ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1521_1523delCTT (p.Phe508delPhe) (rs113993960)

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Total submissions: 39
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007523 SCV000071392 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007523 SCV000071493 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211188 SCV000268159 drug response ivacaftor response - Efficacy 2018-03-27 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000417138 SCV000494683 drug response ivacaftor / lumacaftor response - Efficacy 2018-03-28 reviewed by expert panel curation PharmGKB Level of Evidence 1B: Annotation for a variant-drug combination where the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant p-values, and preferably will have a strong effect size.
Invitae RCV000007523 SCV000074347 pathogenic Cystic fibrosis 2020-01-13 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 11 of the CFTR mRNA (c.1521_1523delCTT). This leads to the deletion of one amino acid residue in the CFTR protein (p.Phe508del) but otherwise preserves the integrity of the reading frame. This single amino acid deletion (also known as F508) disrupts protein function and is the most common cause of cystic fibrosis (PMID: 2475911, 15371902, 23974870). For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000007523 SCV000221179 pathogenic Cystic fibrosis 2020-04-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000058929 SCV000329246 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing The c.1521_1523delCTT pathogenic variant in the CFTR gene (also known as p.Phe508del or delta F508) is the most common variant identified in the CFTR gene, with up to 90% of individuals with cystic fibrosis (CF) having at least one copy of the c.1521_1523delCTT variant (Cai et al., 2011). The c.1521_1523delCTT variant results in an in-frame deletion of a single Phenylalanine residue at codon 508. Individuals who are homozygous for the c.1521_1523delCTT variant demonstrate the classic features of CF, whereas individuals compound heterozygous for the c.1521_1523delCTT variant and another CFTR variant may have a modified disease phenotype (Ong et al., 2017). Heterozygous carriers of the c.1521_1523delCTT variant are usually asymptomatic, however, may be at increased risk for developing a CFTR-related disorder, as an increased prevalence of single CFTR pathogenic variants has been observed among individuals with chronic pulmonary conditions, CAVD and pancreatitis (Cuppens et al., 2004; Bombieri et al., 2011). We interpret the c.1521_1523delCTT variant as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000058929 SCV000330918 pathogenic not provided 2017-01-03 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000058929 SCV000511517 pathogenic not provided 2016-10-28 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000007523 SCV000538017 pathogenic Cystic fibrosis 2016-03-30 criteria provided, single submitter clinical testing The c.1521_1523delCTT (p.Phe508del), also known as ΔF508, is an in-frame deletion in the CFTR gene. This variant is the most common CF-causing mutation, accounting for an estimated 72% of mutant alleles in people of European ancestry (Watson et al., 2004). This p.Phe508del variant is classified as a class II mutation that blocks the processing of the CFTR protein (Welsh et al., 2001). This variant has been reported at low frequencies (1.0%) in 1000 Genomes and ExAc population databases, but has not been reported in the Exome Sequencing Project database (ESP). The CFTR2 database has 32,833 patients that have this mutation, which they classify as CF-causing (http://www.cftr2.org/mutation.php?view=general&mutation_id=1). Therefore, this collective evidence supports the classification of the c.1521_1523delCTT (p.Phe508del) as a recessive pathogenic variant for Cystic fibrosis.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007523 SCV000584079 pathogenic Cystic fibrosis 2013-10-21 criteria provided, single submitter research
Genetic Services Laboratory, University of Chicago RCV000007523 SCV000594089 pathogenic Cystic fibrosis 2016-08-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000022 SCV000602968 pathogenic not specified 2018-07-02 criteria provided, single submitter clinical testing The CFTR p.Phe508del (F508del) variant is the most common pathogenic CFTR variant that has been reported in Caucasians (Sosnay 2013, CFTR2 database). This variant is considered to cause severe cystic fibrosis when identified with another severe pathogenic variant on the opposite chromosome. REFERENCES CFTR2 database: http://cftr2.org/ Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-7.
Ambry Genetics RCV000624683 SCV000741228 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626692 SCV000747395 likely pathogenic Duodenal stenosis 2017-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626693 SCV000747396 pathogenic Recurrent pancreatitis 2017-01-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000007523 SCV000864219 pathogenic Cystic fibrosis 2019-01-15 criteria provided, single submitter clinical testing
Mendelics RCV000007523 SCV000886152 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000058929 SCV000889288 pathogenic not provided 2016-02-05 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000007523 SCV000891676 pathogenic Cystic fibrosis 2017-12-30 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000058929 SCV000928113 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000007523 SCV001149705 pathogenic Cystic fibrosis 2020-01-17 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000007523 SCV001161676 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing A homozygous 3 base pair deletion in exon 11 of the CFTR gene that results in the in-frame deletion of Phenylalanine was detected. The observed variant c.1521_1523del (p.Phe508del) has a minor allele frequency of 0.4% and 0.68% in the 1000 Genomes and ExAC databases respectively. The observed variation has previously been identified in patients affected with cystic fibrosis and it lies in the ABC transporter domain of the CFTR protein (Riordan et al 1989). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Baylor Genetics RCV001004459 SCV001163504 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007523 SCV001169465 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Women's Health, Inc. RCV000007523 SCV001193905 pathogenic Cystic fibrosis 2019-10-18 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 15371902. Classification of NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000007523 SCV001244997 pathogenic Cystic fibrosis 2018-09-03 criteria provided, single submitter clinical testing A heterozygous inframe deletion variant, NM_000492.3(CFTR):c.1521_1523del, has been identified in exon 11 of 27 in the CFTR gene. The variant is predicted to result in an inframe deletion of a single amino acid at position 508 of the protein, NP_000483.3(CFTR):p.(Phe508del). The phenylalanine at this position has very high conservation (UCSC, 100 vertebrates), and is located in the ABC transporter 1 functional domain. This variant is present in the gnomAD database at a frequency of 0.7% (2027 heterozygotes, 1 homozygote), and has been previously reported multiple times in individuals with cystic fibrosis, being the most common causative variant in the CFTR gene (ClinVar; Egan, ME. et al. (2016)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000058929 SCV001246813 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000007523 SCV001251533 pathogenic Cystic fibrosis criteria provided, single submitter research The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic CFTR variant (PMID: 20301428, 2233932).
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000058929 SCV001251746 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197556 SCV001368335 pathogenic Hypermelanotic macule; Chronic pancreatitis; Recurrent pancreatitis 2019-10-22 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. This variant was detected in heterozygous state.
Centogene AG - the Rare Disease Company RCV000007523 SCV001424387 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing
OMIM RCV000007523 SCV000027724 pathogenic Cystic fibrosis 2015-05-17 no assertion criteria provided literature only
OMIM RCV000007524 SCV000053487 risk factor Bronchiectasis with or without elevated sweat chloride 1, modifier of 2015-05-17 no assertion criteria provided literature only
SNPedia RCV000058929 SCV000090450 not provided not provided no assertion provided not provided
GeneReviews RCV000119038 SCV000153744 pathogenic Hereditary pancreatitis 2014-03-13 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000007523 SCV000536740 pathogenic Cystic fibrosis 2016-06-10 no assertion criteria provided research
GenomeConnect, ClinGen RCV000007523 SCV000607274 not provided Cystic fibrosis no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000007523 SCV000883108 pathogenic Cystic fibrosis 2019-06-04 no assertion criteria provided clinical testing

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