Submissions for variant NM_000492.4(CFTR):c.4243-2A>G

gnomAD frequency: 0.00001  dbSNP: rs397508705

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668313	SCV000792891	likely pathogenic	Cystic fibrosis	2017-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004308	SCV001163185	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668313	SCV002500099	likely pathogenic	Cystic fibrosis	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4243-2A>G 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: three predict the variant abolishes a 3' acceptor site, and three predict the variant creates a 3' acceptor site seven nucleotides downstream, potentially leading to a frameshift. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250108 control chromosomes (gnomAD). c.4243-2A>G has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Zahav_2023). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 35934641). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Additionally, other variants disrupting the same splice acceptor site, including c.4243-2A>C, c.4243-1G>C, and c.4243-1G>T, have been reported in association with Cystic fibrosis (HGMD). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003472099	SCV004213395	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668313	SCV004298566	uncertain significance	Cystic fibrosis	2023-08-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 26 of the CFTR gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 552958). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV004721538	SCV005326647	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Observed in an individual in a cystic fibrosis patient registry, however, clinical and genotype information was not provided (PMID: 35934641); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35934641)