Menu
GeneBe

rs199826652

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM4_SupportingPP3PP5_Very_Strong

The NM_000492.4(CFTR):c.1521_1523del(p.Phe508del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,612,320 control chromosomes in the GnomAD database, including 58 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★★★).

Frequency

Genomes: 𝑓 0.0079 ( 1 hom., cov: 32)
Exomes 𝑓: 0.012 ( 57 hom. )

Consequence

CFTR
NM_000492.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic practice guideline P:80O:7

Conservation

PhyloP100: 7.54
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000492.4
PM4
Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 7-117559590-ATCT-A is Pathogenic according to our data. Variant chr7-117559590-ATCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 7105.Status of the report is practice_guideline, 4 stars. Variant chr7-117559590-ATCT-A is described in Lovd as [Pathogenic]. Variant chr7-117559590-ATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.1521_1523del p.Phe508del inframe_deletion 11/27 ENST00000003084.11
CFTR-AS1NR_149084.1 linkuse as main transcriptn.221+1140_221+1142del intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.1521_1523del p.Phe508del inframe_deletion 11/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.00789
AC:
1200
AN:
152088
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00261
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00373
Gnomad ASJ
AF:
0.00403
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00311
Gnomad FIN
AF:
0.00151
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0143
Gnomad OTH
AF:
0.00766
GnomAD3 exomes
AF:
0.00707
AC:
1776
AN:
251256
Hom.:
1
AF XY:
0.00693
AC XY:
941
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.00295
Gnomad AMR exome
AF:
0.00367
Gnomad ASJ exome
AF:
0.00556
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00199
Gnomad FIN exome
AF:
0.00222
Gnomad NFE exome
AF:
0.0123
Gnomad OTH exome
AF:
0.00686
GnomAD4 exome
AF:
0.0124
AC:
18037
AN:
1460114
Hom.:
57
AF XY:
0.0121
AC XY:
8794
AN XY:
726470
show subpopulations
Gnomad4 AFR exome
AF:
0.00230
Gnomad4 AMR exome
AF:
0.00396
Gnomad4 ASJ exome
AF:
0.00632
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00247
Gnomad4 FIN exome
AF:
0.00276
Gnomad4 NFE exome
AF:
0.0150
Gnomad4 OTH exome
AF:
0.0101
GnomAD4 genome
AF:
0.00788
AC:
1200
AN:
152206
Hom.:
1
Cov.:
32
AF XY:
0.00722
AC XY:
537
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.00260
Gnomad4 AMR
AF:
0.00373
Gnomad4 ASJ
AF:
0.00403
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00311
Gnomad4 FIN
AF:
0.00151
Gnomad4 NFE
AF:
0.0143
Gnomad4 OTH
AF:
0.00758
Alfa
AF:
0.00312
Hom.:
0
Bravo
AF:
0.00785
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0138
EpiControl
AF:
0.0123

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:80Other:7
Revision: practice guideline
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:41Other:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 17, 2015- -
Pathogenic, criteria provided, single submittercurationInstitute of Human Genetics, University of Leipzig Medical CenterSep 05, 2022This 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 -
Pathogenic, practice guidelinecurationAmerican College of Medical Genetics and Genomics (ACMG)Mar 03, 2004- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 02, 2023- -
Pathogenic, criteria provided, single submitterclinical testing3billionFeb 23, 2023The 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. -
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
Pathogenic, reviewed by expert panelresearchCFTR2Mar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterDec 30, 2021PS3, PP1, PM1, PM3, PM4 -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This 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. -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 02, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 11, 2019- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 03, 2022The 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. -
Pathogenic, criteria provided, single submitterclinical testingDASAFeb 14, 2022Well-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. -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This 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. -
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyOct 21, 2013- -
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaJun 10, 2016- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 30, 2016The 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. -
Pathogenic, criteria provided, single submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsOct 18, 2019A 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. -
Pathogenic, criteria provided, single submitterclinical testingArcensusFeb 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-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. -
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsNov 05, 2018- -
Pathogenic, criteria provided, single submitterclinical testingDepartment Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos UniversityDec 30, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 26, 2016- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Genomics, Sir Ganga Ram HospitalNov 06, 2023This 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. -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-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. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteSep 03, 2018A 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. -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityJan 15, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyFeb 04, 2022This 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. -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneJun 04, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenDec 08, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 06, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenJan 17, 2020- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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. -
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic CFTR variant (PMID: 20301428, 2233932). -
not provided Pathogenic:19Other:1
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 19, 2023The 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. -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalJul 29, 2014- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 03, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 30, 2018The 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. -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
not provided, no classification providedliterature onlySNPedia-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 15, 2023- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 24, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 17, 2020The 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. -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalDec 17, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 28, 2016- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsDec 12, 2018- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting -
Hereditary pancreatitis Pathogenic:4Other:1
Pathogenic, criteria provided, single submittercurationSema4, Sema4May 12, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMar 01, 2023The 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. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 22, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM4. -
Pathogenic, criteria provided, single submitterclinical testingHuman Genetics Bochum, Ruhr University BochumFeb 28, 2023ACMG criteria used to clasify this variant:PS4, PM3_STR, PM4, PS3_SUP, PP1 -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 15, 2024- -
Pathogenic, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del LiliNov 07, 2023- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 15, 2022- -
CFTR-related disorders Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 11, 2019- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Recurrent pancreatitis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
CFTR-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 19, 2024The 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. -
Cystic fibrosis;C0238339:Hereditary pancreatitis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinFeb 01, 2022ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PM3 strong, PM4 moderate, PP3 supporting -
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLifecell International Pvt. Ltd-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. -
Obstructive azoospermia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Reproductive Genetics, University of MünsterAug 23, 2021- -
Duodenal stenosis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMay 03, 2019ACMG classification criteria: PS3, PM2, PM4, PP1, PP4, PP5 -
ivacaftor / lumacaftor response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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. Drug-variant association: Efficacy
ivacaftor / tezacaftor response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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. Drug-variant association: Efficacy
Bronchiectasis with or without elevated sweat chloride 1, modifier of Other:1
risk factor, no assertion criteria providedliterature onlyOMIMMay 17, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs113993960; hg19: chr7-117199644; API