PharmGKB clinical annotations provide information about variant-drug pairs based on a summary of the individual variant annotations in the database. Therefore, each clinical annotation could represent information from a single paper or multiple papers. The rating system used to assign "Strength of Evidence" levels is described here. The individual variant annotations, including the PMID for each supporting PubMed publication, can be found on the "PGx Research" tab above.
This information is manually curated by PharmGKB. All alleles are displayed on the positive chromosomal strand.
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PharmGKB variant annotations provide information about variant-drug pairs or variant-disease pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
List of all variant annotations for this variant.
There are 17 annotations for this variant. Register or sign in to see them.
| PharmGKB Accession ID: | PA166157516 |
| Type: | SNP |
| Class: | Missense |
| Clinical Significance: | Not reported |
| Genes: | CFTR |
Variant mapping information: c. 1652G>A (NM_000492.3), Gly551Asp (NP_000483.3), rs75527207.
This variant is a single nucleotide polymorphism (SNP) at position c.1652G>A that causes a Gly to Asp change at amino acid position 551. The resulting G551D-CFTR protein belongs to the class III group of CFTR variants: it is expressed at the plasma membrane but is defective in ATP hydrolysis and channel gating [Articles:22698459, 8910473]. In homozygotes, or when in combination with another nonfunctional disease-causing allele, it is associated with causing cystic fibrosis (CF) characterized by a pancreatic insufficiency phenotype (CFTR2 database). It is one of the variants in a recommended panel for newborn screening of CF by the American College of Medical Genetics [Article:15371902]. Global allele frequencies are calculated at 0.02 in Caucasian, 0.025 in African, 0.004 in Mexican, 0.003 in South American, 0.002 in Mediterranean and 0.001 in Middle Eastern CF patients (see CPIC CFTR-ivacaftor guideline supplement for individual references [Article:24598717]).
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]. Ivacaftor targets the gating defect of CFTR-G551D to enhance activity; in vitro studies show it enhances open channel probability and increases chloride transport of G551D-CFTR expressing cells [Articles:22293084, 19846789, 22942289, 23590265, 23757361, 23891399]. It has also been shown to enhance cilia beating and decrease sodium absorption in bronchial epithelial cells from a patient with the G551D/F508del genotype [Article:19846789]. It may also have anti-bacterial properties [Article:24618508]. In vivo, clinical trials or case reports of CF patients with at least one copy of the G551D variant demonstrate improved lung function with ivacaftor treatment [Articles:21083385, 22047557, 23590265, 23313410, 24066763, 24927234]. The response in patients with severe CF with at least one copy of the G551D variant seems variable, and a case report suggests that the drug may be more effective in patients homozygous for G551D-CFTR [Articles:23757359, 23313410, 24066763, 24522694]. As ivacaftor is such a new therapeutic, it is not currently possible to assess its long-term efficacy or harm-benefit balance, discussed further in [Article:24298579], though a recent study provides results up to 144 weeks of treatment [Article:25311995].
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 the Table below). 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]. The FDA-approved drug label refers to a clinical trial carried out in 39 patients who had at least one of these variants. Clinical trials of ivacaftor in patients with one of a number of non- G551D CFTR gating variants are currently underway or have been completed (NCT01705145, NCT01946412, and results from the phase 3 KONNECTION study were recently announced in press releases and at the 37th European CF Society conference (June 2014). However to our knowledge no published peer-reviewed clinical data regarding these trials are available to date.
Ivacaftor alone or in combination with other drugs may also be effective in patients with CFTR variants other than the gating defects listed in the Table below, as has been shown in vitro [Article:23891399]. A clinical trial in patients with the R117H (c.350G>A, rs78655421) variant has been completed (KONDUCT study), results from this trial and a rollover study of patients who completed this trial have been announced in press releases and at the 37th European CF Society conference (June 2014) but to our knowledge are not currently published in peer-reviewed literature. According to press releases, Vertex plans to submit a supplemental New Drug Application in the US and a marketing authorization application variation in Europe for patients 18 years and older who have the R117H variant.
| 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 | 23 | Yes | 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 | Gly1349Asp | 25 | NA | NA | [Article:22293084] |
| 5. | G178R | rs80282562 | 532G>A | Gly178Arg | 5 | Yes | 0.0007 | [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 | NA | NA | [Article:22293084] |
| 9. and 10. | S549R | rs121908757 and rs121909005 | 1645A>C and 1647T>G | Ser549Arg | 12 | Yes | 0.0007 | [Article:22293084] |
Table 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.
| Citation |
PharmGKB summary: very important pharmacogene information for CFTR. Pharmacogenetics and genomics. 2014. McDonagh Ellen M, Clancy John P, Altman Russ B, Klein Teri E.
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| Reviewed | 11/12/2014 |
| Key Publications: |
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| Drugs / Other Molecules |
Drug (1)
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| Evidence | Drug |
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| Evidence | Disease |
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