ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.580-2A>G

gnomAD frequency: 0.00001  dbSNP: rs193922730
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV001038806 SCV001981565 pathogenic Cystic fibrosis 2021-09-24 reviewed by expert panel research
Labcorp Genetics (formerly Invitae), Labcorp RCV001038806 SCV001202302 pathogenic Cystic fibrosis 2019-12-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 24129438). This variant is present in population databases (rs193922730, ExAC 0.009%). This sequence change affects an acceptor splice site in intron 5 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Institute of Human Genetics, University of Leipzig Medical Center RCV001038806 SCV002573888 pathogenic Cystic fibrosis 2022-09-05 criteria provided, single submitter curation This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PM2_SUP, PP4
Neuberg Centre For Genomic Medicine, NCGM RCV001038806 SCV004047401 pathogenic Cystic fibrosis criteria provided, single submitter clinical testing The c.580-2A>G splice acceptor variant in CFTR gene has been observed in individual(s) with cystic fibrosis (Masvidal et al., 2014). This variant is reported with the allele frequency (0.001%) in the gnomad and novel in 1000 genome database. This variant has been reported in the ClinVar database as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle & Baralle., 2005), and loss-of-function variants in CFTR are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001038806 SCV004099591 pathogenic Cystic fibrosis 2023-09-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.580-2A>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: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251424 control chromosomes. c.580-2A>G has been reported in the literature and Cystic Fibrosis databases in individuals affected with Cystic Fibrosis, including at least one individual where it was reported in trans with F508del (e.g. De Wachter_2017, McCague_2019, Duursma_2022, CFTR2 Database, SickKids Cystic Fibrosis Mutation Database). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28830496, 35697137, 30888834). Three 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.
Baylor Genetics RCV004570114 SCV005057446 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-01-17 criteria provided, single submitter clinical testing

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