ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.870-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1290078234
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587438 SCV000697052 likely pathogenic Cystic fibrosis 2024-02-21 criteria provided, single submitter clinical testing Variant summary: CFTR c.870-2A>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 3' acceptor site. Two predict the variant creates a 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 249644 control chromosomes. c.870-2A>G has been reported in the literature in individuals affected with Cystic Fibrosis (Quinton_2012, Trujillano_2013, Behar_2017). 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: 22859523, 23687349, 28546993). ClinVar contains an entry for this variant (Variation ID: 495962). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000587438 SCV001589597 pathogenic Cystic fibrosis 2024-11-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 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 0.009%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 22859523, 23687349, 27717243, 28546993). This variant is also known as 1002-2A>G. ClinVar contains an entry for this variant (Variation ID: 495962). 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.
Undiagnosed Diseases Network, NIH RCV000587438 SCV002523172 pathogenic Cystic fibrosis 2020-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000587438 SCV002685912 likely pathogenic Cystic fibrosis 2024-07-10 criteria provided, single submitter clinical testing The c.870-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the CFTR gene. This variant was identified in an individual with cystic fibrosis in conjunction with p.G1244E; however, the phase was not specified (Trujillano D et al. J Med Genet, 2013 Jul;50:455-62). It was also identified a pancreatic sufficient adult with elevated sweat chloride levels in conjunction with p.F508del; however, the phase was not specified (Quinton P et al. Am J Respir Crit Care Med, 2012 Oct;186:732-9). 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 and will result in the creation or strengthening of a novel splice acceptor site. 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.
GeneDx RCV003159994 SCV003915388 likely pathogenic not provided 2022-10-06 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Also known as c.1002-2A>G; This variant is associated with the following publications: (PMID: 28546993, 31036917, 27717243, 22859523, 23687349)
PreventionGenetics, part of Exact Sciences RCV004530643 SCV004105965 likely pathogenic CFTR-related disorder 2022-12-05 criteria provided, single submitter clinical testing The CFTR c.870-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in one patient with Cystic fibrosis who was also carrying the p.Gly1224Glu pathogenic variant in CFTR. The phase was not specified (Patient 79, Table S3, Trujillano et al. 2013. PubMed ID: 23687349). This variant was also detected as part of a large study investigating efficacy of NGS-based cystic fibrosis carrier screening. Details on the individual carrying the 870-2A>G were not provided (Table S3, Beauchamp et al. 2019. PubMed ID: 31036917). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117180152-A-G). Variants that disrupt the consensus splice acceptor site in CFTR are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Baylor Genetics RCV003471943 SCV004213461 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-11-11 criteria provided, single submitter clinical testing
Counsyl RCV000587438 SCV001132360 likely pathogenic Cystic fibrosis 2016-12-09 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.