ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2988+1G>A

gnomAD frequency: 0.00030  dbSNP: rs75096551
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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
American College of Medical Genetics and Genomics (ACMG) RCV000007645 SCV000071402 pathogenic Cystic fibrosis 2004-03-03 practice guideline curation Converted during submission to Pathogenic.
CFTR2 RCV000007645 SCV000071456 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
Labcorp Genetics (formerly Invitae), Labcorp RCV000007645 SCV000074751 pathogenic Cystic fibrosis 2025-01-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 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 (rs75096551, gnomAD 0.1%). 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 3120+1G>A. ClinVar contains an entry for this variant (Variation ID: 7224). 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.
Eurofins Ntd Llc (ga) RCV000759761 SCV000226734 pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000007645 SCV000603044 pathogenic Cystic fibrosis 2024-05-26 criteria provided, single submitter clinical testing The CFTR c.2988+1G>A variant (rs75096551), also known as 3120+1G>A, is reported in patients diagnosed with cystic fibrosis (Chavez-Saldana 2010, Masekela 2013, Wilschanski 1995), and is associated with elevated sweat levels and pancreatic insufficiency (Masekela 2013, Ooi 2012, Sosnay 2013, see CFTR2 database). This variant is reported in ClinVar (Variation ID: 7224), and is found in the general population with an overall allele frequency of 0.01% (33/282364 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 18, which is likely to negatively impact gene function. Functional characterization indicates that exon 18 is skipped in the CFTR mRNA, and results in the absence of CFTR protein (Sharma 2014). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database link: https://cftr2.org/ Chavez-Saldana M et al. CFTR allelic heterogeneity in Mexican patients with cystic fibrosis: implications for molecular screening. Rev Invest Clin. 2010; 62(6):546-52. PMID: 21416780 Masekela R et al. Phenotypic expression of the 3120+1G>A mutation in non-Caucasian children with cystic fibrosis in South Africa. J Cyst Fibros. 2013; 12(4):363-6. PMID: 23206872 Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012; 11(5):355-62. PMID: 22658665 Sharma N et al. Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions. Hum Mutat. 2014; 35(10):1249-59. PMID: 25066652 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 Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995; 127(5):705-10. PMID: 7472820
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000007645 SCV000784252 pathogenic Cystic fibrosis 2018-03-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759761 SCV000889304 pathogenic not provided 2020-04-11 criteria provided, single submitter clinical testing The pathogenic c.2988+1G>A variant (also known as 3120+1G>A) is located in a canonical splice-donor site and interferes with/prevents normal CFTR mRNA splicing (PMID: 25066652 (2014)). It is a known CF pathogenic variant associated with pancreatic insufficiency, and has been reported in individuals affected with CF in the published literature (PMIDs: 9683582 (1998), 9950364 (1999), 23206872 (2013), and 23974870 (2013)).
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000007645 SCV000891677 pathogenic Cystic fibrosis 2017-12-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763580 SCV000894419 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000007645 SCV001137489 pathogenic Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004285 SCV001163161 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000007645 SCV001169503 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000007645 SCV001194076 pathogenic Cystic fibrosis 2019-11-12 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.2988+1G>A(aka 3120+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.2988+1G>A(aka 3120+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.
Baylor Genetics RCV000007645 SCV001523283 pathogenic Cystic fibrosis 2019-09-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000759761 SCV001714239 pathogenic not provided 2024-07-09 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000759761 SCV002019242 pathogenic not provided 2021-06-18 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000007645 SCV002512247 pathogenic Cystic fibrosis 2021-08-20 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderate, PM3 strong
Ambry Genetics RCV000007645 SCV002751244 pathogenic Cystic fibrosis 2022-02-09 criteria provided, single submitter clinical testing The c.2988+1G>A pathogenic mutation (also known as 3120+1G>A in published literature), is located one nucleotide after coding exon 18 of the CFTR gene. This is one of the most common pathogenic mutations in African American individuals with cystic fibrosis (CF) (Zampoli On Behalf Of The Msac M. S. Afr. Med. J., 2018 Dec;109:16-19). In one study, this mutation was identified in ten affected African American individuals with pancreatic insufficiency (PI) and elevated sweat chloride levels (Macek M Am. J. Hum. Genet. 1997 May;60(5):1122-7). This pathogenic mutation was further described in four African American individuals, one who was homozygous and three compound heterozygous with another mutation. All individuals demonstrated compromised lung function, elevated sweat chloride levels, and PI (Carles S et al. J. Med. Genet. 1996 Sep;33(9):802-4). A functional in vitro study of splice site alterations in CFTR noted this mutation generated no detectable CFTR protein (Sharma N et al Hum. Mutat. 2014 Oct;35(10):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 pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital RCV000007645 SCV002818169 pathogenic Cystic fibrosis 2024-10-04 criteria provided, single submitter research PVS1, PM3_VeryStrong, PM2, PP4, PS3
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000007645 SCV004034122 pathogenic Cystic fibrosis 2023-07-01 criteria provided, single submitter research
Baylor Genetics RCV003473046 SCV004213277 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-03-28 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000007645 SCV004807375 pathogenic Cystic fibrosis 2024-03-26 criteria provided, single submitter clinical testing
OMIM RCV000007645 SCV000027846 pathogenic Cystic fibrosis 1998-08-01 no assertion criteria provided literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007645 SCV000052162 pathogenic Cystic fibrosis 2015-06-22 no assertion criteria provided clinical testing
Natera, Inc. RCV001027899 SCV001190622 pathogenic CFTR-related disorder 2019-05-20 no assertion criteria provided clinical testing
GeneReviews RCV000007645 SCV001622803 not provided Cystic fibrosis no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000759761 SCV001741020 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000759761 SCV001957727 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000759761 SCV001966485 pathogenic not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV001027899 SCV004118258 pathogenic CFTR-related disorder 2024-09-28 no assertion criteria provided clinical testing The CFTR c.2988+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has previously been reported to be causative for cystic fibrosis (Wilschanski et al. 1995. PubMed ID: 7472820; Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic.

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