Submissions for variant NM_000492.4(CFTR):c.1116+1G>A

dbSNP: rs397508158

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056340	SCV000071449	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056340	SCV000485674	pathogenic	Cystic fibrosis	2016-01-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000056340	SCV000886239	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004255	SCV001163131	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
CFTR-France	RCV000056340	SCV001169440	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056340	SCV001361720	pathogenic	Cystic fibrosis	2019-06-20	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1116+1G>A 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. 5/5 computational tools predict the variant abolishes a 5 splicing donor site and a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250560 control chromosomes (gnomAD). The variant, c.1116+1G>A, has been reported in the literature in multiple individuals affected with Cystic Fibrosis or CBAVD (Kambouris_2000, Huber_2002, Kammesheidt_2006, Steiner_2011, Qiu_2018, Petrova_2019). 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. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056340	SCV001592611	pathogenic	Cystic fibrosis	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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 (rs397508158, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 10834512, 15365999, 21520337, 23974870, 30548586). This variant is also known as c.1248+1G>A. ClinVar contains an entry for this variant (Variation ID: 53190). 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.
Ambry Genetics	RCV000056340	SCV002745784	pathogenic	Cystic fibrosis	2023-03-01	criteria provided, single submitter	clinical testing	The c.1116+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide(s) after coding exon 8 of the CFTR gene. This alteration was identified in an individual with cystic fibrosis; however a second CFTR variant was not detected (Kambouris M et al. Eur. J. Pediatr., 2000 May;159:303-9). It was also identified in a cohort of individuals with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a second CFTR variant; however, the phase was not provided (Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20). This alteration is also associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 1248+1G>A in published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056340	SCV003927241	pathogenic	Cystic fibrosis	2023-03-10	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Baylor Genetics	RCV003473444	SCV004213450	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001027907	SCV001190630	pathogenic	CFTR-related disorder	2019-05-20	no assertion criteria provided	clinical testing