ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)

dbSNP: rs113993960
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Total submissions: 87
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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 RCV001787370 SCV002031250 drug response ivacaftor / lumacaftor response - Efficacy 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787371 SCV002031251 drug response ivacaftor / tezacaftor response - Efficacy 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Invitae RCV000007523 SCV000074347 pathogenic Cystic fibrosis 2024-01-31 criteria provided, single submitter clinical testing This variant, c.1521_1523del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Phe508del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199826652, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis and is the most common cause of the condition (PMID: 2475911, 15371902, 23974870). It has also been observed to segregate with disease in related individuals. This variant is also known as ∆F508. ClinVar contains an entry for this variant (Variation ID: 7105). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 2475911, 23974870). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000007523 SCV000221179 pathogenic Cystic fibrosis 2022-11-03 criteria provided, single submitter clinical testing The p.Phe508del variant in CFTR (also known as ΔF508) is a deletion of a single amino acid at position 508 and is well-established as a pathogenic variant for autosomal recessive cystic fibrosis (Kerem 1989 PMID:2570460, Fuller 1992 PMID:1381146, Southern 1997 PMID:9135274, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870). This is the most common pathogenic variant reported in CFTR and has been classified as Pathogenic by the ACMG practice guideline for cystic fibrosis carrier screening and the ClinGen-approved CFTR2 expert panel (ClinVar Variation ID 7105). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3, PM4_Supporting.
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.
Eurofins Ntd Llc (ga) 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
Ambry Genetics RCV000007523 SCV000741228 pathogenic Cystic fibrosis 2023-03-06 criteria provided, single submitter clinical testing The c.1521_1523delCTT (p.F508del) alteration is located in coding exon 11 of the CFTR gene, results from an in-frame CTT deletion at nucleotide positions 1521 to 1523. This results in the deletion of a phenylalanine residue at codon 508. Based on data from gnomAD, the c.1521_1523delCTT allele has an overall frequency of 0.717% (2027/282630) total alleles studied. The highest observed frequency was 1.238% (1598/129034) of European (non-Finnish) alleles. This mutation accounts for approximately 70% of cystic fibrosis chromosomes worldwide and is associated with elevated sweat chloride levels, lung disease, pancreatic insufficiency, and Pseudomonas infection (Sosnay, 2013). Disease expression is variable, even among individuals homozygous for p.F508del (Bronsveld, 2001). In vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay, 2013). It is a class II mutation which results in a misfolded CFTR protein that is subsequently degraded (Esposito, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
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
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000007523 SCV000883108 pathogenic Cystic fibrosis 2019-06-04 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 2020-02-17 criteria provided, single submitter clinical testing The c.1521_1523del (p.Phe508del or Delta F508) pathogenic variant is an in-frame deletion of the phenylalanine amino acid at position p.508 of the CFTR protein. It is the most common cystic fibrosis pathogenic variant that accounts for approximately 70% of alleles in affected patients and causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMID: 23857699 (2013), 23974870 (2013), 25148434 (2014), and 26581802 (2016)). Based on the available information, this variant is classified as pathogenic.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University 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 Munich, Klinikum Rechts Der Isar, TU München 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 Genetics, 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 Center for Human Genetics Tuebingen RCV000058929 SCV001246813 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting
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 RCV000119038 SCV001368335 pathogenic Hereditary 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: PS1,PM1,PM3,PM4.
Centogene AG - the Rare Disease Company RCV000007523 SCV001424387 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000058929 SCV001450105 pathogenic not provided 2014-07-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000007523 SCV001527339 pathogenic Cystic fibrosis 2023-05-02 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000058929 SCV001713417 pathogenic not provided 2023-05-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000007523 SCV001810348 pathogenic Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Institute of Reproductive Genetics, University of Münster RCV001642198 SCV001860325 pathogenic Obstructive azoospermia 2021-08-23 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000058929 SCV002009133 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000058929 SCV002019253 pathogenic not provided 2023-02-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000058929 SCV002048630 pathogenic not provided 2023-10-19 criteria provided, single submitter clinical testing The CFTR c.1521_1523del; 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 cystic fibrosis when identified with another 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. PMID: 23974870.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000007523 SCV002053836 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000007523 SCV002061800 pathogenic Cystic fibrosis 2021-12-30 criteria provided, single submitter clinical testing PS3, PP1, PM1, PM3, PM4
Institute of Human Genetics, University of Leipzig Medical Center RCV000007523 SCV002072562 pathogenic Cystic fibrosis 2022-09-05 criteria provided, single submitter curation This variant was identified in 8 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3, PM3_VSTR, PM4, PP4
DASA RCV000007523 SCV002097285 pathogenic Cystic fibrosis 2022-02-14 criteria provided, single submitter clinical testing Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 30030066; 27738188) - PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7105; PMID: 30089726; 29614238; 29668297; 29944384) - PS4. The p.(Phe508del) was detected in trans with a pathogenic variant (PMID: 30089726; 29614238) - PM3_very strong. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics RCV000058929 SCV002502414 pathogenic not provided 2022-03-30 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV000007523 SCV002503785 pathogenic Cystic fibrosis 2023-03-30 criteria provided, single submitter clinical testing This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein, p.(Phe508del). The region deleted is highly conserved (100 vertebrates, UCSC) in a nonrepeat region, and is located in the ABC transporter domain. The variant is present in a large population cohort at a frequency of 0.7% (rs1297060838, 2,027/282,630 alleles, 1 homozygote in gnomAD v2.1). It is the most commonly reported pathogenic variant in CFTR, and is assigned a practice guideline pathogenic classification (ClinVar ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases (PMID: 8092189, 1379413, 2570460). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM4_Supporting.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000007523 SCV002507372 pathogenic Cystic fibrosis 2019-10-11 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002243627 SCV002512246 pathogenic Cystic fibrosis; Hereditary pancreatitis 2022-02-01 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PM3 strong, PM4 moderate, PP3 supporting
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251888 SCV002523540 pathogenic See cases 2019-05-03 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PM2, PM4, PP1, PP4, PP5
Sema4, Sema4 RCV000119038 SCV002529678 pathogenic Hereditary pancreatitis 2021-05-12 criteria provided, single submitter curation
Suma Genomics RCV001004459 SCV002543782 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Arcensus RCV000007523 SCV002564582 pathogenic Cystic fibrosis 2013-02-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000007523 SCV002579737 pathogenic Cystic fibrosis 2022-08-30 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000007523 SCV002759371 pathogenic Cystic fibrosis 2022-12-08 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000007523 SCV002761398 pathogenic Cystic fibrosis 2022-02-04 criteria provided, single submitter clinical testing This sequence change is an inframe deletion of 3 bp predicted to cause the deletion of phenylalanine at position 508 of the CFTR protein (p.Phe508del). The region deleted is highly conserved (100 vertebrates, UCSC) in a nonrepeat region, and is located in the ABC transporter domain. The variant is present in a large population cohort at a frequency of 0.7% (rs1297060838, 2,027/282,630 alleles, 1 homozygote in gnomAD v2.1). It is the most commonly reported pathongenic variant in CFTR, and is assigned a practice quideline pathogenic classification in ClinVar (ID: 7105). It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases (PMID: 8092189, 1379413, 2570460). Additionally, a Cftr Phe508del/Phe508del mouse model lack CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM4_Supporting.
Fulgent Genetics, Fulgent Genetics RCV002490332 SCV002810876 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2022-03-15 criteria provided, single submitter clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV000058929 SCV002818128 pathogenic not provided 2022-12-17 criteria provided, single submitter clinical testing
3billion RCV000007523 SCV003841941 pathogenic Cystic fibrosis 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.717%). Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000007105 / PMID: 2475911 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Lifecell International Pvt. Ltd RCV003227599 SCV003925476 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing A Heterozygous inframe indel variant c.1520_1522delTCT in Exon 11 of the CFTR gene that results in the amino acid substitution p.Phe508del was identified. The observed variant has a minor allele frequency of 0.00707/0.00800% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic. (Variant ID 7105). This variant has been previously reported for Indian patients with congenital absence of the vas deferens by Sharma H et al., 2014. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Suma Genomics RCV000007523 SCV004037030 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV000119038 SCV004042777 pathogenic Hereditary pancreatitis 2023-02-28 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant:PS4, PM3_STR, PM4, PS3_SUP, PP1
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000007523 SCV004046363 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing This variant has been previously reported as the most common pathogenic variant in the CFTR gene, accounting for an estimated 30%-80% of pathogenic variants in cystic fibrosis (CF) (PMID: 20301428). Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID: 2475911). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.72% (2027/282630) and thus is presumed to be rare. Based on the available evidence, the c.1521_1523del (p.Phe508del) variant is classified as Pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital RCV000007523 SCV004100881 pathogenic Cystic fibrosis 2023-11-06 criteria provided, single submitter clinical testing This is the most common CFTR pathogenic variant. The c.1521_1523delCTT variant results in an in-frame deletion of a single Phenylalanine residue at codon 508.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili RCV002490332 SCV004101389 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2023-11-07 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000007523 SCV004101520 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing The CFTR c.1521_1523del (p.Phe508del) variant has been reported in heterozygous state in individuals affected with Cystic fibrosis (Watson MS et al.). Experimental studies have shown that this variant decreases the affinity of the CFTR protein (Colak Y et al.). This variant has been submitted allele frequency 0.7% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as pathogenic. 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 disrupts protein function and is the most common cause of cystic fibrosis (Riordan JR et al.). For these reasons, this variant has been classified as Pathogenic. The observed variant is also detected in the spouse.
PreventionGenetics, part of Exact Sciences RCV001831519 SCV004105952 pathogenic CFTR-related disorder 2024-01-19 criteria provided, single submitter clinical testing The CFTR c.1521_1523delCTT variant is predicted to result in an in-frame deletion (p.Phe508del). This variant, frequently described as ΔF508, is known to disrupt protein function and is the most common cause of autosomal recessive cystic fibrosis (Riordan et al. 1989. PubMed ID: 2475911; Watson et al. 2004. PubMed ID: 15371902; Sosnay. 2013. PubMed ID: 23974870). This variant is reported in 1.2% of alleles in individuals of European (Non-Finnish) descent. In summary, we classify this variant as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf RCV003444054 SCV004171185 pathogenic Bronchiectasis with or without elevated sweat chloride 1 criteria provided, single submitter not provided
Neuberg Centre For Genomic Medicine, NCGM RCV000119038 SCV004176446 pathogenic Hereditary pancreatitis 2023-03-01 criteria provided, single submitter clinical testing The inframe deletion c.1521_1523del (p.Phe508del) variant in the CFTR gene has been reported previously in multiple individuals in homozygous/compound heterozygous state affected with Cystic fibrosis related disorders (Sosnay et al., 2013; Terlizzi et al., 2021). The p.Phe508del variant is the most frequent deletion that occurs in ~85% of Cystic fibrosis patients worldwide and is described to affect CFTR (class II) protein processing (Awatade et al. 2019). Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995). The p.Phe508del variant is reported with an allele frequency of 0.7% in the gnomAD exomes database and is novel (not in any individuals) in the 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This p.Phe508del causes the deletion of the amino acid Phenylalanine at position 508. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003444054 SCV004211619 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-10-31 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000058929 SCV004242533 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV003444054 SCV004698102 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-02-15 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000007523 SCV004805438 pathogenic Cystic fibrosis 2024-03-25 criteria provided, single submitter research
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 not provided Hereditary pancreatitis no assertion 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 Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/28/2022 by ARUP Laboratories, INC, 06/29/2018 by Genetic Services Laboratory, University of Chicago, and 08/20/2015 by Mayo Clinic Genetic Testing Laboratories. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000058929 SCV001553614 pathogenic not provided no assertion criteria provided clinical testing The CFTR p.F508del variant is the most common variant known to cause cystic fibrosis (CF); this variant acounts for ~70% of CFTR variants and is present in approximately 85% of CF patients worldwide (Maiuri_2015_PMID:26046070). The variant was identified in dbSNP (ID: rs113993960) and ClinVar (classified as pathogenic by the American College of Medical Genetics and Genomics, Laboratory for Molecular Medicine and 20+ other laboratories). The variant was identified in control databases in 2027 of 282630 chromosomes (1 homozygous) at a frequency of 0.007172 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 1598 of 129034 chromosomes (freq: 0.01238), Other in 49 of 7214 chromosomes (freq: 0.006792), Ashkenazi Jewish in 58 of 10368 chromosomes (freq: 0.005594), Latino in 135 of 35426 chromosomes (freq: 0.003811), African in 65 of 24958 chromosomes (freq: 0.002604), European (Finnish) in 61 of 25074 chromosomes (freq: 0.002433) and South Asian in 61 of 30608 chromosomes (freq: 0.001993), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a phenylalanine (F) residue at codon 508; the deletion of p.F508 results in a misfolded mutant protein that is prematurely degraded before it reaches the plasma membrane (Maiuri_2015_PMID:26046070). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
GeneReviews RCV000007523 SCV001622798 not provided Cystic fibrosis no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000058929 SCV001744105 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000058929 SCV001929598 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000058929 SCV002035293 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001831519 SCV002080609 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001831519 SCV002507456 pathogenic CFTR-related disorder 2019-10-11 no assertion criteria provided clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University RCV000007523 SCV004024086 pathogenic Cystic fibrosis no assertion criteria provided research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000007523 SCV004101106 pathogenic Cystic fibrosis 2023-11-02 no assertion criteria provided clinical testing

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