Submissions for variant NM_000492.4(CFTR):c.3717+40A>G

dbSNP: rs397508595

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000576505	SCV000677605	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000727551	SCV000854777	likely pathogenic	not provided	2017-08-31	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009536	SCV001169631	pathogenic	Cystic fibrosis; CFTR-related disorder	2021-01-18	criteria provided, single submitter	curation	when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727551	SCV001472091	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	The CFTR c.3717+40A>G variant (rs397508595) is reported in the literature in multiple individuals affected with cystic fibrosis and one individual with congenital bilateral absence of the vas deferens (Lee 2017, Steiner 2011, CFTR2 database). In addition, this variant has been observed in testing performed at ARUP Laboratories in an individual with elevated sweat chloride and a second pathogenic variant. The c.3717+40A>G variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Indeed, functional studies of this variant demonstrate it leads to the inclusion of 40 additional nucleotides, causing a frameshift and decreased mRNA levels (Lee 2017). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org/ Lee M et al. Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites. Am J Hum Genet. 2017;100(5):751-765. PMID: 28475858. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011;32(8):912-920. PMID: 21520337.
Baylor Genetics	RCV000576505	SCV001527342	pathogenic	Cystic fibrosis	2018-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000576505	SCV001591261	pathogenic	Cystic fibrosis	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 23974870, 28475858). This variant is also known as 3849+40A>G. ClinVar contains an entry for this variant (Variation ID: 53789). Studies have shown that this variant results in activation of a cryptic donor 40 nucleotides downstream of the exon 22 canonical donor and introduces a premature termination codon (PMID: 28475858). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000576505	SCV002570392	pathogenic	Cystic fibrosis	2022-05-05	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Ambry Genetics	RCV000576505	SCV002623114	pathogenic	Cystic fibrosis	2021-11-30	criteria provided, single submitter	clinical testing	The c.3717+40A>G intronic variant results from an A to G substitution 40 nucleotides after coding exon 22 in the CFTR gene. This variant was identified in two siblings with elevated sweat chloride levels and p.F508del confirmed in trans; one sibling had asymptomatic diffuse bronchiectasis and pancreatic sufficiency while the second sibling had diffuse bronchiectasis with recurrent bronchopulmonary infections, pancreatic insufficiency, nasal polyps, and recurrent sinusitis (Priou-Guesdon M et al. Ann. Endocrinol. (Paris), 2010 Feb;71:46-50). Another individual heterozygous for c.3717+40A>G and p.F508del was described as having mild CF based on late diagnosis (at age 14) and pancreatic sufficiency (Lee M et al. Am J Hum Genet, 2017 May;100:751-765). In one study, reverse transcription PCR (RT-PCR) on nasal epithelial cells from a patient with cystic fibrosis (heterozygous for c.3717+40A>G and p.Phe508del) was performed. Results indicated that this variant results in the retention of the first 40 nucleotides of intron 22. In addition, a minigene expression assay suggests this variant results in leaky splicing, as evidenced by the presence of both fully glycosylated and immature core-glycosylated CFTR protein on Western blot analysis (Lee M et al. Am J Hum Genet, 2017 May;100:751-765). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474586	SCV004213426	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000576505	SCV000794669	likely pathogenic	Cystic fibrosis	2017-10-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826670	SCV002075871	pathogenic	CFTR-related disorder	2019-12-13	no assertion criteria provided	clinical testing