Submissions for variant NM_000492.4(CFTR):c.579+1G>T

gnomAD frequency: 0.00004  dbSNP: rs77188391

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
American College of Medical Genetics and Genomics (ACMG)	RCV000043566	SCV000071410	pathogenic	Cystic fibrosis	2004-03-03	practice guideline	curation	Converted during submission to Pathogenic.
CFTR2	RCV000043566	SCV000071462	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000723838	SCV000331548	pathogenic	not provided	2016-05-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000043566	SCV000886197	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780140	SCV000917185	pathogenic	not specified	2018-03-19	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.579+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site and one predicts the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 275871 control chromosomes (gnomAD and publications). c.579+1G>T has been reported in the literature in multiple individuals affected with Classic Cystic Fibrosis (McKone_2003, Zielenski_1991, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001004437	SCV001163482	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000043566	SCV001169304	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000043566	SCV001194161	pathogenic	Cystic fibrosis	2019-11-11	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.579+1G>T(aka 711+1G>T) 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.579+1G>T(aka 711+1G>T) 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.‚Äã
Invitae	RCV000043566	SCV001578675	pathogenic	Cystic fibrosis	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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 (rs77188391, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (CF) (PMID: 1710599, 20880762, 23974870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 711+1G>T. ClinVar contains an entry for this variant (Variation ID: 38494). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000723838	SCV001715942	pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000043566	SCV002653053	pathogenic	Cystic fibrosis	2021-06-17	criteria provided, single submitter	clinical testing	The c.579+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This mutation has been described in three siblings who presented with severe pulmonary symptoms, growth retardation, and pancreatic insufficiency and who also carried the c.489+1G>T mutation (De Braekeleer M et al. Clin Genet. 1997;51(3):214-216). In vitro studies of mRNA isolated from the nasal epithelial cells of a pancreatic insufficient CF patient who also carried the c.579+1G>T mutation, suggested that this mutation results in a transcript missing exon 5 (Zielenski J et al. Hum Mol Genet 1993;2(6):683-7). This mutation is typically associated with elevated sweat chloride levels, pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). Of note, this alteration is also referred to as 711+1G>T in the literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473240	SCV004213304	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-10-16	criteria provided, single submitter	clinical testing
GeneReviews	RCV000043566	SCV001622796	not provided	Cystic fibrosis		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000723838	SCV001744187	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000723838	SCV001967910	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826530	SCV002082513	pathogenic	CFTR-related disorders	2017-03-17	no assertion criteria provided	clinical testing