Submissions for variant NM_000492.4(CFTR):c.2989-1G>A

dbSNP: rs397508470

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056376	SCV000071457	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Counsyl	RCV000056376	SCV000220378	likely pathogenic	Cystic fibrosis	2014-06-06	criteria provided, single submitter	literature only
Mendelics	RCV000056376	SCV000886245	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780171	SCV000917219	pathogenic	not specified	2017-12-26	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.2989-1G>A 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 a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/245874 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This variant was found in multiple CF patients (Sosnay_2013, Behar_2017, Alibakhshi_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
CFTR-France	RCV000056376	SCV001169554	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000056376	SCV001251839	pathogenic	Cystic fibrosis	2020-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781375	SCV002019244	pathogenic	not provided	2022-08-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056376	SCV002229343	pathogenic	Cystic fibrosis	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 18 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 present in population databases (rs397508470, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with cystic fibrosis or congenital bilateral absence of the vas deferens (PMID: 9452048, 10875853, 17662673, 27086061, 28546993). This variant is also known as c.3121-1G>A. ClinVar contains an entry for this variant (Variation ID: 53613). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23974870). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000056376	SCV002751249	pathogenic	Cystic fibrosis	2022-07-06	criteria provided, single submitter	clinical testing	The c.2989-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 19 of the CFTR gene. This mutation has been reported in multiple cystic fibrosis patients with a second mutation confirmed in trans and is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002490613	SCV002800479	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466906	SCV004215771	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2022-08-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000056376	SCV004848807	pathogenic	Cystic fibrosis	2022-11-03	criteria provided, single submitter	clinical testing	The c.2989-1G>A variant in CFTR (also know as c.3121-1G>A) has been reported in several individuals with cystic fibrosis or congenital bilateral absence of the vas deferens (selected references: Feldmann 1998 PMID: 9452048, Casals 2000 PMID: 10875853, Alibakhshi 2008 PMID:17662673, Gaitch 2016 PMID: 27086061, Behar 2017 PMID: 28546993). It was absent from large population studies. This variant was classified as Pathogenic on Mar 17 2017 by the ClinGen-approved CFTR2 expert panel (Variation ID 53613). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In vitro functional studies provide some evidence that this variant impacts mRNA splicing (Sosnay 2013 PMID: 23974870) . In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM2_supporting, PM3_Very Strong, PS3_Supporting, PVS1.
Natera, Inc.	RCV001831764	SCV002083575	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing