rs199826652
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2_SupportingPM4_SupportingPP3PP5_Very_Strong
The NM_000492(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 0.00789 in 152088 control chromosomes in the gnomAD Genomes database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★★★).
Frequency
Genomes: 𝑓 0.0079 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0071 ( 1 hom. )
Consequence
CFTR
NM_000492 inframe_deletion
NM_000492 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.54
Links
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 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
PM2
?
Too low homozygotes in high coverage region: FrequencyAnnotationDto(name=gnomad, af=0.00789017, ac=1200, an=152088, hom=1, dpMedian=32, dpMean=null, pass=true, afMale=0.00722823, acMale=537, anMale=74292, popmax=nfe, popmaxAf=0.0143021, popmaxAn=67962, popmaxAc=972, popmaxAf95=0.0135558).
PM4
?
Nonframeshift variant in NON repetitive region in NM_000492. 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 |
|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1521_1523del | p.Phe508del | inframe_deletion | 11/27 | ENST00000003084.11 | |
| CFTR-AS1 | NR_149084.1 | n.221+1140_221+1142del | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.1521_1523del | p.Phe508del | inframe_deletion | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00789 AC: 1200AN: 152088Hom.: 1 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:69Other:7
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:36Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Klinikum rechts der Isar | Jan 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | UNC 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). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 17, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 04, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 30, 2016 | 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. - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 21, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 26, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 30, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jan 15, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 30, 2021 | PS3, PP1, PM1, PM3, PM4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 11, 2019 | - - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jun 10, 2016 | - - |
| Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady 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. - |
| not provided, no assertion provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2022 | 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. - |
| Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Apr 22, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Oct 18, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 04, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| not provided, no assertion provided | phenotyping only | GenomeConnect, 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 submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 03, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 08, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided Pathogenic:18Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Karolinska University Hospital, Karolinska University Hospital | Jul 29, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | PerkinElmer Genomics | Feb 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2022 | - - |
| not provided, no assertion provided | literature only | SNPedia | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 17, 2020 | The variant was found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant is damaging to protein function(s) relevant to disease mechanism. to protein function(s) relevant to disease mechanism. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | Criteria applied: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 12, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department 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 submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 15, 2022 | The CFTR c.1521_1523delCTT; 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 submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 30, 2022 | - - |
Hereditary pancreatitis Pathogenic:3Other:1
| not provided, no assertion provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | May 12, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Feb 28, 2023 | ACMG criteria used to clasify this variant:PS4, PM3_STR, PM4, PS3_SUP, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 22, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM4. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
CFTR-related disorders Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 11, 2019 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | 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. - |
Recurrent pancreatitis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 01, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM3 very strong, PM3 strong, PM4 moderate, PP3 supporting - |
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:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell 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 submitter | clinical testing | Institute of Reproductive Genetics, University of Münster | Aug 23, 2021 | - - |
Duodenal stenosis Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 03, 2019 | ACMG classification criteria: PS3, PM2, PM4, PP1, PP4, PP5 - |
ivacaftor / lumacaftor response - Efficacy Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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. Drug-variant association: Efficacy |
ivacaftor / tezacaftor response - Efficacy Other:1
| drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | 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. Drug-variant association: Efficacy |
Bronchiectasis with or without elevated sweat chloride 1, modifier of Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | May 17, 2015 | - - |
Computational scores
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