ABCMdb

ABCC7 p.Val920Met

ClinVar:	c.2758G>A , p.Val920Met ? , not provided c.2758G>T , p.Val920Leu ? , not provided
CF databases:	c.2758G>A , p.Val920Met (CFTR1) D , This sequence variation has been found in one among50 non-[delta]F508 CF chromosomes. The mutation destroys an Maell site. The patient has the [delta]F508 defect on the other chromosomes and was diagnosed by meconium ileus. c.2758G>T , p.Val920Leu (CFTR1) D , This substitution, located in a transmembrane domain and which seems conservative, was found in a CBAVD patient heterozygous for ^ÃF508, but chromosomal assignment was not possible. Eight coding regions remain to be analysed. V920L creates a MaeII restriction site.
Predicted by SNAP2:	A: N (93%), C: N (87%), D: D (59%), E: N (53%), F: D (59%), G: N (87%), H: D (71%), I: D (53%), K: D (59%), L: N (78%), M: D (66%), N: N (61%), P: D (53%), Q: N (57%), R: D (59%), S: N (87%), T: N (87%), W: D (66%), Y: D (75%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: N, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, W: D, Y: N,

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[hide] Variant cystic fibrosis phenotypes in the absence ... N Engl J Med. 2002 Aug 8;347(6):401-7. Groman JD, Meyer ME, Wilmott RW, Zeitlin PL, Cutting GR
Variant cystic fibrosis phenotypes in the absence of CFTR mutations.
N Engl J Med. 2002 Aug 8;347(6):401-7., 2002-08-08 [PMID:12167682]

Abstract [show]
BACKGROUND: Cystic fibrosis is a life-limiting autosomal recessive disorder with a highly variable clinical presentation. The classic form involves characteristic findings in the respiratory tract, gastrointestinal tract, male reproductive tract, and sweat glands and is caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene. Nonclassic forms of cystic fibrosis have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. We assessed whether alteration in CFTR function is responsible for the entire spectrum of variant cystic fibrosis phenotypes. METHODS: Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic cystic fibrosis who had been referred by 34 medical centers. We evaluated two families that each included a proband without identified mutations and a sibling with nonclassic cystic fibrosis to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium. RESULTS: Of the 74 patients studied, 29 had two mutations in the CFTR gene, 15 had one mutation, and 30 had no mutations. A final genotype of two mutations was more common among patients who had been referred after screening for common cystic fibrosis-causing mutations identified one mutation than among those who had been referred after screening had identified no such mutations (26 of 34 patients vs. 3 of 40 patients, P<0.001). Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with two, one, or no CFTR mutations. Haplotype analysis in the two families revealed no linkage to CFTR. Although each of the affected siblings had elevated sweat chloride concentrations, measurements of cyclic AMP-mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR. CONCLUSIONS: Factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic cystic fibrosis caused by CFTR dysfunction.

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71 MUTATION IDENTIFIED BY SCREENING FOR COMMON MUTATIONS MUTATION IDENTIFIED BY DNA SEQUENCING NO. OF PATIENTS ∆F508 5T* 3 ∆F508 D1152H 2 ∆F508 2789+2insA 2 ∆F508 R117C 2 ∆F508 D110H 1 ∆F508 2789+5G→A 1 ∆F508 P205S 1 ∆F508 L967S 1 ∆F508 I1027T 1 ∆F508 L206W 1 ∆F508 T1053I and 5T 1 ∆F508 V920M and 5T 1 ∆F508 R1070W 1 ∆F508 D579G 1 ∆F508 P67L 1 ∆F508 2811G→T†‡ 1 G85E F191V† 1 R117H G103X and 5T 1 I148T I556V 1 G542X R1162L 1 W1282X D1152H 1 None L138ins and 3272-26 A→G 1 None G463D† and 5T 1 None F693L and 5T 1 ∆F508 None 6 G551D None 1 W1282X None 1 None 5T 4 None 2307insA 1 None L997F 1 None V520I 1 None None 30 in Subject II-2 in Family 1. Login to comment

[hide] CFTR, PRSS1 and SPINK1 mutations in the developmen... JOP. 2003 Sep;4(5):169-77. Bernardino AL, Guarita DR, Mott CB, Pedroso MR, Machado MC, Laudanna AA, Tani CM, Almeida FL, Zatz M
CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients.
JOP. 2003 Sep;4(5):169-77., [PMID:14526128]

Abstract [show]
CONTEXT: Mutations in cystic fibrosis transmembrane conductance regulator (CFTR), in cationic trypsinogen (PRSS1) and in serine protease inhibitor Kazal type 1 (SPINK1) genes have been associated with chronic pancreatitis (alcohol related, idiopathic and hereditary). However, the inheritance pattern is still not clear. PATIENTS: Eighty-two unrelated Brazilian patients with chronic pancreatitis (alcohol-related disease in 64, idiopathic disease in 16, and hereditary disease in 2). Two hundred unrelated individuals with an ethnic distribution comparable to the patients were studied as controls. MAIN OUTCOME MEASURE: Detection of mutations in CFTR, PRSS1, and SPINK1 genes. RESULTS: Mutations in the CFTR gene were found in 8 patients (9.8%) with chronic pancreatitis, 5 of them with idiopathic disease. Interestingly, the only clinical symptom in a male patient in the alcoholic group, who was a compound heterozygote (DeltaF508/R170C) for two CFTR mutations, was pancreatitis without infertility or pulmonary involvement. In the PRSS1 gene, the E79K change in exon 3 was found in one patient (1.2%) with alcohol-related chronic pancreatitis. Four different alterations were identified in the SPINK1 gene. CONCLUSIONS: Mutations in the CFTR gene represent the major cause of idiopathic chronic pancreatitis in Brazilian patients. No mutation was found in the PRSS1 gene among our patients suggesting further genetic heterogeneity for hereditary and idiopathic chronic pancreatitis. Interestingly, the most frequent SPINK1 N34S mutation was not present in patients or controls. Moreover, the -253C allele for the SPINK1 gene was significantly more frequent in patients than controls (P=0.004), suggesting that it might represent a risk factor for the development of pancreatitis in our population.

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68 A total of 13 changes were found: 7 in the CFTR gene (∆F508/R851L, ∆F508/R170C, ∆F508/L206W, 2 N/∆F508, N/P205S, N/R31C and N/V920M), 2 in the PRSS1 gene (E79K and N246N) and 4 in the SPINK1 gene (-253T>C, -164G>C, -7T>G, c75C>T) (Table 1). Login to comment
69 The CFTR Gene Molecular analysis showed that 8 patients (9.8%) had mutations in the CFTR gene: 3 were compound heterozygotes (∆F508/R851L, ∆F508/R170C and ∆F508/L206W) and 5 had mutations on just one allele (2 N/∆F508, N/P205S, N/R31C and N/V920M). Login to comment
70 Among the 16 patients with idiopathic chronic pancreatitis, 5 (31.3%) had mutations in the CFTR gene (∆F508/R851L, ∆F508/L206W, N/∆F508, N/P205S and N/V920M). Login to comment
72 One (∆F508/R851L) referred only bronchitis in childhood and the last two (N/∆F508 and N/V920M) had no other additional signs. Three of the 64 patients (4.7%) with alcohol-related chronic pancreatitis but with no pulmonary problems also had CFTR mutations: N/∆F508, N/R31C and compound heterozygote ∆F508/R170C. None of these 3 patients reported azoospermia. Login to comment
78 Gene Localization Mutation Polymorphism Frequency in patients' chromosomes Frequency in controls' chromosomes P value Exon 2 R31C 1/164 (0.6%) - - Exon 5 R170C 1/164 (0.6%) - - P205S 1/164 (0.6%) - -Exon 6 L206W 1/164 (0.6%) - - Exon 10 ∆F508 5/164 (3.0%) - - Exon 14a R851L 1/164 (0.6%) - - CFTR Exon 15 V920M 1/164 (0.6%) - - Exon 3 E79K 1/164 (0.6%) 1/300 (0.3%) 1.000a PRSS1 Exon 5 N246N 47/164 (28.7%) 85/300 (28.3%) 1.000b -253T>C 20/164 (12.2%) 20/400 (5.0%) 0.004b Promoter -164G>C 4/164 (2.4%) 13/400 (3.3%) 0.788a Exon 1 -7T>G 5/164 (3.0%) 8/300 (2.7%) 0.777a SPINK1 Exon 2 c75C>T 1/164 (0.6%) 3/300 (1.0%) 1.000a a Fisher's exact test b Yates' corrected chi-squared test alcohol-related chronic pancreatitis, but with no family history. Login to comment
94 Molecular analysis showed that 9.8% of the total group of patients had mutations in the CFTR gene: 3 were compound heterozygotes (∆F508/R851L, ∆F508/R170C and ∆F508/L206W) and 5 had mutations on just one allele (2 N/∆F508, N/P205S, N/R31C and N/V920M). Login to comment
96 Among the 16 patients with idiopathic chronic pancreatitis, 5 had mutations in the CFTR gene (∆F508/R851L, ∆F508/L206W, N/∆F508, N/P205S and N/V920M). Login to comment
98 One (∆F508/R851L) referred only bronchitis in childhood and the last two (N/∆F508 and N/V920M) had no other additional signs. Three (4.7%) of the 64 patients with alcohol-related chronic pancreatitis but with no pulmonary problems also had CFTR mutations: N/∆F508, N/R31C and compound heterozygote ∆F508/R170C. None of these 3 patients reported azoospermia. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... Reprod Biomed Online. 2009 Nov;19(5):685-94. Gallati S, Hess S, Galie-Wunder D, Berger-Menz E, Bohlen D
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.
Reprod Biomed Online. 2009 Nov;19(5):685-94., [PMID:20021716]

Abstract [show]
The objective of this study was to investigate the contribution of cystic fibrosis transmembrane conductance regulator (CFTR) to human infertility and to define screening and counselling procedures for couples asking for assisted reproduction treatment. Extended CFTR mutation screening was performed in 310 infertile men (25 with congenital absence of the vas deferens (CAVD), 116 with non-CAVD azoospermia, 169 with severe oligospermia), 70 female partners and 96 healthy controls. CFTR mutations were detected in the majority (68%) of CAVD patients and in significant proportions in azoospermic (31%) and oligospermic (22%) men. Carrier frequency among partners of infertile men was 16/70, exceeding that of controls (6/96) significantly (P = 0.0005). Thus, in 23% of infertile couples both partners were carriers, increasing the risk for their offspring to inherit two mutations to 25% or 50%. This study emphasizes the necessity to offer extended CFTR mutation screening and counselling not only to patients with CAVD but also to azoospermic and oligozoospermic men and their partners before undergoing assisted reproduction techniques. The identification of rare and/or mild mutations will not be a reason to abstain from parenthood, but will allow adequate treatment in children at risk for atypical or mild cystic fibrosis as soon as they develop any symptoms.

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81 In 70 women whose partners had tested positive for either CFTR mutations or 5T alleles, extended screening of the CFTR gene was also performed revealing a mutation spectrum similar to that of oligospermic men including four 5T alleles, three S1235R, three F508del and one I148T, V754M, V920M, D1152H, 3905insT and Q1352H each (Table 1). Login to comment
117 Based on discriminant analysis, this study predicts a high probability for the presence of CFTR mutations especially in patients with reduced ejaculate volumes (<3 ml) and structural abnormalities such as CAVD, inguinal hernia, hypotrophic testes or cryptorchidism, confirming former findings reported by Casals et al. (2000) and representing symptoms that are also frequently observed in Table 3 (continued) Couple no. Infertile male CFTR mutation Female partner CFTR mutation Offspring genotype Risk for genotype (%) 14 R31C/wt oligospermia V920M/wt R31C/V920M 25 R31C/wt 25 V920M/wt 25 wt/wt 25 15 R31C/wt azoospermia I148T/wt R31C/I148T 25 R31C/wt 25 I148T/wt 25 wt/wt 25 16 V754M/wt oligospermia V754M/wt V754M/V754M 25 V754M/wt 50 wt/wt 25 Bold = mutations associated with classic cystic fibrosis; italic = mutations associated with a mild or uncertain, unpredictable phenotype; CAVD = congenital absence of the vas deferens; wt = wildtype allele. Login to comment

[hide] p.Ser1235Arg should no longer be considered as a c... Eur J Hum Genet. 2011 Jan;19(1):36-42. Epub 2010 Aug 18. Rene C, Paulet D, Girodon E, Costa C, Lalau G, Leclerc J, Cabet-Bey F, Bienvenu T, Blayau M, Iron A, Mittre H, Feldmann D, Guittard C, Claustres M, Georges M
p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study.
Eur J Hum Genet. 2011 Jan;19(1):36-42. Epub 2010 Aug 18., [PMID:20717170]

Abstract [show]
Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, 26 patients (5 having CF, 10 CBAVD (congenital bilateral absence of the vas deferens) and 11 with CF-like symptoms) and 14 healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from >2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution, give several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD.

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78 The second carried the rare missense mutation p.Val920Met and depressed values of digestive enzymes were observed at 17 weeks of pregnancy. Login to comment
95 of subjects Allele 1 Allele 2 p.Ser1235Arg;p.Arg785X p.Phe508del Severe CF 2 p.Ser1235Arg;p.Arg785X NAa Severe CF 1 p.Ser1235Arg;875+1G4A (c.743+1C4A) 3629delT (c.3497delT) Severe CF 1 p.Ser1235Arg;p.Arg785X p.Gly542X Severe CF 1 p.Ser1235Arg;(TG)13(T)5 p.Gly551Asp Mild CF 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CBAVD 6 p.Ser1235Arg;(TG)13(T)5 p.Arg1070Trp CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Arg117His; (T)7 CBAVD 1 p.Ser1235Arg p.Phe508del CBAVD 1 p.Ser1235Arg - CBAVD 1 p.Ser1235Arg;(TG)13(T)5 p.Phe508del CUAVD 1 Suspicion CF/mild phenotype: p.Ser1235Arg - Genital symptoms 5 p.Ser1235Arg - Respiratory symptoms 16 p.Ser1235Arg;(TG)13(T)5 p.Phe508del Respiratory symptoms 2 p.Ser1235Arg 406-6T4C (c.274-6T4C) Respiratory symptoms 1 p.Ser1235Arg p.Tyr1092X Respiratory symptoms 1 p.Ser1235Arg p.Glu831X Respiratory symptoms 1 p.Ser1235Arg p.Gln493X Respiratory symptoms 1 p.Ser1235Arg p.Ile507del Respiratory symptoms 1 p.Ser1235Arg - Digestive symptoms 13 p.Ser1235Arg p.Gly542X Digestive symptoms 1 p.Ser1235Arg - Hyperechogenic fetal bowel 5 p.Ser1235Arg p.Arg668Cys; p.Arg576Ala Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Val920Met Hyperechogenic fetal bowel 1 p.Ser1235Arg p.Phe508del Hyperechogenic fetal bowel 1 aNA: not available; we could only test the mother and a healthy sister (the patient was deceased and the father`s DNA was not available). Login to comment

[hide] Comprehensive description of CFTR genotypes and ul... Hum Genet. 2011 Apr;129(4):387-96. Epub 2010 Dec 24. de Becdelievre A, Costa C, Jouannic JM, LeFloch A, Giurgea I, Martin J, Medina R, Boissier B, Gameiro C, Muller F, Goossens M, Alberti C, Girodon E
Comprehensive description of CFTR genotypes and ultrasound patterns in 694 cases of fetal bowel anomalies: a revised strategy.
Hum Genet. 2011 Apr;129(4):387-96. Epub 2010 Dec 24., [PMID:21184098]

Abstract [show]
Fetal bowel anomalies may reveal cystic fibrosis (CF) and the search for CF transmembrane conductance regulator (CFTR) gene mutations is part of the diagnostic investigations in such pregnancies, according to European recommendations. We report on our 18-year experience to document comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. CFTR gene analysis was performed in a multistep process, including search for frequent mutations in the parents and subsequent in-depth search for rare mutations, depending on the context. Ultrasound patterns were correlated with the genotypes. Cases were distinguished according to whether they had been referred directly to our laboratory or after an initial testing in another laboratory. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5/30 CF fetuses. 21.2% of fetuses carrying a frequent mutation had a second rare mutation, indicative of CF. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The results emphasize the need to search for rearrangements in the diagnosis strategy of fetal bowel anomalies. The diagnostic value of ultrasound patterns combining hyperechogenic bowel, loop dilatation and/or non-visualized gallbladder reveals a need to revise current strategies and to offer extensive CFTR gene testing when the triad is diagnosed, even when no frequent mutation is found in the first-step analysis.

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188 - Born, not CF (no MI) 2 rare mutations (n = 1) [V920M]? Login to comment
279 Much more difficult cases to manage are those where mutations of unknown significance are found, such as D36N (p.Asp36Asn, c.106G[A), L548Q (p.Leu548Gln, c.1643T[A) and V920M (p.Val920Met, c.2758G[A), which were considered as potentially CF-causing. Login to comment
281 Qualification of a potential deleterious effect of V920M could not be done because the fetus also carried the mild S1235R mutation on the other allele and was not affected with CF. Login to comment

[hide] The role of common single-nucleotide polymorphisms... Hum Mutat. 2004 Aug;24(2):120-9. Steiner B, Truninger K, Sanz J, Schaller A, Gallati S
The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles.
Hum Mutat. 2004 Aug;24(2):120-9., [PMID:15241793]

Abstract [show]
Classic cystic fibrosis (CF) is caused by two loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whereas patients with nonclassic CF have at least one copy of a mutant gene that retains partial function of the CFTR protein. In addition, there are several other phenotypes associated with CFTR gene mutations, such as idiopathic chronic pancreatitis. In CFTR-associated disorders and in nonclassic CF, often only one CFTR mutation or no CFTR mutations can be detected. In this study, we screened 23 patients with CFTR-associated disorders for CFTR mutations by complete gene testing and quantitative transcript analysis. Mutations were found in 10 patients. In cells from respiratory epithelium, we detected aberrant splicing of CFTR mRNA in all investigated individuals. We observed a highly significant association between the presence of coding single-nucleotide polymorphisms (coding SNPs, or cSNPs) and increased skipping of exon 9 and 12. This association was found both in patients and in normal individuals carrying the same cSNPs. The cSNPs c.1540A>G, c.2694T>G, and c.4521G>A may have affected pre-mRNA splicing by changing regulatory sequence motifs of exonic splice enhancers, leading to lower amounts of normal transcripts. The analysis of CFTR exons indicated that less frequent and weak exonic splicing enhancer (ESE) motifs make exon 12 vulnerable to skipping. The number of splice variants in individuals with cSNPs was similar to previously reported values for the T5 allele, suggesting that cSNPs may enhance susceptibility to CFTR related diseases. In addition, cSNPs may be responsible for variation in the phenotypic expression of CFTR mutations. Quantitative approaches rather than conventional genomic analysis are required to interpret the role of cSNPs.

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88 RESULTS Characterization of the CFTR Gene Mutations Mutations (c.575T4C (p.I148T), c.2890G4A (p.V920M), c.3586G4C (p.D1152H), and c.3837T4G (p.S1235R)) were found in 4 out of 66 healthy individuals (6%), a nonsignificant increase compared to the 4% carrier frequency reported in the literature for the Swiss population [Hergersberg et al., 1997]. Login to comment

[hide] Increased risk of idiopathic chronic pancreatitis ... Hum Mutat. 2005 Oct;26(4):303-7. Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W, McFaul C, Mountford R, Sommer SS
Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers.
Hum Mutat. 2005 Oct;26(4):303-7., [PMID:16134171]

Abstract [show]
Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.

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93 Abnormal CFTR Genotypes Detected in 52 Patients with ICPa Genotype categorya ] Patients Genotypes detectedb Compound heterozygotes and homozygotes 3 p.F508del / p.L967S p.D1152H / p.D1152H p.V920M / p.L967S Heterozygotes, common mutation causing classic CFa 7 p.F508del /^ ('ve subjects)c p.R560T/^ p.G542X /^ Heterozygotes, uncommon mutation causing variable phenotype 3 p.S1235R /^ p.A209S /^ p.L997F/^ Heterozygotes, common CBAVD-associated mutation 2 IVS8(5T) /^ (two subjects) a Common CF-mutations consistently cause classic CF in compound heterozygotes and homozygotes [Rosenstein and Cutting, 1998]. Login to comment

[hide] Extensive molecular analysis of patients bearing C... J Mol Diagn. 2012 Jan;14(1):81-9. Epub 2011 Oct 20. Amato F, Bellia C, Cardillo G, Castaldo G, Ciaccio M, Elce A, Lembo F, Tomaiuolo R
Extensive molecular analysis of patients bearing CFTR-related disorders.
J Mol Diagn. 2012 Jan;14(1):81-9. Epub 2011 Oct 20., [PMID:22020151]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs) may present with pancreatic sufficiency, normal sweat test results, and better outcome. The detection rate of mutations is lower in CFTR-RD than in classic CF: mutations may be located in genes encoding proteins that interact with CFTR or support channel activity. We tested the whole CFTR coding regions in 99 CFTR-RD patients, looking for gene mutations in solute carrier (SLC) 26A and in epithelial Na channel (ENaC) in 33 patients who had unidentified mutations. CFTR analysis revealed 28 mutations, some of which are rare. Of these mutations, RT-PCR demonstrated that the novel 1525-1delG impairs exon 10 splicing; by using minigene analysis, we excluded the splicing effect of three other novel intronic variants. Analysis of SLC26A genes revealed several variants, some of which are novel, that did not affect mRNA expression. Other mutations occurred in the ENaC genes encoding the ENaC subunits, but their frequency did not significantly differ between patients and controls. Our data, although obtained on a preliminary cohort of CFTR-RD patients, exclude a role of mutations in SLC26A and in SCNN genes in the pathogenesis of such disease; we confirm that CFTR analysis has a relevant role in CFTR-RD patients; and it appears mandatory to use CFTR scanning techniques and approaches to reveal the effect of novel mutations.

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69 Allele Frequency and CFTR Mutations in Patients Bearing CFTR-RDs Mutation (traditional name) HGVS nomenclature15 CBAVD (118 alleles)* RP (42 alleles)* DB (38 alleles)* Total (198 alleles)* TG12-T5-470V 34 (28.8) 2 (4.8) 10 (26.3) 46 (23.2) F508del c.1521_1523del 19 (16.1) 7 (16.7) 4 (10.5) 30 (15.2) 3195del6 c.3063_3069del 9 (7.6) 0 0 9 (4.5) N1303K c.3909CϾG 3 (2.5) 1 (2.4) 4 (10.5) 8 (4.0) G542X c.1624GϾT 4 (3.4) 1 (2.4) 1 (2.6) 6 (3.0) D1152H c.3454GϾC 1 (0.8) 2 (4.8) 2 (5.3) 5 (2.5) G85E c.254GϾA 2 (1.7) 3 (7.1) 0 5 (2.5) 1525-1delG c.1394de 3 (2.5) 1 (2.4) 0 4 (3.0) 4016insT c.3885insT 2 (1.7) 1 (2.4) 0 3 (1.5) 2789ϩ5GϾA c.2657ϩ5GϾA 0 3 (7.1) 0 3 (1.5) Q1476X c.4426CϾT 3 (2.5) 0 0 3 (1.5) 2183AAϾG c.2051_2052delinsG 1 (0.8) 1 (2.4) 0 2 (1.0) R553X c.1657CϾT 1 (0.8) 1 (2.4) 0 2 (1.0) L568F c.1704GϾT 2 (1.7) 0 0 2 (1.0) R1158X c.3472CϾT 2 (1.7) 0 0 2 (1.0) V920M c.2758GϾA 1 (0.8) 0 1 (2.6) 2 (1.0) 711ϩ1GϾT c.579ϩ1GϾT 0 1 (2.4) 0 1 (0.5) D614G c.1841AϾG 1 (0.8) 0 0 1 (0.5) 2184insA c.2052del 0 1 (2.4) 0 1 (0.5) 621ϩ1GϾT c.489ϩ1GϾT 1 (0.8) 0 0 1 (0.5) R1438W c.4312CϾT 0 1 (2.4) 0 1 (0.5) E193X c.577GϾT 0 1 (2.4) 0 1 (0.5) G1244E c.3731GϾA 1 (0.8) 0 0 1 (0.5) K68E c.202AϾG 1 (0.8) 0 0 1 (0.5) R347P c.1040GϾC 1 (0.8) 0 0 1 (0.5) 621ϩ3AϾG c.489ϩ3AϾG 1 (0.8) 0 0 1 (0.5) L997F c.2991GϾC 0 1 (2.4) 0 1 (0.5) F508C c.1523TϾG 1 (0.8) 0 0 1 (0.5) Total 94 (79.7) 28 (66.7) 22 (57.9) 144 (72.7) Undetected 24 (20.3) 14 (33.3) 16 (42.1) 54 (27.3) *Data are given as number (percentage). Login to comment
144 This detection rate is higher than that reported for other patients affected by CBAVD,20 RP,21-24 or DB.25-28 Most previous studies tested restricted mutation panels for first-level analysis, whereas we used sequencing analysis, and 11 mutations identified in our study (3195del6, Q1476X, L568F, V920M, 1525-1delG, D614G, R1438W, E193X, K68E, 621ϩ3AϾG, and L997F), present in approximately 13% of chromosomes of CFTR-RD patients, are not included in most mutation panels. Login to comment

[hide] Spectrum of CFTR mutations in cystic fibrosis and ... Hum Mutat. 2000;16(2):143-56. Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, Girodon E, Cazeneuve C, Bienvenu T, Lalau G, Dumur V, Feldmann D, Bieth E, Blayau M, Clavel C, Creveaux I, Malinge MC, Monnier N, Malzac P, Mittre H, Chomel JC, Bonnefont JP, Iron A, Chery M, Georges MD
Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France.
Hum Mutat. 2000;16(2):143-56., [PMID:10923036]

Abstract [show]
We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7, 420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes. The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies >0. 4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes. We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients. In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78. 90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations.

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109 h M1K, K14X, W19X, 211delG, G27E, R31C, 237insA, 241delAT, Q39X, 244delTA, 296+2T>C, 297-3C>T, W57X+F87L, 306delTAGA, P67L, A72D, 347delC, R75Q, 359insT, 394delT, 405+4A>G, Q98R, 457TAT>G, R117H+5T, R117H+I1027T, R117L, R117P, H139R, A141D, M152V, N186K, D192N, D192del, E193X, 711+1G>A, 711+3A>G, 712-1G>T, L206F, W216X, C225R, Q237E, G241R, 852del22, 876-14del12, 905delG, 993del5, E292K, Y304X, F311del, 1161delC, R347L, R352Q, W361R, 1215delG, S364P, S434X, D443Y, S466X, C491R, T501A, I506T, F508C, I507del+F508C, F508del+L467F, 1774delCT, R553G, 1802delC, 1806delA, A559E, Y563N, 1833delT, Y569C, Y569H, Y569X, G576X, G576A, T582I, 1898+3A>G+186-13C>G, 1918delGC, R600G, L610S, G628R, 2043delG, 2118del4, E664X, 2174insA, Q689X, K698R, K716X, L732X, 2347delG, 2372del8, R764X, 2423delG, S776X, 2634insT, 2640delT, C866Y, 2752-1G>T, W882X, Y913C, V920M, 2896insAG, H939D, H939R, D979V, D985H, D993Y, 3120G>A, I1005R, 3195del6, 3293delA, 3320ins5, W1063X, A1067T, 3359delCT, T1086I, W1089X, Y1092X+S1235R, W1098X, E1104X, R1128X, 3532AC>GTA, 3548TCAT>G, M1140del, 3600G>A, R1162L, 3667ins4, 3732delA+K1200E, S1206X, 3791delC, S1235R+5T, Q1238R, Q1238X, 3849+4A>G, T1246I, 3869insG, S1255P, R1283K, F1286S, 4005+1G>T, 4006-8T>A, 4015delA, N1303H, N1303I, 4172delGC, 4218insT, 4326delTC, Q1382X, 4375-1C>T, 4382delA, D1445N, CF40kbdel4-10, Cfdel17b. Login to comment
171 CFTR Mutation Genotypes Identified Both in Cystic Fibrosis (CF) and in Congenital Bilateral Absence of the Vas Deferens (CBAVD) CF CBAVD F508del/5T 3 143 F508del/2789+5G>A 53 1 F508del/3272-26A>G 17 4 F508del/R117H* 10 39 F508del/R117C 2 2 F508del/L206W 12 4 F508del/R347H 10 5 F508del/R347L 1 1 F508del/D443Y 1 5 F508del/Y569C 1 1 F508del/P574H 3 1 F508del/G628R(G>A) 2 1 F508del/V920M 1 1 F508del/R1070W 2 3 F508del/D1152H 6 8 F508del/S1235R 3 1 F508del/T1246I 1 1 F508del/D1270N+R74W 2 3 F508delN1303I 1 1 3659delC/R347H 1 1 G542X/T338I 2 2 R347H/R1066H 1 1 *The only case with CF whose alleles at IVS8(T)n were reported had mutation R117H associated with a 5T allele. Login to comment