Submissions for variant NM_000492.4(CFTR):c.1585-1G>A

gnomAD frequency: 0.00008  dbSNP: rs76713772

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000007532	SCV000071393	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission from pathogenic to Pathogenic.
CFTR2	RCV000007532	SCV000071452	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007532	SCV000074364	pathogenic	Cystic fibrosis	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs76713772, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with cystic fibrosis, and is included in the American College of Medical Genetics (ACMG) panel of CF variants (PMID: 15371902, 23974870). This variant is also known as 1717-1G>A. ClinVar contains an entry for this variant (Variation ID: 7112). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224919	SCV000281124	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000224919	SCV000322328	pathogenic	not provided	2018-10-26	criteria provided, single submitter	clinical testing	The c.1585-1G>A pathogenic variant in the CFTR gene is one of the common pathogenic variants associated with cystic fibrosis (Kerem et al., 1990; Hull et al., 1993; Ooi et al., 2012). This splice site variant destroys the canonical splice acceptor site in intron 11. Functional studies show this variant results in skipping of exon 12 with a frameshift that results in a premature termination codon, and the mRNA is not able to generate a stable protein product (Hull et al., 1993; Sharma et al., 2014). Although not present in the homozygous state, the NHLBI Exome Sequencing Project reports that c.1585-1G>A was observed in 12/8600 alleles (0.14%) from individuals of European American background, indicating it may be a rare variant in this population. We interpret c.1585-1G>A as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224919	SCV000603007	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The CFTR c.1585-1G>A variant (rs76713772), also known as 1717-1G>A, has been reported in patients with the pancreatic insufficient form of cystic fibrosis (Guillermit 1990, Kerem 1990, Ivady 2011, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 7112), is found in the non-Finnish European population with an allele frequency of 0.015% (19/128,796 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 11, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Guillermit H et al. A 3' splice site consensus sequence mutation in the cystic fibrosis gene. Hum Genet. 1990 85(4):450-3. PMID: 2210769 Ivady G et al. Distribution of CFTR mutations in Eastern Hungarians: relevance to genetic testing and to the introduction of newborn screening for cystic fibrosis. J Cyst Fibros. 2011 10(3):217-20. PMID: 21296036 Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990 87(21):8447-51. PMID: 2236053 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007532	SCV000696853	pathogenic	Cystic fibrosis	2016-04-25	criteria provided, single submitter	clinical testing	Variant summary: The c.1585-1G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant. 5/5 splice-tools in Alamut predict that this variant affects the 3' splicing acceptor site and may generate an alternative 3' splicing acceptor site leading to c.1717delG. These predictions were confirmed by minigene and in vivo RNA analysis (Sosnay_2013). This variant is found in 11/120496 control chromosomes at a frequency of 0.0000913, which does not exceed maximal expected frequency of a pathogenic allele (0.0129603). This variant is a commonly known pathogenic variant, and multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000224919	SCV000854844	pathogenic	not provided	2018-03-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000007532	SCV000886199	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000007532	SCV000915202	pathogenic	Cystic fibrosis	2018-08-24	criteria provided, single submitter	clinical testing	The CFTR c.1585-1G>A variant, also known as c.1717-1G>A, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1585-1G>A variant is listed by the ACMG as part of a panel recommended for routine diagnostic and carrier testing for cystic fibrosis (Watson et al. 2004). The c.1585-1G>A variant is one of the ten most common CFTR variants in persons of northern European descent, accounting for 0.6% of disease and is associated with a classic cystic fibrosis phenotype (Moskowitz et al. 2001). The variant is found in 635/79392 disease-associated alleles in individuals from North America and Europe (Sosnay et al. (2013). Control data are unavailable for this variant, which is reported at a frequency of 0.001395 in the European American cohort of the Exome Sequencing Project. Based on the collective evidence the c.1585-1G>A variant classified as pathogenic for cystic fibrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224919	SCV001134116	pathogenic	not provided	2024-05-22	criteria provided, single submitter	clinical testing	The CFTR c.1585-1G>A (also known as 1717-1G>A) variant disrupts a canonical splice-acceptor site and interferes with normal CFTR mRNA splicing. This variant is associated with cystic fibrosis (CF) (PMIDs: 29261177 (2018), 31036917 (2019), and 34782259 (2021)), and has been reported along with other pathogenic CFTR variants in individuals with classic CF (PMID: 7689009 (1993)), pancreatic insufficiency (PMIDs: 2236053 (1990), 2210769 (1990), 1757966 (1991), and 23974870 (2013)) and in at least one individual with chronic obstructive pulmonary disease (PMID: 34996830 (2022)). Experimental studies have also shown that this variant results in exon 12 skipping and therefore disrupts protein production (PMIDs: 7689009 (1993), 23974870 (2013) and 25066652 (2014)). The frequency of this variant in the general population, 0.0002 (10/50648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV001004462	SCV001163507	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000007532	SCV001169469	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000007532	SCV001172724	pathogenic	Cystic fibrosis	2024-07-11	criteria provided, single submitter	clinical testing	The c.1585-1G>A intronic pathogenic mutation (also known as 1717-1G>A) results from a G to A substitution one nucleotide upstream from coding exon 12 of the CFTR gene. This pathogenic mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and higher rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). A functional in vitro study reported an absence of normally spliced RNA in expression minigenes transfected into HEK293 cells (Sharma N et al. Hum. Mutat., 2014 Oct;35:1249-59). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000007532	SCV001194078	pathogenic	Cystic fibrosis	2019-11-12	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.1585-1G>A(aka 1717-1G>A) 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. Classification of NM_000492.3(CFTR):c.1585-1G>A(aka 1717-1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Johns Hopkins Genomics, Johns Hopkins University	RCV000007532	SCV001433649	pathogenic	Cystic fibrosis	2019-12-11	criteria provided, single submitter	clinical testing	Disease-causing CFTR mutation. See www.CFTR2.org for phenotype information.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224919	SCV001713421	pathogenic	not provided	2024-05-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000224919	SCV002019218	pathogenic	not provided	2022-08-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007532	SCV002573957	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient 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: PVS1, PS3_SUP, PM2_SUP, PM3_VSTR
Fulgent Genetics, Fulgent Genetics	RCV002496295	SCV002815046	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-02-26	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000007532	SCV004046364	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing	This variant has also been reported in the literature as c.1717-1G>A. This variant affects the canonical splice acceptor site of intron 10 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a common pathogenic variant in individuals with cystic fibrosis (CF) (PMID: 2236053, 23974870, 20301428). Functional studies have demonstrated that this variant results in aberrant transcription of the CFTR gene (PMID: 25066652). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0071% (20/282220) and thus is presumed to be rare. Based on the available evidence, the c.1585-1G>A variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV001027893	SCV004114468	pathogenic	CFTR-related disorder	2023-09-01	criteria provided, single submitter	clinical testing	The CFTR c.1585-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant, previously described as c.1717-1G>A, is known to be causative for cystic fibrosis (see for example Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117227792-G-A). Variants that disrupt the consensus splice acceptor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003473004	SCV004213274	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-20	criteria provided, single submitter	clinical testing
OMIM	RCV000007532	SCV000027733	pathogenic	Cystic fibrosis	1990-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001027893	SCV001190615	pathogenic	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing
GeneReviews	RCV000007532	SCV001622799	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224919	SCV001739956	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224919	SCV001955455	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224919	SCV001974900	pathogenic	not provided		no assertion criteria provided	clinical testing