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

gnomAD frequency: 0.00001  dbSNP: rs1290078234

Total submissions: 8

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