rs121908745
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000492.4(CFTR):c.1519_1521del(p.Ile507del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,612,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★★). Synonymous variant affecting the same amino acid position (i.e. I506I) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1519_1521del | p.Ile507del | inframe_deletion | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1144_221+1146del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1519_1521del | p.Ile507del | inframe_deletion | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251266Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135794
GnomAD4 exome AF: 0.0000760 AC: 111AN: 1460626Hom.: 0 AF XY: 0.0000771 AC XY: 56AN XY: 726692
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74310
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:12Other:1
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | The CFTR c.1519_1521delATC (p.I507del) variant has been reported in individuals with cystic fibrosis (PMID: 2236053; 1999342; 8092189). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Aug 09, 2022 | ACMG classification criteria: PS4 strong, PM2 moderated, PM3 very strong, PM4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 07, 2021 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This variant, c.1519_1521del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Ile507del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763199062, gnomAD 0.01%). This variant has been observed in individuals with cystic fibrosis (CF) (PMID: 15371902, 23974870). ClinVar contains an entry for this variant (Variation ID: 7106). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_000492.3(CFTR):c.1519_1521delATC(aka I507del) is classified as pathogenic and is a classic variant in the context of cystic fibrosis. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.1519_1521delATC(aka I507del) 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 | Ambry Genetics | May 31, 2022 | The p.I507del pathogenic mutation (also known as c.1519_1521delATC) is located in coding exon 11 of the CFTR gene. This pathogenic mutation results from an in-frame ATC deletion at nucleotide positions 1519 to 1521. This results in the in-frame deletion of an isoleucine at codon 507. This mutation was first reported in trans with p.F508del in an individual with cystic fibrosis (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1994 | - - |
not provided Pathogenic:10
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 20, 2023 | The CFTR c.1519_1521del; p.Ile507del (I507del) variant has been reported in multiple cystic fibrosis patients and is associated with pancreatic insufficiency (CFTR2 database, McKone 2003, Sosnay 2013). This variant is considered to cause cystic fibrosis when identified with another pathogenic variant on the opposite chromosome. References: CFTR2 database: http://cftr2.org/ McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 May 17;361(9370):1671-6. PMID: 12767731. Sosnay PR 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 13, 2018 | The best available variant frequency is uninformative. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 08, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 03, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2021 | In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Published functional studies demonstrate a damaging effect: decreased chloride conductance (Sosnay 2013); Observed multiple times with a pathogenic variant in patients with cystic fibrosis or disseminated bronchiectasis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Kerem 1990, Girodon 1997, McKone 2003); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31036917, 12767731, 31665830, 29261177, 25797027, 2236053, 18456578, 21228398, 22658665, 22975760, 9272738, 24440181, 23974870) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 12, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 16, 2014 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2017 | Variant summary: The CFTR c.1519_1521delATC (p.Ile507del) variant involves the deletion of three nucleotides, leading to an in-frame deletion of a isoleucine residue in the ABC transporter-like and AAA+ ATPase domains (InterPro). One in silico tool predicts a damaging outcome for this variant. This variant was found in 10/276978 control chromosomes at a frequency of 0.0000361, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been identified in many CF patients and is considered a common variant, as it was found in 1.6% of CF alleles in a large, nationwide retrospective study (McKone_2003). Patients with this variant have a mean chloride conductance of 0.2% as of the WT CFTR (Sosnay_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor 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:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 25, 2022 | - - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at