rs113993960 in CFTR

Clinical Annotations

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.

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.

Variant Overview

VIP Variant in CFTR

F508del-CFTR

Variant mapping information: c.1521_1523delCTT and c. 1520_1522delTCT (NM_000492.3), Phe508del (NP_000483.3), rs113993960 and rs199826652, respectively. Also referred to as delta-F508, F508del.

This variant was originally identified in 1989 after comparison of cDNA sequences from patients with CF and unaffected individuals [Article:2475911]. It currently has two dbSNP reference sequence IDs (rsIDs) that represent the same variant, likely due to differences in how the DNA sequence can be read:

• rs113993960 refers to a CTT deletion at cDNA position c.1521_1523delCTT (NM_000492.3). This is the cDNA sequence referred to by the Cystic Fibrosis Mutation Database and is flagged by ClinVar] as having a pathogenic allele.

• rs199826652 refers to a TCT deletion (cDNA sequence 1520_1522) and is more likely to be called in sequencing analysis due to the left justification of indels - a minor allele count of 0.006 is provided from 1000 genomes.

Whichever way the DNA sequence is read, the 3 basepair deletion ultimately results in a loss of a phenylalanine amino acid at position 508 in the Nuclear Binding Domain (NBD) of the protein [Article:2475911]. It is a class II variant: F508del-CFTR gets trapped in the endoplasmic reticulum where it is prematurely degraded and largely fails to traffic to the plasma membrane (Table 1) [Articles:7511616, 23895508, 22698459]. It is associated with causing CF (in homozygotes or when in combination with another disease-causing allele) and is also associated with pancreatic insufficiency (CFTR2 database). In most populations, this is the most frequent CF-causing CFTR variant, although allele frequencies vary in different population groups of CF patients, from 100% in an isolated Danish population to around 20% in Turkey (WHO report, 2004). In Ashkenazis from Israel the W1282X-CFTR (c.3846G>A, rs77010898) variant is more common than F508del-CFTR (WHO report, 2004). Global frequencies are estimated at 0.66 in Caucasian, 0.48 in Mediterranean, 0.44 in Mexican, 0.42 in African, 0.39 in South American, and 0.21 in Middle Eastern CF patients (see CPIC CFTR-ivacaftor guideline supplement for individual references [Article:24598717]).

Pharmacogenetics

Numerous different correctors targeting F508del-CFTR defective function are being identified, developed and investigated (Table 1) [Articles:24392786, 22698459, 19502384, 24038832, 23982976]. Lumacaftor (VX-809) is an investigational drug currently undergoing clinical trials that acts as a corrector (Clinical trials NCT01897233, NCT01807923, and NCT01807949). In vitro it is thought to improve F508del-CFTR maturation and chloride transport by suppressing folding defect and increasing exit from the ER, though F508del-CFTR remains thermodynamically unstable [Articles:21976485, 23104983, 23924900]. Human bronchial epithelial cells from F508del-CFTR homozygous patients treated with lumacaftor were reported to have enhanced CFTR maturation and chloride secretion in vitro [Article:21976485]. In a clinical trial to assess safety in CF patients homozygous for F508del-CFTR, sweat chloride levels were significantly decreased in patients given 100mg/day or 200mg/day lumacaftor over 28 days compared to placebo-treated patients. No improvements in other clinical parameters were observed, however the study was not powered to determine differences in these measurements [Article:21825083]. Clinical trials of other correctors have also failed to show clinical efficacy in CF patients homozygous for F508del-CFTR (see Table 1 footnote) [Article:23818513]. Due to the complex nature of the F508del-CFTR defect, it is likely that combinations of correctors, and/or correctors in combination with a potentiator will be necessary to achieve clinical efficacy in these patients [Articles:23818513, 24737137]. Compounds with dual corrector and potentiator activities have been reported in vitro and may have therapeutic potential [Articles:21730204, 24561283].

Currently, ivacaftor monotherapy is not recommended in CF patients homozygous for the F508del-CFTR variant (rs113993960 or rs199826652 genotype del/del) [Article:24598717], CPIC guidline. This may be due to ivacaftor¿s mechanism of action as a potentiator (Table 1). Since F508del-CFTR is a class II variant that results in minimal cell surface protein expression, ivacaftor would likely be ineffective in these patients. Indeed, a study examining the safety of ivacaftor in CF patients homozygous for the F508del-CFTR variant saw no differences in efficacy compared to placebo; however, was not powered to examine efficacy [Article:22383668]. In vitro studies suggest that if expression to the cell surface is restored (by temperature treatment, a correcting mutation or a cell-free system), ivacaftor can potentiate F508del-CFTR activity [Articles:19846789, 21602569, 22942289, 23788656, 22293084, 23891399, 24796242]. Therefore, the hypothesis is that combination therapy with a potentiator such as ivacaftor and a corrector may be effective in these patients. Results from a double-blind, placebo-controlled phase 2 study in patients either homozygous or heterozygous for F508del-CFTR were recently published (NCT01225211) [Article:24973281]; results for the clinical efficacy of the combination compared to placebo were less than the effect of ivacaftor monotherapy that has been demonstrated in patients with G551D-CFTR. The one treatment arm that showed significant differences in absolute change in percent predicted FEV1 compared to placebo at treatment completion, was the group of patients homozygous for F508del-CFTR treated with a monotherapy of 600mg lumacaftor once per day for 28 days, followed by combination with 250mg ivacaftor twice a day for an additional 28 days. In this treatment group, the occurrence of dyspnoea and chest tightness during both monotherapy and combination therapy periods, compared to no occurrences in the placebo group, is of concern (at least one patient in each treatment arm withdrew due to an adverse event starting on day 1 of lumacaftor monotherapy). In this cohort, the placebo group was a mix of F508del-CFTR homozygotes and heterozygotes. This is therefore not reflective of the wholly homozygous or heterozygous patient treatment arms within this cohort that were compared against this mixed placebo group. Comparing treatment efficacy in patients with varying genotypes can introduce confounders that could influence study outcomes. Another issue was the lack of correlation between FEV1 responses and sweat chloride responses observed, limiting the use of sweat chloride to predict F508del-CFTR restoration.

Other registered clinical trials in F508del homozygous patients investigating a combinational treatment of ivacaftor with lumacaftor are currently ongoing (Clinical trials NCT01897233, NCT01807923, and NCT01807949). Results at 24 weeks of the TRAFFIC and TRANSPORT Phase 3 studies were recently announced by press release, though to our knowledge are not yet published in peer-reviewed literature.

Chronic treatment of primary epithelial cells homozygous for F508del-CFTR or F508del-CFTR-expressing cell lines with ivacaftor or several other potentiators has recently been reported to reduce stability and increase turnover of lumacaftor-corrected F508del-CFTR, and thus may have implications for long-term treatment [Articles:24561283, 25101886, 25101887].

Table 1: CFTR variants and potential treatment strategy ^a

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) ^vi, 4-phenylbutyrate ^vi, miglustat, sildenafil, vardenafil, taladafil, suberoylanilide hydroxamic acid, VRT-325, CF-106951, VX-661, KM11060, Corr 2a, 3a, 4a, 4b, benzoquinolizinium, curcumin ^vi, 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]).

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.
Reviewed	11/12/2014
Key Publications:
Drugs / Other Molecules	Drug (2) ivacaftor lumacaftor

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