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.
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| PharmGKB Accession ID: | PA166157534 |
| Type: | SNP |
| Class: | Missense |
| Clinical Significance: | Not reported |
| Genes: | CFTR |
Variant mapping information: c. 4046G>A (NM_000492.3), Gly1349Asp (NP_000483.3), rs193922525.
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 the table below), including G1349D-CFTR. View the updated CPIC guidelines for ivacaftor.
All nine 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.
| No. | 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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| Evidence | Drug |
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| Evidence | Disease |
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