ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.274-2A>G

dbSNP: rs397508426
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000577517 SCV000924241 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Counsyl RCV000577517 SCV000799014 pathogenic Cystic fibrosis 2018-04-04 criteria provided, single submitter clinical testing
CFTR-France RCV000577517 SCV001169510 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000577517 SCV001361715 pathogenic Cystic fibrosis 2024-08-12 criteria provided, single submitter clinical testing Variant summary: CFTR c.274-2A>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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CFTR function. Several computational tools predict a significant impact on normal splicing: Five 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 was absent in 250598 control chromosomes. c.274-2A>G has been reported in the literature and in our internal database in multiple homozygous individuals affected with Cystic Fibrosis (el-Harith 1997, Panickar 2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 53556). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000577517 SCV001590841 pathogenic Cystic fibrosis 2024-09-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 9429141). This variant is also known as 406-2A>G. ClinVar contains an entry for this variant (Variation ID: 53556). 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.
3billion, Medical Genetics RCV000577517 SCV003841753 pathogenic Cystic fibrosis 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000053556). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV003474551 SCV004213527 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-04-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000577517 SCV005107522 likely pathogenic Cystic fibrosis 2024-05-28 criteria provided, single submitter clinical testing The c.274-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Designated 406-2 A to G, this variant was detected as homozygous in a 20-month-old child with CF diagnosed at birth due to meconium ileus and since diagnosed with pancreatic insufficiency and failure to thrive (el-Harith EA et al. J Med Genet, 1997 Dec;34:996-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577517 SCV000679017 not provided Cystic fibrosis no assertion provided literature only
Natera, Inc. RCV001831755 SCV002080109 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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