Gene:
CFTR
cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)

last updated 05/06/2014

CPIC Dosing Guideline for ivacaftor and CFTR

Summary

Ivacaftor treatment is recommended only in cystic fibrosis (CF) patients that are either homozygous or heterozygous for certain CFTR variants. See full guideline for disclaimers, further details and supporting evidence.

Annotation

April 2014 Update on PharmGKB

March 2014

Accepted article preview online March 2014; Advance online publication March 2014.

Table 1: Recommended therapeutic use of ivacaftor based on CFTR genotype

Adapted from Table 2 of the 2014 guideline manuscript (April 2014 Update on PharmGKB). Variants have been added to the table below that are not in the published 2014 guideline or supplement; specifically, variants other than G551D and F508del.

CFTR Genotype Examples of diplotypes Implications for ivacaftor effects Recommendations for ivacaftor therapy Classification of recommendation for ivacaftor therapy c
Homozygous or Heterozygous G551D-CFTR, rs75527207 genotype AA or AG G551D/ F508del, G551D/ G551D Significant improvement in lung function, weight, risk of pulmonary exacerbation, patient reported outcomes, and reduction in sweat chloride concentrations through enhanced CFTR channel activity (increase probability of open channel). Use ivacaftor according to the product label (e.g., 150 mg every 12 hours for patients age 6 and older without other diseases; modify dose in patients with hepatic impairment) Strong
Homozygous for F508del-CFTR, rs113993960 or rs199826652 genotype del/del F508del/F508del No significant reduction in sweat chloride concentrations; no changes in other clinical measurements including spirometric measurements, pulmonary exacerbations, or body weight b. Unlikely to respond to treatment. Ivacaftor is not recommended a Moderate b
Homozygous or heterozygous for one of the following CFTR variants that affect gating: G1244E (rs267606723 genotype AA or AG), G1349D (rs193922525 genotype AA or AG), G178R (rs80282562 genotype AA or AG), G551S (rs121909013 genotype AA or AG), S1251N (rs74503330 genotype AA or AG), S1255P (rs121909041 genotype CC or CT), S549N (rs121908755 genotype AA or AG), S549R (rs121909005 genotype GG or GT, rs121908757 genotype CC or CA) d F508del/S549N Significantly enhanced channel open probability in vitro [Article:22293084]. In vitro assays with CFBEo- cells expressing S549N-CFTR showed ivacaftor potentiated chloride channel function [Article:23027855], and a case study showed improved lung function after ivacaftor treatment in a 12-year-old girl with CF with a copy of the S549N variant [Article:24081349]. Use ivacaftor according to the product label (e.g., 150 mg every 12 hours for patients age 6 and older without other diseases; modify dose in patients with hepatic impairment) Moderate

a These recommendations are based on treatment of CF patients with ivacaftor alone and current evidence. Clinical trials are currently underway to investigate ivacaftor alone or in combination with other drugs to treat CF patients with CFTR variants other than G551D, therefore there is potential that ivacaftor may be effective in these patients. See the 2014 guidelines for further details.
b The recommendation for patients with the F508del/F508del genotype is based on ivacaftor mechanism of action and clinical observational data. The clinical study however was a safety study and was not powered to detect a difference in efficacy [Article:22383668].
c Rating scheme described in the 2014 supplement.
d Variants listed in this table include those added to the amended drug label for ivacaftor which was approved by the FDA on February 21, 2014. The modifications to this table were made after the acceptance of publication of the 2014 CPIC Ivacaftor-CFTR guideline [Article:24598717] and are not reflected in the PDFs of the CPIC guideline main manuscript or supplement.

Figure 1: Treatment algorithm for clinical use of Ivacaftor for cystic fibrosis patients based on CFTR genotype.

Adapted from Figure 1 of the 2014 guideline manuscript (April 2014 Update on PharmGKB). Variants have been added to this figure that are not in the published 2014 guideline or supplement; specifically, variants other than G551D and F508del.

e Ivacaftor is not recommended for CF patients with other CFTR variants or in patients homozygous for the F508del variant (see 2014 guideline for further details, supporting evidence and disclaimers). Future clinical trials for other CFTR variants are ongoing.


PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 03/05/2014

FDA Label for ivacaftor and CFTR

This label is on the FDA Biomarker List
Genetic testing required

Summary

Ivacaftor is indicated in patients with cystic fibrosis (CF) who have one of the following variants in the CFTR gene: G551D (rs75527207), G1244E (rs267606723), G1349D (rs193922525), G178R (rs80282562), G551S (rs121909013), S1251N (rs74503330), S1255P (rs121909041), S549N (rs121908755) or S549R (rs121908757 and rs121909005). Genetic testing is required prior to initiating treatment with Ivacaftor if a patient's CFTR genotype is not known. The label also states that ivacaftor is not effective in patients homozygous for the F508del variant (rs113993960 and rs199826652).

Annotation

The FDA recommends genetic testing prior to initiating treatment with Ivacaftor if a patient's CFTR genotype is not known. The drug is indicated in cystic fibrosis (CF) patients who have at least one of the following variants in the CFTR gene: G551D (rs75527207), G1244E (rs267606723), G1349D (rs193922525), G178R (rs80282562), G551S (rs121909013), S1251N (rs74503330), S1255P (rs121909041), S549N (rs121908755) or S549R (rs121908757 and rs121909005).

The FDA label also contains information regarding metabolism of ivacaftor by CYP3A enzymes, therefore concomitant use with strong CYP3A inhibitors is not recommended or adjustments to dose are required. Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's Wort) substantially decreases exposure of ivacaftor which may diminish effectiveness.

Excerpts from the ivacaftor (Kalydeco) label:

KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use.


Limitations of Use:

  • Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the ivacaftor (Kalydeco) drug label. This label was amended and approved by the FDA on Feb/21/2014. One amendment includes the addition of CFTR variants to the indication (ivacaftor was originally indicated for use in CF patients with the G551D variant).

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Cystic Fibrosis
    • Indications & usage section, Information for patients section, Clinical studies section, Use in specific populations section
    • source: FDA Label
  • CFTR
    • Indications & usage section, Information for patients section, Clinical pharmacology section, Clinical studies section, Pharmacodynamics section, Use in specific populations section, efficacy
    • source: FDA Label
  • CYP3A4
    • Dosage & administration section, Drug interactions section, Pharmacokinetics section, Warnings and precautions section, dosage
    • source: FDA Label
  • CYP3A5
    • Dosage & administration section, Drug interactions section, Pharmacokinetics section, Warnings and precautions section, dosage
    • source: FDA Label

last updated 10/27/2013

European Medicines Agency (EMA) Label for ivacaftor and CFTR

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) contains pharmacogenetic information regarding the indication of ivacaftor (Kalydeco) in cystic fibrosis patients who have one of the following variants in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R. Treatment in patients who do not have one of these variants is not recommended, and if a patient's genotype is not known, testing should be carried out before treatment.

Annotation

Update Oct/22/2014: The EPAR originally contained information regarding indication in patients with the CFTR-G551D variant. It is now contains information regarding the indication of ivacaftor in patients with one of nine CFTR variants.

Excerpts from the ivacaftor (Kalydeco) EPAR:

Kalydeco is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who have one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R (see sections 4.4 and 5.1).


Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of one of the above-listed gating (class III) mutations in at least one allele of the CFTR gene before starting treatment.

The EPAR also contains information regarding the role of CYP3A4 and CYP3A5 in the metabolism of ivacaftor, and that if taken concomitantly with inhibitors or inducers of these enzymes, ivacaftor may require dose adjustments.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the ivacaftor EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • CFTR
    • Information for patients section, Pharmacodynamics section, efficacy
    • source: European Medicines Agency (EMA) Label
  • CYP3A4
    • Drug interactions section, Warnings and precautions section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • CYP3A5
    • Drug interactions section, Warnings and precautions section, metabolism/PK
    • source: European Medicines Agency (EMA) Label

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below. Please follow the link in the "Position" column for more information about a particular variant. Each link in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Related Drugs?
LabCorp Cystic Fibrosis (CF) Gene Sequencing CFTR Sequencing of CFTR gene
ARUP Lab CFTR 32 mutations (PCR,oligonucleotide ligation, fragment analysis) rs113993960 , rs75527207 , CFTR F508del , CFTR I507del , CFTR G542X , CFTR G551D , CFTR W1282X , CFTR N1303K , CFTR R553X , CFTR 621+1GT , CFTR R117H , CFTR 1717-1GA , CFTR A455E , CFTR R560T , CFTR R1162X , CFTR G85E , CFTR R334W , CFTR R347P , CFTR 711+1GT , CFTR 1898+1GA , CFTR 2184delA , CFTR 1078delT , CFTR 3849+10kbCT , CFTR 2789+5GA , CFTR 3659delC , CFTR 2183delAA>G , CFTR 3120+1GA , CFTR R347H , CFTR V520F , CFTR S549N , CFTR S549R , CFTR 3905insT , CFTR 3876del , CFTR 394delTT
23andme.com rs113993960 , rs75527207 , CFTR 1898+1G>A , CFTR N1303K , CFTR R347H , CFTR 2789+5G>A , CFTR 711-+1G>T , CFTR S549N , CFTR 3849+10kb C>T , CFTR R334W , CFTR S549R , CFTR A455E , CFTR 1717-1G>A , CFTR V520F , CFTR R1162X , CFTR W1282X , CFTR 394deITT , CFTR R560T , CFTR R117H , CFTR 3876deIA , CFTR 3120+1G>A , CFTR 621+1G>T , CFTR 3905insT , CFTR 3659delC , CFTR R347P , CFTR G551D , CFTR R553X , CFTR 1078delT , CFTR G85E , CFTR 2184delA , CFTR G542X , CFTR deltaI507 , CFTR deltaF508 , CFTR F508C
Ambry Genetics Cystic Fibrosis (pyrosequencing) rs113993960 , rs75527207 , CFTR deltaI507 , CFTR deltaF508 , CFTR A455E , CFTR E60X , CFTR G542X , CFTR G551D , CFTR G85E , CFTR N1303K , CFTR R117H , CFTR R334W , CFTR R347P , CFTR R553X , CFTR R560T , CFTR R1066C , CFTR R1162X , CFTR S492F , CFTR S549N , CFTR W1282X , CFTR 394delTT , CFTR 406-1G>A , CFTR 621+1G>T , CFTR 711+1G>T , CFTR 1717-1G>A , CFTR 1898+1G>A , CFTR 2055del9>A , CFTR 2105-2117del13insAGAAA , CFTR 2184delA , CFTR 2789+5G>A , CFTR 3120+1G>A , CFTR 3849+10kbC>T , CFTR 3659delC , CFTR 3876delA
Medical Diagnostic Laboratories Cystic Fibrosis Gene Carrier Screening (PCR, Bio-Plex liquid microarray analysis) rs113993960 , rs75527207 , CFTR F508 , CFTR A455E , CFTR 2789+5G>A , CFTR G85V , CFTR I507 , CFTR R560T , CFTR 3659delC , CFTR R347L , CFTR G542X , CFTR R1162X , CFTR 3120+1G>A , CFTR G551D , CFTR G85E , CFTR W1282C , CFTR W1282X , CFTR R334W , CFTR R553G , CFTR N1303K , CFTR R347P , CFTR R117L , CFTR R553X , CFTR 711+1G>T , CFTR R117P , CFTR 621+1G>T , CFTR 1898+1G>A , CFTR 1898+1G>T , CFTR R117H , CFTR 2184delA , CFTR K684K , CFTR 1717-1G>A , CFTR 3849+10kbC>T , CFTR R560K
Abbott Molecular Cystic Fibrosis Genotyping Assay (PCR, oligonucleotide ligation assay) rs113993960 , rs75527207 , CFTR 1898+1G>A , CFTR N1303K , CFTR R347H , CFTR 2789+5G>A , CFTR 711-+1G>T , CFTR S549N , CFTR 3849+10kb C>T , CFTR R334W , CFTR S549R , CFTR A455E , CFTR 1717-1G>A , CFTR V520F , CFTR R1162X , CFTR W1282X , CFTR 394deITT , CFTR R560T , CFTR R117H , CFTR 3876deIA , CFTR 3120+1G>A , CFTR 621+1G>T , CFTR 3905insT , CFTR 3659delC , CFTR R347P , CFTR 2183AA>G , CFTR G551D , CFTR R553X , CFTR 1078delT , CFTR G85E , CFTR 2184delA , CFTR G542X , CFTR deltaI507 , CFTR deltaF508 , CFTR F508C
Quest Diagnostics Cystic Fibrosis Screen (PCR, oligonucleotide ligation assay) rs113993960 , rs75527207 , CFTR 621+1G>T , CFTR 3120+1G>A , CFTR G85E , CFTR R347P , CFTR 5T/7T/9Ta , CFTR 711+1G>T , CFTR 3659delC , CFTR G542X , CFTR R553X , CFTR ¿506V , CFTR 1717-1G>A , CFTR 3849+10kbC>T , CFTR G551D , CFTR R560T , CFTR ¿507V , CFTR 1898+1G>A , CFTR A455E , CFTR N1303K , CFTR R1162X , CFTR 2184delA , CFTR deltaI507 , CFTR R117H , CFTR W1282X , CFTR 2789+5G>A , CFTR deltaF508 , CFTR R334W , CFTR 1078delT , CFTR 2183AA>G , CFTR 3876delA , CFTR 3905insT , CFTR 394delTT , CFTR R347H , CFTR S549N , CFTR S549R , CFTR V520F
Mayo Medical Laboratories Cystic Fibrosis Mutation Analysis, 106-Mutation Panel (multiplex PCR, sequenom mass array) rs113993960 , rs75527207 , CFTR deltaF508 , CFTR deltaI507 , CFTR G542X , CFTR G85E , CFTR R117H , CFTR W1282X , CFTR 621+1 G->T , CFTR 711+1 G->T N1303K (C->A and C->G) , CFTR R334W , CFTR R347P , CFTR A455E , CFTR 1717-1 G->A , CFTR R553X , CFTR R560T , CFTR G551D , CFTR 1898+1 G->A , CFTR 2184delA , CFTR 2789+5 G->A , CFTR 3120+1 G->A , CFTR R1162X , CFTR 3659delC , CFTR and 3849+10kb C->T) as well as the deletion exons 2-3 , CFTR 296+2 T->A , CFTR E60X , CFTR R75X , CFTR 394delTT , CFTR 405+1 G->A , CFTR 406-1 G->A , CFTR E92X , CFTR 444delA , CFTR 457TAT->G , CFTR R117C , CFTR Y122X , CFTR 574delA , CFTR 663delT , CFTR G178R , CFTR 711+5 G->A , CFTR 712-1 G->T , CFTR H199Y , CFTR P205S , CFTR L206W , CFTR 852del22 , CFTR 935delA , CFTR 936delTA , CFTR deltaF311 , CFTR 1078delT , CFTR G330X , CFTR T338I , CFTR R347H , CFTR R352Q , CFTR Q359K , CFTR T360K , CFTR 1288insTA , CFTR S466X (C->A) , CFTR S466X (C->G) , CFTR G480C , CFTR Q493X , CFTR 1677delTA , CFTR C524X , CFTR S549N , CFTR S549R , CFTR Q552X , CFTR A559T , CFTR 1811+1.6kb A->G , CFTR 1812-1 G->A , CFTR 1898+1 G->T , CFTR 1898+1 G->C , CFTR 1898+5G->T , CFTR P574H , CFTR 1949del84 , CFTR 2043delG , CFTR 2055del9->A , CFTR 2105del13ins5 , CFTR 2108delA , CFTR 2143delT , CFTR 2183AA->G , CFTR 2184insA , CFTR R709X , CFTR K710X , CFTR 2307insA , CFTR R764X , CFTR Q890X , CFTR 2869insG , CFTR 3171delC , CFTR 3199del6 , CFTR R1066C , CFTR W1089X , CFTR Y1092X (C->G) , CFTR Y1092X (C->A) , CFTR M1101K , CFTR M1101R , CFTR D1152H , CFTR R1158X , CFTR 3667del4 , CFTR S1196X , CFTR W1204X , CFTR 3791delC , CFTR Q1238X , CFTR 3876delA , CFTR S1251N , CFTR S1255X , CFTR 3905insT , CFTR 4016insT

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
rs113993960 117559592_117559594delCTT, 1521_1523delCTT, 1845_1847delCTT, 55052813_55052815delCTT, 98809_98811delCTT, F508del, Phe508del, Phe616del, c.1521_1523delCTT, deltaF508, p.Phe508del, rs199826652
CTT > -
Not Available
rs121908755 117587800G>A, 117587800G>T, 127017G>A, 127017G>T, 1646G>A, 1646G>T, 1970G>A, 1970G>T, 55081021G>A, 55081021G>T, S549N, Ser549Asn, Ser549Ile, Ser657Asn, Ser657Ile, c.1646G>A, p.Ser549Asn
G > A
G > T
Not Available
Ser657Asn
Ser657Ile
rs121908757 117587799A>C, 127016A>C, 1645A>C, 1969A>C, 55081020A>C, S549R, Ser549Arg, Ser657Arg, c.1645A>C, p.Ser549Arg
A > C
Not Available
Ser657Arg
rs121909005 117587801T>G, 127018T>G, 1647T>G, 1971T>G, 55081022T>G, S549R, Ser549Arg, Ser657Arg, c.1647T>G, p.Ser549Arg
T > G
Not Available
Ser657Arg
rs121909013 G551S, c.1651G>A, p.Gly551Ser
G > A
Not Available
Gly551Ser
rs121909041 117642483T>C, 181700T>C, 3763T>C, 4087T>C, 55135704T>C, S1255P, Ser1255Pro, Ser1363Pro, c.3763T>C, p.Ser1255Pro
T > C
Not Available
Ser1363Pro
rs193922525 117664770G>A, 203987G>A, 4046G>A, 4370G>A, 55157991G>A, G1349D, Gly1349Asp, Gly1457Asp, c.4046G>A, p.Gly1349Asp
G > A
Not Available
Gly1457Asp
rs267606723 117642451G>A, 117642451G>T, 181668G>A, 181668G>T, 3731G>A, 3731G>T, 4055G>A, 4055G>T, 55135672G>A, 55135672G>T, G1244E, Gly1244Glu, Gly1244Val, Gly1352Glu, Gly1352Val, c.3731G>A, p.Gly1244Glu
G > A
G > T
Not Available
Gly1352Val
Gly1352Glu
rs74503330 117282526G>A, 167510G>A, 55315369G>A, S1251N, c.3752G>A, p.Ser1251Asn
G > A
Not Available
Ser1251Asn
rs75527207 117587806G>A, 127023G>A, 1652G>A, 1976G>A, 55081027G>A, G551D, Gly551Asp, Gly659Asp, c.1652G>A, p.Gly551Asp
G > A
Not Available
Gly659Asp
rs80282562 117534318G>A, 532G>A, 55027539G>A, 73535G>A, 856G>A, G178R, Gly178Arg, Gly286Arg, c.532G>A, p.Gly178Arg
G > A
Not Available
Gly286Arg
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138

Overview

Alternate Names:  ATP-binding cassette sub-family C, member 7
Alternate Symbols:  ABC35; CFTR/MRP; MRP7; TNR-CFTR; dJ760C5.1
PharmGKB Accession Id: PA109

Details

Cytogenetic Location: chr7 : q31.2 - q31.2
GP mRNA Boundary: chr7 : 117120017 - 117308719
GP Gene Boundary: chr7 : 117110017 - 117311719
Strand: plus
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

Introduction

The cystic fibrosis transmembrane conductance regulator (CFTR, ATP-binding cassette sub-family C, member 7, ABCC7) protein is 1480 amino acids in length. It is encoded by a single large gene with 27 exons spanning around 250kbp on chromosome 7q31.2, which was identified in the search to find the gene underlying cystic fibrosis (CF) disease [Articles:22698459, 1710598, 2772657, 1375392]. The protein structure is made up of two units, each with six transmembrane helices and an intracellular nucleotide-binding domain (NBD) that can interact with adenosine triphosphate (ATP). A regulatory "R" domain connects the two units and contains sites for protein kinase phosphorylation [Article:22698459]. The structure creates a channel in the plasma membrane through which anions can flow, and the gate is thought to be opened and closed by ATP binding and hydrolysis (NBDs) and phosphorylation mechanisms (R domain) which alter the protein's conformation [Articles:22698459, 8910473, 24727426].

CFTR is expressed predominantly in epithelial tissues, but is also found in other cell types such as smooth muscle, cardiac myocytes, macrophages, and erythrocytes [Article:22698459]. CFTR is multi-functional. It is an anion channel that transports chloride (Cl-) and bicarbonate. It is also involved in the regulation of a range of transporters including the epithelial sodium channel (ENaC encoded by SCNN1A, SCNN1B, SCNN1D and SCNN1G) and outwardly rectifying chloride channels (ORCC) [Articles:22698459, 24004658, 7683773, 7515570, 23895508]. In addition, CFTR has been proposed to be a hub for signaling pathways and may regulate a variety of other physiological processes including exocytosis and endocytosis, ATP export, proinflammatory cytokine expression and intracellular pH [Articles:22698459, 23895508]. Defective CFTR therefore results in widespread cellular homeostasis dysfunction [Article:23895508].

CF is an autosomal recessive disease resulting from a defect-causing variant on each CFTR allele. More than 1800 variants in the CFTR gene have been reported (CF mutation database). Despite a large collection of variants, there is a gap in our knowledge regarding which cause CF disease. To address this, the Clinical and Functional Translation of CFTR project was established to collect information regarding the functional consequences and resulting phenotypes associated with CFTR variants [Article:23974870]. Data for 39,696 subjects from 25 CF patient registries or specialty clinics were collected for the CFTR2 database, and an initial set of 159 CFTR variants (those with a frequency of =0.01% in the CFTR2 database) was evaluated for whether they cause CF disease by both clinical phenotype and functional analysis. A variant was defined clinically as causing CF if mean sweat chloride concentration was =60mM for at least three individuals with the variant or >90mM if only 2 individuals with the variant were available; 140 variants met the clinical criteria to be CF-causing. The variants were sorted by their predicted functional effect, and 77 were investigated further using in vitro assays appropriate to the genetic variant (<10% of wild-type CFTR function was considered disease-causing); 133 variants were deemed CF-causing by functional criteria. In total, 127 variants met both the clinical and functional criteria, and were defined as CF-causing. Penetrance analysis in fathers with CF children was carried out on the variants that did not meet both/either criteria and 12 variants were deemed non-CF causing, with the remaining 20 variants indeterminate [Article:23974870].

CF is a disease that predominantly affects the lungs but has a diverse array of phenotypes due to the expression of CFTR in different tissues, its wide-ranging physiological role, and its involvement in many signaling pathways [Articles:22698459, 24004658, 23895508]. Progressive lung disease, pancreatic dysfunction, infertility in males and elevated sweat electrolytes characterize a "classical" CF diagnosis (WHO report, 2004). CF is also associated with a reduced life expectancy (early adulthood) and an increased risk of cancer [Articles:22698459, 23895508]. There is however wide variability in clinical presentation, severity and the rate of disease progression between patients, which can be influenced by the underlying CFTR genotype as well as other genetic modifiers and environmental factors [Articles:22698459, 24004658, 2233932, 24057835, 21602797, 23895508] (WHO report, 2004). The incidence of CF is thought to be around 70,000 cases worldwide (CFF.org), though it may be largely under-diagnosed in parts of Asia, Africa and Latin America (WHO report, 2004)[Article:24736905]. Genetic testing is now a routine part of CF diagnosis in many countries. A recommended panel for genetic screening for determining prenatal and preconception carrier status of CF in the US includes 23 CFTR variants, designed to cover variants with a frequency of at least 0.1% in CF patients that are associated with classical CF disease, for a pan-ethnic US population [Articles:21422883, 15371902, 24014130]. The WHO recommends sequencing of the complete CFTR gene in CF patients from populations where CF is likely under-diagnosed in order to establish panels of population-specific variants known to cause disease (WHO report, 2004).

Pharmacogenetics (PGx)

Traditionally, drugs used in the treatment of CF have focused on ameliorating symptoms, fighting infection, thinning mucus and dampening inflammation, rather than directly targeting the cause: variants in the CFTR gene. Gene therapy techniques aimed at replacing defective CFTR with a functional version of the gene have been extensively researched and remain a hope for curing CF after the discovery of the underlying disease cause. Unfortunately, gene therapy has encountered several barriers that have kept it from becoming a treatment option for CF [Article:24282073], though the results of an ongoing clinical trial are eagerly awaited [Article:24464978]. Drugs that are designed to correct specific defects of the CFTR protein are being developed as novel therapies for CF; these are termed "modulators" of CFTR. Repurposing of drugs for CF treatment due to their mechanism of action as a CFTR modulator is also a potential therapeutic option (see [Article:22698459]). This summary focuses on pharmacogenetics, and thus therapies that directly target defects resulting from variants in the CFTR gene. CFTR variants can be grouped into 6 classes depending on the resulting effect on the protein, and each could potentially be targeted by a treatment strategy aimed at the underlying defect: see Table 1. Modulator molecules also have the benefit of being administered orally, thus potentially targeting multiple organs and cell types affected by a defect in CFTR [Article:24561283]. Included in the spectrum of modulators are "correctors" and "potentiators". Correctors are molecules that 'correct' the misfolding/trafficking of defective CFTR protein to increase expression at the cell surface, whereas potentiators enhance the channel opening of the defective protein within the cell membrane [Article:22723294].

Currently, the most commonly accepted efficacy endpoints for late phase clinical trials in CF include lung function (forced expiratory volume in one second), pulmonary exacerbation rates, growth/body mass index, and patient reported outcomes [Article:22047557]. Additional outcome measures are in development and may serve to accelerate CFTR modulator development in CF, including multiple breath washout (lung clearance index), pulmonary imaging (including CT and mucociliary clearance), cardiopulmonary exercise testing, gastrointenstinal pH, a variety of sputum biomarkers and changes in microbiome [Articles:24461666, 24927234, 25251804, 25171465]. Change in mean sweat chloride concentration is also currently used as a biomarker of CF, however there is controversy regarding sweat chloride as a predictive biomarker for improvement in lung function [Articles:23276841, 24258833, 24660233]. Guidelines recommending particular biomarkers for CF therapy trials have been published [Article:22878883]. Modulators may have different effects in different tissues/cells which should be taken into account when personalizing CF treatment for an individual patient [Article:24561283].

Table 1: CFTR variants and potential treatment strategy a

Class Description Associated CF phenotype Example variants b Potential treatment strategy that may target this class Potential examples of possible drugs/compounds e
I Cause splicing defects, frameshift mutations or a premature stop codon resulting in a lack of CFTR expression and impaired biosynthesis. Severe. W1282X (c.3846G>A, rs77010898), G542X (c.1624G>T, rs113993959), R553X (c.1657C>T, rs74597325). A suppressor which prevents premature termination by reading through premature termination codons. This allows for complete translation. Gentamicin (repurposed from use as an antibiotic). Synthetic aminoglycoside NB124 [Article:24251786]. Ataluren (PTC-124): in a Phase 3 clinical trial it did not improve lung function in the overall CF patient population, but may be beneficial in patients not receiving chronic inhaled tobramycin [Article:24836205]. There is debate over whether ataluren has suppressor function [Articles:23824517, 23824301, 24483936], and whether it may resurrect dormant retroelements [Article:19394530].
II Result in an immature protein that is consequently mostly degraded. Severe. F508del (c.1521_1523delCTT, rs199826652 or rs113993960: view VIP variant summary for further details), N1303K (c.3909C>G, rs80034486). A corrector, which restores folding and increases trafficking to the membrane and/ or a potentiator which increases CFTR open probability/gating. See lists c and d.
III Result in proteins which are present at the plasma membrane but have disrupted activation or regulation, resulting in defective CFTR channel gating. Severe. G551D (c.1652G>A, rs75527207: view VIP variant summary for further details). A potentiator, which increases CFTR open probability/gating. Ivacaftor is indicated for variants detailed in Table 2, for other variants see list d.
IV Result in CFTR present at the plasma membrane but with reduced conductance of chloride. Mild. R347P (c.1040G>C, rs77932196), R334W (c.1000C>T, rs121909011). A potentiator which increases gating may be able to overcome reduced channel conductance. See list d.
V Result in partly defective processing or synthesis of CFTR. Mild. 3272-26 A>G (c.3140-26A>G), 3849 +10kb C>T (c.3717+12191C>T, rs75039782). A potentiator, which increases gating may be able to overcome reduced CFTR availability. See list d.
VI Result in CFTR present at the plasma membrane but with reduced conductance of ions (not including chloride) or reduced membrane stability. Severe. 1811 + 1.6kb A>G (c.1679+1.6kbA>G), corrected F508del. Drugs that stabilize CFTR at the plasma membrane.
Table 1 legend:
a = Table based on [Articles:22698459, 24004658, 22723294, 24727426] and The Clinical and Functional TRanslation of CFTR (CFTR2) with additional references as indicated below.
b = All examples of variants are CF-causing variants.
c = Examples of potential drugs/compounds that may function as CFTR correctors: Lumacaftor (VX-809) f, 4-phenylbutyrate f, miglustat, sildenafil, vardenafil, taladafil, suberoylanilide hydroxamic acid, VRT-325, CF-106951, VX-661, KM11060, Corr 2a, 3a, 4a, 4b, benzoquinolizinium, curcumin f, glafanine, RDR1 ([Articles:21976485, 23104983, 22698459, 19502384, 24737137, 24004658, 22723294, 24727426, 23818513] (ClinicalTrials.gov).
d = Examples of potential drugs/compounds that may function as CFTR potentiators: ivacaftor (VX-770) (indicated for variants in Table 2), phloxine B, genistein, GPact-11a, NS004, resveratrol, phenylglycine PG-01, curcumin [Articles:22698459, 24004658, 22723294, 24727426, 24380236, 23818513, 24561283].
e For most of the compounds listed, toxicity studies and clinical trials in CF patients have not been carried out to date.
f Compounds that lacked efficacy in clinical trials with F508del-CFTR homozygous patients (reviewed in [Article:23818513]).



Ivacaftor (VX-770, kalydeco) is a potentiator and is the first FDA-approved therapeutic developed to target a specific CFTR defect. It was originally indicated in CF patients 6 years and older who have at least one G551D variant (rs75527207 genotype AA or GA) [Article:24598717]. The indication section of the FDA-approved ivacaftor drug label was amended in February 2014 to include a further eight CFTR variants (corresponds to a total of ten genetic variants listed in Table 2). All variants show defects in gating in vitro, as measured by decreased open channel probability and chloride transport, compared to wild-type CFTR [Article:22293084]. Evidence for the efficacy of ivacaftor for each variant is also provided in the table. See individual variant VIP summaries on variant pages for more detailed information.

Table 2: CFTR variants included in the indication for ivacaftor a

Legacy name b rsID b cDNA reference b,c Protein reference b,d Exon b CF causing? e Allele frequency e Published evidence
1. G551D rs75527207 1652G>A Gly551Asp 12 Yes 0.0202 In vitro and clinical data [Articles:22293084, 19846789, 22942289, 23590265, 23757361, 23891399, 21083385, 22047557, 23313410, 24066763, 23757359]
2. S549N rs121908755 1646G>A Ser549Asn 12 Yes 0.0013 In vitro studies [Articles:22293084, 23027855], and a case study of a 12 year old girl with this variant who showed improved lung function after ivacaftor treatment [Article:24081349].
3. G1244E rs267606723 3731G>A Gly1244Glu 23Yes 0.0007 In vitro study with CFTR variant-expressing Fisher Rat Thyroid cells showing significantly enhanced channel open probability [Article:22293084].
4. G1349D rs193922525 4046G>A Gly1349Asp25 NA NA [Article:22293084]
5. G178R rs80282562 532G>A Gly178Arg 5 Yes0.0007 [Article:22293084]
6. G551S rs121909013 1651G>A Gly551Ser 12 NA NA [Article:22293084]
7. S1251N rs74503330 3752G>A Ser1251Asn 23 Yes 0.0012 [Article:22293084]
8. S1255P rs121909041 3763T>C Ser1255Pro 23 NANA [Article:22293084]
9. and 10. S549R rs121908757 and rs121909005 1645A>C and 1647T>G Ser549Arg12 Yes 0.0007 [Article:22293084]
Table 2 legend:
a according to the FDA-approved drug label for ivacaftor, amended 21st Feb 2014.
b information from CFTR mutation database.
c cDNA sequence: NM_000492.3.
d Protein sequence: NP_000483.3.
e As reported in [Article:23974870]. Allele frequency in CFTR2 = alleles/70,777. NA indicates that it was not included in supplemental table S2 for this article.

Conclusions

Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by variants in the CFTR gene, with considerable treatment burden and morbidity. Strategies to modify defects in CFTR are being developed in a potential new wave of CF therapies. The first to be approved by the FDA, a potentiator named ivacaftor, targets CFTR protein variants defective in gating and is indicated in patients who carry certain underlying CFTR genetic variants. Correctors and combinations of modulators are currently in clinical trials in patients with the commonly found F508del-CFTR variant. Future hopes are a panel of therapies that can be tailored for a patient's underlying genetic variants for a more effective treatment strategy to minimize symptoms and extend longevity.

Citation
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
History

Submitted by Ellen M. McDonagh, John P. Clancy, Russ B. Altman, Teri E. Klein.

Key Publications
  1. Understanding how cystic fibrosis mutations disrupt CFTR function: From single molecules to animal models. The international journal of biochemistry & cell biology. 2014. Wang Yiting, Wrennall Joe A, Cai Zhiwei, Li Hongyu, Sheppard David N. PubMed
  2. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. Clinical pharmacology and therapeutics. 2014. Clancy John P, Johnson Samuel G, Yee Sook Wah, McDonagh Ellen M, Caudle Kelly E, Klein Teri E, Cannavo Matthew, Giacomini Kathleen M. PubMed
  3. Ivacaftor treatment of cystic fibrosis patients with the G551D mutation: a review of the evidence. Therapeutic advances in respiratory disease. 2013. Kotha Kavitha, Clancy John P. PubMed
  4. Personalized medicine in cystic fibrosis: dawning of a new era. American journal of respiratory and critical care medicine. 2012. Clancy John P, Jain Manu. PubMed
  5. Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clinical biochemistry. 2012. Lubamba Bob, Dhooghe Barbara, Noel Sabrina, Leal Teresinha. PubMed
Variant Summaries rs113993960, rs121908755, rs121908757, rs121909005, rs121909013, rs121909041, rs193922525, rs267606723, rs74503330, rs75527207, rs80282562
Drugs
Drug (1)
Diseases

Haplotype Overview

These haplotypes represent a collection of variants within the CFTR gene for which Clinical PGx information is available. The variants are represented by their "Legacy" name - cDNA and protein mapping information can be found in the downloadable table.

More than 1800 variants in the CFTR gene have been reported - see the CF mutation database for more information regarding CFTR variants.

Source: PharmGKB

All alleles in the download file are on the positive chromosomal strand. PharmGKB considers the first haplotype listed in each table as the reference haplotype for that set.

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

PharmGKB contains no curated pathways for this gene. If you would like to volunteer to work on a pathway, please let us know.

External Pathways

Links to non-PharmGKB pathways.

  1. cystic fibrosis transmembrane conductance regulator (cftr) and beta 2 adrenergic receptor (b2ar) pathway - (BioCarta via Pathway Interaction Database)
  2. Transmembrane transport of small molecules - (Reactome via Pathway Interaction Database)
No related genes are available

Curated Information ?

Curated Information ?

Evidence Disease
Cystic Fibrosis

Publications related to CFTR: 45

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells. American journal of physiology. Lung cellular and molecular physiology. 2014. Favia Maria, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2014. Sheikh Shahid I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. The Lancet. Respiratory medicine. 2014. Boyle Michael P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis: Toward personalized therapies. The international journal of biochemistry & cell biology. 2014. Ikpa Pauline T, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls. Pharmacology & therapeutics. 2014. Bell Scott C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Gene therapy in cystic fibrosis. Archives of disease in childhood. 2014. Armstrong David K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Understanding how cystic fibrosis mutations disrupt CFTR function: From single molecules to animal models. The international journal of biochemistry & cell biology. 2014. Wang Yiting, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype. Clinical pharmacology and therapeutics. 2014. Clancy John P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A little CFTR goes a long way: CFTR-dependent sweat secretion from G551D and R117H-5T cystic fibrosis subjects taking ivacaftor. PloS one. 2014. Char Jessica E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Rescue of functional CFTR channels in cystic fibrosis: a dramatic multivalent effect using iminosugar cluster-based correctors. Chembiochem : a European journal of chemical biology. 2013. Compain Philippe, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013. McGarry Meghan E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Discovery of novel potent deltaF508-CFTR correctors that target the nucleotide binding domain. EMBO molecular medicine. 2013. Odolczyk Norbert, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nature genetics. 2013. Sosnay Patrick R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Ivacaftor treatment of cystic fibrosis patients with the G551D mutation: a review of the evidence. Therapeutic advances in respiratory disease. 2013. Kotha Kavitha, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor in a G551D homozygote with cystic fibrosis. The New England journal of medicine. 2013. Harrison Michael J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harbor perspectives in medicine. 2013. Rowe Steven M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Van Goor Fredrick, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of VX-770 (Ivacaftor) and OAG on Ca(2+) influx and CFTR activity in G551D and F508del-CFTR expressing cells. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Vachel Laura, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of ivacaftor on severely ill patients with cystic fibrosis carrying a G551D mutation. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Hebestreit Helge, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation. American journal of respiratory and critical care medicine. 2013. Davies Jane C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The expression profile of ATP-binding cassette transporter genes in breast carcinoma. Pharmacogenomics. 2013. Hlaváč Viktor, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest. 2013. Durmowicz Anthony G, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis therapeutics: the road ahead. Chest. 2013. Hoffman Lucas R, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The use of ivacaftor in an adult with severe lung disease due to cystic fibrosis (deltaF508/G551D). Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2013. Polenakovik Hari M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A young Hispanic with c.1646G>A mutation exhibits severe cystic fibrosis lung disease: is ivacaftor an option for therapy?. American journal of respiratory and critical care medicine. 2012. Yarlagadda Sunitha, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Personalized medicine in cystic fibrosis: dawning of a new era. American journal of respiratory and critical care medicine. 2012. Clancy John P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clinical biochemistry. 2012. Lubamba Bob, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. The Journal of biological chemistry. 2012. Eckford Paul D W, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012. Flume Patrick A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Ivacaftor potentiation of multiple CFTR channels with gating mutations. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2012. Yu Haihui, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2012. Clancy J P, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PloS one. 2012. Sloane Peter A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. The Annals of pharmacotherapy. 2012. Pettit Rebecca S. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proceedings of the National Academy of Sciences of the United States of America. 2011. Van Goor Fredrick, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. The New England journal of medicine. 2011. Ramsey Bonnie W, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators. American journal of physiology. Lung cellular and molecular physiology. 2011. Pyle Louise C, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. The Journal of biological chemistry. 2011. Yu Wilson, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. The New England journal of medicine. 2010. Accurso Frank J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The CFTR Met 470 allele is associated with lower birth rates in fertile men from a population isolate. PLoS genetics. 2010. Kosova Gülüm, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proceedings of the National Academy of Sciences of the United States of America. 2009. Van Goor Fredrick, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic variation in the proximal promoter of ABC and SLC superfamilies: liver and kidney specific expression and promoter activity predict variation. PloS one. 2009. Hesselson Stephanie E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science (New York, N.Y.). 2008. Rogers Christopher S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genetics in medicine : official journal of the American College of Medical Genetics. 2004. Watson Michael S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics of the cystic fibrosis transmembrane conductance regulator (CFTR) and the cystic fibrosis drug CPX using genome microarray analysis. Molecular medicine (Cambridge, Mass.). 1999. Srivastava M, et al. PubMed

LinkOuts

UniProtKB:
CFTR_HUMAN (P13569)
Ensembl:
ENSG00000001626
GenAtlas:
CFTR
GeneCard:
CFTR
MutDB:
CFTR
ALFRED:
LO000194O
HuGE:
CFTR
Comparative Toxicogenomics Database:
1080
ModBase:
P13569
HumanCyc Gene:
HS00075
HGNC:
1884

Common Searches