Submissions for variant NM_000492.4(CFTR):c.165-1G>A

dbSNP: rs397508249

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046382	SCV000245916	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000280788	SCV000339100	pathogenic	not provided	2016-01-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046382	SCV000696859	pathogenic	Cystic fibrosis	2016-09-28	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.165-1G>A (a.k.a. IVS2-1G>A, 297-1G>A) variant involves the alteration of a conserved intronic nucleotide, at a location known to affect splicing, with 5/5 splice prediction tools predicting alterations to normal splicing and the removal of two ESE binding sites, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals as compound heterozytoges via publications, In addition, multiple databases/clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Ambry Genetics	RCV000046382	SCV002705563	pathogenic	Cystic fibrosis	2018-08-14	criteria provided, single submitter	clinical testing	The c.165-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 3 of the CFTR gene. This mutation was first reported in the literature in a patient with meconium ileus, severe lung disease, and pancreatic insufficiency, who also carried a p.F508del mutation on the paternal allele (Orozco L et al. Hum Genet. 2000;106:360-5). 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	RCV000046382	SCV003219444	pathogenic	Cystic fibrosis	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 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 individuals with cystic fibrosis (PMID: 10798368, 12000363, 16980811, 26098992). This variant is also known as 297-1G>A. ClinVar contains an entry for this variant (Variation ID: 53314). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000046382	SCV004239026	pathogenic	Cystic fibrosis	2023-12-20	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000046382	SCV004847364	pathogenic	Cystic fibrosis	2024-01-02	criteria provided, single submitter	clinical testing	The c.165-1G>A variant in CFTR has been reported in the compound heterozygous state with another pathogenic variant in CFTR in at least 3 individuals with clinical features of cystic fibrosis (Orozco 2000 PMID: 10798368, Kammesheidt 2006 PMID: 16980811, Kay 2015 PMID: 26098992). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 53314) and was absent from large population studies (gnomAD, v.3.1.2). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting.
Counsyl	RCV000046382	SCV000790424	pathogenic	Cystic fibrosis	2017-03-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826617	SCV002080078	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing