ClinVar Genomic variation as it relates to human health

In 7 patients, including 2 sibs, with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a G-to-A change at nucleotide 1784 in exon 11 of the CFTR gene that was responsible for substitution of aspartic acid for glycine at amino acid 551 (G551D). In 6 of these patients the delta-F508 mutation (602421.0001) was present on the other allele; 3 of these patients, aged 11 to 13 years, had mild lung disease with normal pulmonary function test results. In the seventh patient, with mild lung disease, the mutation on the other allele was unknown. Curtis et al. (1991) described this mutation in 2 sibs in homozygous state and in an unrelated adult who was a compound heterozygote for G551D and delta-I507 (602421.0002). All 3 showed clinically mild disease. The G551D mutation creates an MboI recognition site at codon 551 in the CFTR gene. Burger et al. (1991) suggested that heterozygosity for the G551D mutation is a causative factor in recurrent polyposis nasi (nasal polyps). Hamosh et al. (1992) stated that the gly551-to-asp mutation, which is within the first nucleotide-binding fold of the CFTR, is the third most common CF mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta-F508, Hamosh et al. (1992) studied 79 compound heterozygotes for the 2 mutations in comparison with age- and sex-matched delta-F508 homozygotes from 9 CF centers in Europe and North America. There was less meconium ileus among the compound heterozygotes but otherwise no statistically significant difference was found between the 2 groups. Clinical outcome (after survival of meconium ileus) was indistinguishable. Delaney et al. (1996) showed that mice carrying the human G551D mutation in the Cftr gene show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice showed greatly reduced CFTR-related chloride transport, displaying activity (equivalent to approximately 4% of wildtype Cftr) intermediate between that of 'null' mice and Cftr insertional mutants with residual activity. The authors stated that long-term survival of these animals should provide an excellent model for the study of cystic fibrosis. The G551D allele is associated characteristically with populations of Celtic descent and is seen at its highest prevalence in regions such as Ireland and Brittany. It is seen in diminishing frequencies as one moves to the southern and eastern portions of Europe. An initially puzzling phenomenon was the relatively high incidence of this mutation in the Czech Republic (3.8%). As pointed out by Bobadilla et al. (2002), however, population movements of the past provide an explanation. Accurso et al. (2010) reported the results of a 2-phase clinical trial using VX-770, a CFTR potentiator, in 39 adults with cystic fibrosis and at least 1 G551D allele. Subjects received 150 mg of VX-770 every 12 hours for 28 days in phase 2 of the study. All showed a change in the nasal potential difference from baseline of -3.5 mV (range, -8.3 to 0.5; P = 0.02 for the within-subject comparison; P = 0.13 vs placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 within-subject, P = 0.56 vs placebo). The VX-770 was well tolerated. None of the subjects withdrew from the study. All severe adverse events resolved without the discontinuation of VX-770. Ramsey et al. (2011) conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770) in subjects 12 years of age or older with cystic fibrosis and at least 1 G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of the drug every 12 hours (84 subjects, of whom 83 received at least 1 dose) or placebo (83, of whom 78 received at least 1 dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of forced expiratory volume in 1 second (FEV1). The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (p less than 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have pulmonary exacerbation than were patients receiving placebo, through week 48 (p less than 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory symptoms domain of the Cystic Fibrosis Questionnaire revised instrument (p less than 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (p less than 0.001). The change from baseline through week 48 in the concentration of sweat chloride with ivacaftor as compared with placebo was -48.1 mmol per liter (p less than 0.001). The incidence of adverse events was similar with treatment and controls, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs 42%). On January 31, 2012, the FDA approved Kalydeco, formerly VX-770 (ivacaftor), for use in cystic fibrosis patients with the G551D mutation, as reported by Ledford (2012). (less)