ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2658-1G>C

dbSNP: rs397508416
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000190990 SCV000245915 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
CFTR-France RCV000190990 SCV001169519 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV000190990 SCV002107681 likely pathogenic Cystic fibrosis 2023-12-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 16 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 (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 25580864). This variant is also known as c.2790-1G>C. ClinVar contains an entry for this variant (Variation ID: 209045). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000190990 SCV005559944 pathogenic Cystic fibrosis 2024-10-02 criteria provided, single submitter clinical testing The c.2658-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide before coding exon 17 of the CFTR gene. This variant (also referred to as c.2790-1G>C) has been identified in conjunction with other CFTR variants in individuals with features consistent with cystic fibrosis or CFTR-related disorders (Liu Y et al. Respirology, 2015 Feb;20:312-8; Sismanlar T et al. Eur J Pediatr, 2016 Sep;175:1157-1163). In addition, this variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 10/01/2024). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Another alteration impacting the same acceptor site (c.2658-2A>G) has also been reported in association with cystic fibrosis (Marigo C et al. Mol Cell Probes, 1995 Apr;9:139-41). 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.
Natera, Inc. RCV001833133 SCV002080786 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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