Submissions for variant NM_000492.4(CFTR):c.1516ATC[1] (p.Ile507del)

dbSNP: rs121908745

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007525	SCV000071391	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000007525	SCV000071494	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224705	SCV000280992	pathogenic	not provided	2014-11-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000224705	SCV000331551	pathogenic	not provided	2014-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000007525	SCV000886198	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224705	SCV000889287	pathogenic	not provided	2024-04-03	criteria provided, single submitter	clinical testing	The CFTR c.1519_1521del (p.Ile507del) variant has been reported in the published literature in individuals with cystic fibrosis (CF) (PMIDs: 37313453 (2023), 36832409 (2023), 36102402 (2022), 34782259 (2021)). It is described as a known CF causing variant associated with pancreatic insufficiency (CFTR2 (https://cftr2.org/), UMD (http://www.umd.be/CFTR/), CFTR-France (https://cftr.iurc.montp.inserm.fr/)). Functional studies show the variant to be a Class II variant that results in little to no mature CFTR protein (PMIDs: 36759923 (2023), 24440181 (2014), 23974870 (2013)). The frequency of this variant in the general population, 0.00016 (4/24964 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780118	SCV000917162	pathogenic	not specified	2017-10-30	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007525	SCV001158348	pathogenic	Cystic fibrosis	2024-07-31	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001004458	SCV001163503	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007525	SCV001169464	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000007525	SCV001193880	pathogenic	Cystic fibrosis	2019-12-20	criteria provided, single submitter	clinical testing	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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000007525	SCV001251534	pathogenic	Cystic fibrosis		criteria provided, single submitter	research	The CFTR c.1519_1521delATC (p.I507del) variant has been reported in individuals with cystic fibrosis (PMID: 2236053; 1999342; 8092189).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007525	SCV001581090	pathogenic	Cystic fibrosis	2024-11-30	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224705	SCV001713416	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000007525	SCV001762362	pathogenic	Cystic fibrosis	2021-07-07	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
GeneDx	RCV000224705	SCV001874090	pathogenic	not provided	2021-07-19	criteria provided, single submitter	clinical testing	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)
Revvity Omics, Revvity	RCV000224705	SCV002019234	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007525	SCV002708597	pathogenic	Cystic fibrosis	2022-05-31	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002496293	SCV002810404	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-05-02	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000007525	SCV003807625	pathogenic	Cystic fibrosis	2022-08-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PM3 very strong, PM4
Baylor Genetics	RCV003472998	SCV004213374	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007525	SCV004698105	pathogenic	Cystic fibrosis	2024-02-21	criteria provided, single submitter	clinical testing
OMIM	RCV000007525	SCV000027726	pathogenic	Cystic fibrosis	1994-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000007525	SCV001622797	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224705	SCV001742394	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224705	SCV001957757	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224705	SCV001970167	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826426	SCV002080608	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001826426	SCV005362084	pathogenic	CFTR-related disorder	2024-06-02	no assertion criteria provided	clinical testing	The CFTR c.1519_1521delATC variant is predicted to result in an in-frame deletion (p.Ile507del). This is a well-established pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/7106/), and it is included in the American College of Medical Genetics (ACMG) panel of definitive pathogenic cystic fibrosis variants (Watson et al. 2004. PubMed ID:15371902). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-11738193-C-A). We interpret this variant as pathogenic.