Submissions for variant NM_000492.4(CFTR):c.2908+1G>A

dbSNP: rs1060503164

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000465662	SCV000552136	likely pathogenic	Cystic fibrosis	2018-07-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in the literature in an individual with cystic fibrosis (PMID: 26708955). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 23974870, 12940920). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
CFTR-France	RCV000465662	SCV001169520	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000465662	SCV002750940	likely pathogenic	Cystic fibrosis	2016-08-05	criteria provided, single submitter	clinical testing	The c.2908+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 17 of the CFTR gene. This alteration was first reported in an African American individual with cystic fibrosis (CF), however a second alteration was not reported (Schrijver et al. J Mol Diagn. 2016;18(1):39-50). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration abolishes the splice donor splice site; however, direct evidence is unavailable. 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 likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230503	SCV003929005	likely pathogenic	Hereditary pancreatitis	2023-04-03	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2908+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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251120 control chromosomes (gnomAD). c.2908+1G>A has been reported in the literature in individuals affected with cystic fibrosis (example: Schrijver_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003476096	SCV004213441	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-08-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828481	SCV002083560	likely pathogenic	CFTR-related disorders	2021-06-21	no assertion criteria provided	clinical testing