Submissions for variant NM_000492.4(CFTR):c.869+5G>A

gnomAD frequency: 0.00001  dbSNP: rs533959068

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668284	SCV000792858	uncertain significance	Cystic fibrosis	2017-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781277	SCV000919190	likely pathogenic	not specified	2018-05-24	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.869+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Raynal_2013). The variant allele was found at a frequency of 8.2e-06 in 243092 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-related diseases (8.2e-06 vs 1.30e-02), allowing no conclusion about variant significance. The variant, c.869+5G>A, has been reported in the literature in individuals affected with CF and CBAVD (Girardet_2007, Goh_2007). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. The CFTR-France database cites the variant in a CF patient with classification of 'disease-causing' and UMD and Sickkids cite the variant in a CF patient with deltaF508 in trans. Based on the evidence outlined above, the variant was classified as likely pathogenic.
CFTR-France	RCV000668284	SCV001169323	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000668284	SCV001233424	pathogenic	Cystic fibrosis	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 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 likely results in a shortened protein product. This variant is present in population databases (rs533959068, gnomAD 0.01%). This variant has been observed in individuals with CFTR-related conditions (PMID: 17398169, 23381846). This variant is also known as 1001+5G>A. ClinVar contains an entry for this variant (Variation ID: 552934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 23381846). This variant disrupts a region of the CFTR protein in which other variant(s) (p.Arg258Gly) have been determined to be pathogenic (PMID: 7529962, 9305991, 10376575, 11466205, 16196493, 19810821, 23104983). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000668284	SCV001822025	likely pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000668284	SCV003998970	likely pathogenic	Cystic fibrosis	2023-06-07	criteria provided, single submitter	clinical testing	The c.869+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 7 in the CFTR gene. This variant has been observed in individuals with CFTR-related conditions (Goh DL et al. J Cyst Fibros, 2007 Nov;6:423-5). Minigene RNA studies have demonstrated that this alteration results in skipping of exon 7 (also reported as exon 6b) (Raynal C et al. Hum Mutat, 2013 May;34:774-84). Of note, this alteration is also known as 1001+5G>A in published literature. Another alteration impacting the same donor site (c.869+3A>T) has been shown to have a similar impact on splicing in skipping of exon 7 and the variant has been identified in individuals diagnosed with classic cystic fibrosis (Schrijver I et al. Am J Med Genet A, 2005 Feb;133A:103-5; Faà V et al. J Mol Diagn, 2006 Sep;8:499-503). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics	RCV003472096	SCV004213472	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-07-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892516	SCV004710575	likely pathogenic	CFTR-related condition	2023-11-27	criteria provided, single submitter	clinical testing	The CFTR c.869+5G>A variant is predicted to interfere with splicing. This variant was reported in individuals with congenital absence of vas deferens (described as 1001+5G>A, Goh et al. 2007. PubMed ID: 17398169; Table S1, Fang et al. 2022. PubMed ID: 36437957). A minigene assay showed that this variant results in exon skipping (Raynal et al. 2013. PubMed ID: 23381846). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD and is interpreted as pathogenic or likely pathogenic by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/552934/). This variant is interpreted as likely pathogenic.
Natera, Inc.	RCV000668284	SCV001454034	likely pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing