NM_000492.4:c.1521_1523delCTT
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PM4_SupportingPP5_Very_StrongBS1_Supporting
The NM_000492.4(CFTR):c.1521_1523delCTT(p.Phe508del) variant causes a disruptive 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
Consequence
NM_000492.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1521_1523delCTT | p.Phe508del | disruptive_inframe_deletion | Exon 11 of 27 | ENST00000003084.11 | NP_000483.3 | |
| CFTR-AS1 | NR_149084.1 | n.221+1140_221+1142delAGA | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes 0.00789 AC: 1200AN: 152088Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00707 AC: 1776AN: 251256Hom.: 1 AF XY: 0.00693 AC XY: 941AN XY: 135800
GnomAD4 exome AF: 0.0124 AC: 18037AN: 1460114Hom.: 57 AF XY: 0.0121 AC XY: 8794AN XY: 726470
GnomAD4 genome 0.00788 AC: 1200AN: 152206Hom.: 1 Cov.: 32 AF XY: 0.00722 AC XY: 537AN XY: 74420
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:44Other:2
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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. -
This variant, c.1521_1523delCTT, results in the deletion of 1 amino acid 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 gene product 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. -
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. -
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Criteria applied: PM3_VSTR,PS3,PM4; Identified as compund heterozygous with NM_000492.4:c.350G>A -
The observed 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. Experimental studies have shown that this variant affects CFTR function 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. 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. -
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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. -
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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. -
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. -
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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. -
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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, Multiz Alignments) in a nonrepeat region, and is located in the ABC transporter domain. The highest population minor allele frequency in the population database gnomAD v4.1 is 1.5% (17,610/1,178,514 alleles, 49 homozygotes) in the European (non-Finnish) population. 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 and segregates with disease in multiple families (PMID: 8092189, 1379413, 2570460, 25910067). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, was chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099). Based on the classification scheme RMH ACMG Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Moderate, PM4_Supporting, BS1. -
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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. -
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. -
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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. -
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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. -
The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic CFTR variant (PMID: 20301428, 2233932). -
PVS1, PM3_VeryStrong, PS3, PP4 -
The p.F508del pathogenic mutation (also known as deltaF508 and c.1521_1523delCTT) is located in coding exon 11 of the CFTR gene. This pathogenic mutation results from an in-frame CTT deletion at nucleotide positions 1521 to 1523. This results in the in-frame deletion of a phenylalanine at codon 508. This mutation is associated with elevated sweat chloride levels, lung disease, pancreatic insufficiency, and Pseudomonas infection; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Disease expression is variable, even among individuals homozygous for p.F508del (Bronsveld I et al. J. Clin. Invest., 2001 Dec;108:1705-15). This mutation accounts for approximately 70% of cystic fibrosis chromosomes worldwide; it is a class II mutation which results in a misfolded CFTR protein that is subsequently degraded (Esposito S et al. Mol Cell Pediatr, 2016 Dec;3:13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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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. -
This sequence variant is an in-frame deletion of 3 nucleotides spanning positions 1521 through 1523 of the coding sequence of the CFTR gene that removes Phe508 of the CF transmembrane conductance regulator protein. This is a previously reported (ClinVar 7105), well characterized variant (PMID: 15371902) that is the most common cystic fibrosis-associated variant in the general population (PMID: 23974870). The variant is also known as deltaF508 and similar identifiers in the literature and public databases. This variant is present in 2976 of 403344 alleles (0.7378%) in the gnomAD population dataset. Experimental evidence shows that function of the variant protein is significantly inhibited (PMID: 2475911). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM4, PS3, PS4 -
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not provided Pathogenic:18Other:1
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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. -
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. -
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The CFTR c.1521_1523del (p.Phe508del) variant (also known as F508del and Delta F508) is the most common cystic fibrosis (CF) pathogenic variant that accounts for approximately 70% of alleles in affected patients (PMIDs: 23974870 (2013), 23857699 (2013), 8886242 (1996), 38003474 (2023)). It causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMIDs: 23974870 (2013), 25148434 (2014), 26581802 (2016)). This variant, being so common in European CF cohorts, has a general population frequency of 0.016 (807/50740 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)). Based on the available information, this variant is classified as pathogenic. -
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CFTR: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting -
Hereditary pancreatitis Pathogenic:4Other:1
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM3,PM4. -
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. -
ACMG criteria used to clasify this variant:PS4, PM3_STR, PM4, PS3_SUP, PP1 -
CFTR-related disorder Pathogenic:4
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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 et al. 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. -
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This variant is also known as DeltaF508 and has been previously reported as the most common pathogenic variant in the CFTR gene (PMID: 35650428, 36498475). Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID: 2475911, 17873061). It is present in the gnomAD population database at a frequency of 0.72% (2027/282630) in the heterozygous state and a frequency of 0.0004% (1/282630) in the homozygous state. Based on the available evidence, the c.1521_1523del (p.Phe508del) variant is classified as Pathogenic. -
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:3
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Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2
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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
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Recurrent pancreatitis Pathogenic:1
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Cystic fibrosis;C0238339:Hereditary pancreatitis Pathogenic:1
ACMG 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
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
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Duodenal stenosis Pathogenic:1
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See cases Pathogenic:1
ACMG classification criteria: PS3, PM2, PM4, PP1, PP4, PP5 -
ivacaftor / lumacaftor response - Efficacy Other:1
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at