Submissions for variant NM_000492.4(CFTR):c.1209+1G>A

dbSNP: rs397508176

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056345	SCV000071450	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056345	SCV000074271	pathogenic	Cystic fibrosis	2022-06-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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: 53214). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 23276700, 23974870). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 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).
CFTR-France	RCV000056345	SCV001169446	pathogenic	Cystic fibrosis	2018-01-29	criteria provided, single submitter	curation
Ambry Genetics	RCV000056345	SCV002648518	pathogenic	Cystic fibrosis	2017-09-05	criteria provided, single submitter	clinical testing	The c.1209+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the CFTR gene. This mutation was identified in a Czech individual with cystic fibrosis; however, complete genotype and phenotype info was not provided (Kenková P et al. J. Cyst. Fibros., 2013 Sep;12:532-7). This pathogenic mutation is associated with pancreatic insufficiency, elevated sweat chloride levels, and a higher rate of Pseudomonas infection (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 likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056345	SCV004099636	pathogenic	Cystic fibrosis	2023-09-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1209+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: Two predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249772 control chromosomes (gnomAD). c.1209+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (examples: Essawi_2015, Boutin_2014, Sosnay_2014, Krenkova_2012, Keiles_2006). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25629612, 25688174, 23974870, 23276700, 17003641). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001831722	SCV002080557	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing