Submissions for variant NM_000492.4(CFTR):c.1585-2A>G

dbSNP: rs397508233

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577663	SCV000696852	pathogenic	Cystic fibrosis	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1585-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the complete loss of a canonical splice acceptor site. Functional studies have confirmed the aberrant splicing caused by this variant which includes both the retention of six intronic nucleotides and the skipping of exon 12 (Sharma_2014). This variant is absent in 120436 control chromosomes, and has been reported in CF patients in the literature. Taken together, this variant is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577663	SCV002573914	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, PS1_SUP, PS3_SUP, PM2_SUP, PM3 , PP4
Ambry Genetics	RCV000577663	SCV003911050	likely pathogenic	Cystic fibrosis	2023-02-28	criteria provided, single submitter	clinical testing	The c.1585-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 12 in the CFTR gene. This alteration has been identified in multiple individuals diagnosed with cystic fibrosis (Strandvik B et. al. Genet Test. 2001;5(3): 235-242; Frentescu L et al. J Cyst Fibros. 2008;7(5): 423-428; Silva IAL et al. Biochim Biophys Acta Mol Basis Dis, 2020 Nov;1866:165905). In multiple studies, this alteration resulted in skipping of exon 12 and retention of 6 nucleotides in intron 11 (Sharma N et al. Hum Mutat, 2014 Oct;35:1249-59; Silva IAL et al. Biochim Biophys Acta Mol Basis Dis 2020 11;1866(11):165905). Of note, this alteration is also known as 1717-2A>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577663	SCV004295544	pathogenic	Cystic fibrosis	2023-07-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 53290). This sequence change affects an acceptor splice site in intron 11 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 11788090). This variant is also known as 1717-2A>G. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25066652). For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577663	SCV000679112	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001835654	SCV002080622	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing