Submissions for variant NM_000492.4(CFTR):c.3874-1G>A

dbSNP: rs397508624

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000577716	SCV000886270	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
CFTR-France	RCV000577716	SCV001169347	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Invitae	RCV000577716	SCV002113621	likely pathogenic	Cystic fibrosis	2022-09-21	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53832). This variant is also known as c.4006-1G>A. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 10612849). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 23 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577716	SCV002571988	likely pathogenic	Cystic fibrosis	2022-08-12	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3874-1G>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: Four predict the variant abolishes the canonical 3' acceptor site. One predicts the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245646 control chromosomes (gnomAD). c.3874-1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (example: MIttre_1999). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577716	SCV002573867	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PM2_SUP, PM3, PP4
Baylor Genetics	RCV003474593	SCV004213381	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-19	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577716	SCV000679095	not provided	Cystic fibrosis		no assertion provided	literature only