants with positive NBS results 1 W, H 83.5 p.F508del* c.2554_2555insTy 7T/9T 2 CF 2 H 527.0 p.F508del c.-877C>T p.F1107L 7T/9T 0 CF 3 W 86.5 p.F508del p.V562Iy c.-837T>Cy 5Tyz /9T 1 CF 4 H 222.3 p.F508del p.I556V c.1278delC NA 0 CF 5 H, O 93.5 p.F508del* c.-152G>Cy 7T/9T 2 CF 6 W, H, B, O 95.4 p.F508del* p.L323Py 5Tyz /9T 2 CF 7 H 70.5 p.F508del p.L32M 7T/9T 0 CF 8 W 209.5 p.F508del c.2883_2886dupGTCA 9T/9T 0 CF 9 H 155.7 p.F508del* c.2349_2350insT 7T/9T 1 CF 10 O 146.8 p.F508del* c.3718-24G>Ay 5Tyx /9T 2 CF 11 B 99.4 p.A559T* p.L206Wy c.-448A>G* 7T/9T 2 CF 12 W, H 90.3 p.P205S p.K114del 7T/7T 0 CF 13 H 69.7 p.P205S p.K114del 7T/7T 0 CF 14 H 82.9 c.274-1G>A* c.-602A>Ty 7T/7T 2 CF 15 W 106.6 p.F508del* c.-461A>Gy c.-983A>T* 7T/9T 2 CRMS 16 W, B 83.9 p.F508del c.4243-5C>T 5T*x /9T 1 CRMS 17 W 81.5 p.F508del* p.I1027T* p.Y325C 7T/9T 2 CRMS 18 H 70.7 p.F508del c.-967T>C 9T/9T 0 CRMS 19 W, H 62.4 p.F508del* c.-635A>G 7T/9T 1 CRMS 20 H 65.4 p.F508dely c.2490 &#fe; 14G>T* 7T/9T 2 CRMS 21 W 69.3 p.F508del* c.744-15T>Cy 7T/9T 2 CRMS 22 W, H, O 66.2 p.F508del p.D249Y 7T/9T 0 CRMS 23 H 94.8 p.F508del p.R811S 7T/9T 0 CRMS 24 W 75.8 p.F508del* p.H1375Ny 7T/9T 2 CRMS 25 H 63.0 p.F508del p.L136P 7T/9T 0 CRMS 26 W, O 63.0 p.F508del* p.M1140L 7T/9T 1 CRMS 27 W, O 91.7 p.F508del p.V1198M 9T/9T 0 CRMS 28 H 69.3 p.F508dely c.1767-13T>G* 7T/9T 2 CRMS 29 H 108.8 p.F508del p.V1322L 7T/9T 0 CRMS 30 H 96.4 p.F508dely p.C76R* 7T/9T 2 CRMS 31 H 69.0 c.3140-26A>G c.-510G>A* 7T/7T 1 CRMS 32 H 100.2 p.G542X c.-684G>A* 7T/9T 1 CRMS 33 H 84.1 c.1153_1154insAT* c.-730A>Gy 7T/7T 2 CRMS 34 H 62.9 c.1973_ 1985del13insAGAAA* p.D112Gy 7T/7T 2 CRMS 35 H 116.7 c.3744delA* p.T887P 7T/7T 1 CRMS 36 B 73.3 c.2988 &#fe; 1G>A c.-288G>C 7T/9T 0 CRMS 37 H 93.5 p.R75X c.3367 &#fe; 3A>C 7T/7T 0 CRMS 38 W, H 81.4 c.3717 &#fe; 12191C>T* c.-769A>Gy 7T/7T 2 CRMS 39 W 79.0 c.3717 &#fe; 12191C>Ty p.R668Cy p.T1396P* 7T/9T 2 CRMS 40 H 87.3 c.274-1G>A p.F315S 7T/7T 0 CRMS 41 H 79.7 p.G542X c.869 &#fe; 8G>T 7T/9T 0 CRMS 42 O 79.8 p.R553X p.T1478R 7T/7T 0 CRMS 43 H 70.5 p.A559T* c.-448A>G* 7T/7T 2 Carrier 44 B 76.2 p.A559T* c.-448A>G* 7T/7T 1 Carrier 45 W, H 69.2 p.G85E* c.744-15T>C* 5Tyz /7T 2 Carrier 46 W 69.1 p.N1303K* c.2490 &#fe; 14G>A* 7T/9T 1 Carrier 47 W, O 111.7 p.F508del c.3963 &#fe; 6G>T 7T/9T 0 ND{ 48 W 80.1 p.F508del p.R1128G 7T/9T 0 ND{ (table continues) sequencing. Login to comment 74 ABCC7 p.Ser1235Arg ABCC7 p.Pro355Leu ABCC7 p.Thr629Ala ABCC7 p.Ser13Cys ABCC7 p.Val1022Met ABCC7 p.Pro718Arg ABCC7 p.Gln493His of parents receiving CFTR mutation testing Diagnosis/ status 49 W 80.6 p.F508del p.S13C 7T/9T 0 ND{ 50 H 90.3 c.274-1G>A p.T629A 7T/9T 0 ND{ 51 W, B 100.6 p.F508del p.P355L (c.1064C>T) 7T/9T 0 ND{ 52 H 79.1 p.F508del p.Q493H (c.1479G>C) 7T/9T 0 ND{ 53 W, B 64.8 p.F508del p.V1022M 7T/9T 0 ND{ 54 W 74.7 p.F508del c.-887C>T c.4243-5C>T 7T/9T 0 NDk 55 O 136.6 p.F508del p.P718R 7T/9T 0 ND{ Study participants with negative NBS results 56 H 276.7 c.2822delT c.2822delT 7T/7T 0 CF 57 H 179.2 c.2822delT c.2822delT 7T/7T 0 CF 58 W 15.6 p.S1235R c.-288G>C 7T/9T 0 CF 59 H 35.1 c.164 &#fe; 4T>A* p.G1173S* Not done 1 Carrier 60 O 20.2 c.4136 &#fe; 12A>G* p.M837Ty Not done 2 NDk *Confirmed by parental CFTR mutation testing to be on chromosome 1. y Confirmed by parental CFTR mutation testing to be on chromosome 2. z 5T variant associated with (TG)11. x 5T variant associated with (TG)12. Login to comment 116 ABCC7 p.Phe1107Leu ABCC7 p.Phe1107Leu p.F1107L Although participant 2 did not receiveparental DNA testing to confirm the phase of novel variant p.F1107L, the abnormal SC level (107 mmol/L) and symptoms of pancreatic insufficiency (including fecal elastase level <50 mg/g) indicate that, in addition to p.F508del, another mutation must be associated with CF. Login to comment 118 ABCC7 p.Phe1107Leu Because c.-877C>T is thought to be a none disease-causing polymorphism,15 p.F1107L is indicated as a possible CF-associated variant. Login to comment 119 ABCC7 p.Phe1107Leu ABCC7 p.Phe1107Leu p.F1107L was previously identified by Ambry Genetics in a set of twins who presented with rectal prolapse, elevated SC concentration, and a second deleterious mutation in trans with p.F1107L (S. Keiles, personal communication). Login to comment 126 ABCC7 p.Leu323Pro ABCC7 p.Leu323Pro p.L323P Novel variant p.L323P was identified in participant 6 with a borderline SC level (47 mmol/L) and positive respiratory cultures for Pseudomonas aeruginosa. Login to comment 127 ABCC7 p.Leu323Pro ABCC7 p.Leu323Pro Parental DNA testing confirmed that p.L323P and the (TG)11-5T variant were in trans with p.F508del; therefore, the individual effect of p.L323P on the phenotype is unclear. Login to comment 128 ABCC7 p.Leu323Pro ABCC7 p.Leu323Pro However, of 31 newborns with genotype p.F508del in trans with variant (TG) 11-5T identified during the same period through the California CF NBS program, none had an SC level >26 mmol/ L.16 Therefore, p.L323P alone or p.L323P in conjunctionwith (TG)11-5T is likely associated with the CF manifestations. Login to comment 129 ABCC7 p.Leu32Met ABCC7 p.Leu32Met p.L32M Participant 7 has a novel variant p.L32M and p.F508del; no other mutations or variants were identified, although gross duplications or deletions could not be ruled out because multiplex ligation-dependent probe amplification analysis was not conducted. Login to comment 139 ABCC7 p.Pro205Ser p.K114del Two nontwin siblings with genotype p.P205S/p.K114del were identified [participants 12 and 13 (younger)]. Login to comment 165 ABCC7 p.Val562Ile Participant 3 was identified with novel variant c.-837T>C (found to be in cis with p.V562I after parent testing) and p.F508del on the opposite chromosome. Login to comment 166 ABCC7 p.Ile556Val Participant 4 carried p.F508del, p.I556V, and novel variant c.1278delC. Login to comment 168 ABCC7 p.Ile556Val It is surmised, however, that the frameshift mutation c.1278delC would be more deleterious than the missense mutation p.I556V. Login to comment 170 ABCC7 p.Leu206Trp ABCC7 p.Ala559Thr Participant 11 was identified with novel variant c.-448A>G in cis with p.A559T and in trans with p.L206W. Login to comment 180 ABCC7 p.Ala559Thr Participants 11, 43, and 44 were all shown to carry novel variant c.-448A>G in cis with known mutation p.A559T. Login to comment 182 ABCC7 p.Leu206Trp Participant 11, who was diagnosed as having CF, also carries known mutation p.L206W (case described earlier). Login to comment 184 ABCC7 p.Asn1303Lys ABCC7 p.Gly85Glu ABCC7 p.Gly1173Ser Parental testing for participants 45, 46, and 59, all diagnosed as CFTR carriers, showed the following mutation pairs to be in cis: p.G85E with c.744-15T>C (novel), p.N1303K with c.2490 &#fe; 14G>A (novel), and c.164 &#fe; 4T>A (novel) with p.G1173S (novel), respectively. Login to comment 185 ABCC7 p.Gly1173Ser ESP reported the p.G1173S variant with a frequency of 1 in 10,757 (0.01%), and the c.- 461A>G variant had a frequency of 2 in 2188 (0.09%) according to 1000 Genomes.5 Novel Variants Probably Not Causative of CF Manifestations to Date Twenty-six participants carrying 26 of the 55 novel variants (47%) have not shown consistent manifestations of CF over time. Login to comment 186 ABCC7 p.Tyr325Cys ABCC7 p.His1375Asn ABCC7 p.Thr1396Pro ABCC7 p.Met1140Leu ABCC7 p.Cys76Arg ABCC7 p.Phe315Ser ABCC7 p.Val1198Met ABCC7 p.Asp249Tyr ABCC7 p.Thr1478Arg ABCC7 p.Arg811Ser ABCC7 p.Val1322Leu ABCC7 p.Asp112Gly ABCC7 p.Leu136Pro ABCC7 p.Thr887Pro Participants 16 to 35 and 37 to 42, with the following novel variants, have been classified as having CRMS to date: c.-967T>C, c.-769A>G, c.-730A>G, c.-684G>A, c.-635A>G, c.-510G>A, p.C76R, p.D112G, p.L136P, c.744-15T>C, p.D249Y, c.869 &#fe; 8G>T, p.F315S, p.Y325C, p.R811S, c.1767-13T>G, c.2490 &#fe; 14G>T, p.T887P, c.3367 &#fe; 3A>C, p.M1140L, p.V1198M, p.V1322L, p.H1375N, p.T1396P, c.4243-5C>T, and p.T1478R. Login to comment 187 ABCC7 p.Phe315Ser For these variants, p.F315S was detected in 1613 control subjects one time. Login to comment 188 ABCC7 p.His1375Asn ABCC7 p.Thr1396Pro ESP reported p.T1396P with a frequency of 1 in 10,758 (0.01%), c.744-15T>C with a frequency of 1 in 10,681 (0.01%), and p.H1375N with a frequency of 2 in 10,758 (0.02%). Login to comment 191 ABCC7 p.Pro355Leu ABCC7 p.Arg1128Gly ABCC7 p.Thr629Ala ABCC7 p.Ser13Cys ABCC7 p.Val1022Met ABCC7 p.Pro718Arg ABCC7 p.Gln493His 47 to 55 and 60) with the following novel variants owing to inadequate follow-up: p.S13C, p.P355L, p.Q493H, p.T629A, p.P718R, p.V1022M, p.R1128G, and c.3963 &#fe; 6G>T. Login to comment 193 ABCC7 p.Val1022Met ABCC7 p.Met837Thr The novel variants that these two participants carried were c.4136 &#fe; 12A>G with p.M837T (participant 60), and c.4243-5C>T(participant54).IndbSNP,6 thep.P718Rvariant was reported with a frequency of 2 in 4492 (0.04%), and the p.V1022M variant was reported with a frequency of 1in 4550 (0.02%). Login to comment