ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.490-1G>A

gnomAD frequency: 0.00002  dbSNP: rs397508734
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672764 SCV000797902 likely pathogenic Cystic fibrosis 2018-02-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004433 SCV001163478 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000672764 SCV001425431 pathogenic Cystic fibrosis 2020-02-19 criteria provided, single submitter clinical testing This variant has been previously identified in patients with cystic fibrosis and is classified as likely pathogenic by one ClinVar submitter. It (rs397508734) is rare (<0.1%) in a large population dataset ( gnomAD: 4/249200 total alleles; 0.002%; no homozygotes). Bioinformatic analysis predicts that this canonical splice site variant would affect normal exon 4 splicing, although this has not been confirmed experimentally to our knowledge. We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000672764 SCV001589435 pathogenic Cystic fibrosis 2025-01-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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 (rs397508734, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 23857699, 26160248). This variant is also known as c.622-1G>A. ClinVar contains an entry for this variant (Variation ID: 53974). 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.
Ambry Genetics RCV000672764 SCV002639617 likely pathogenic Cystic fibrosis 2022-09-12 criteria provided, single submitter clinical testing The c.490-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 5 of the CFTR gene. This alteration was reported as compound heterozygous in two individuals with cystic fibrosis (CF) and pancreatic insufficiency (PI), moderate pulmonary disease, and elevated sweat chloride levels (Zielenski J et. al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids;1995). Additionally, this alteration was detected as compound heterozygous in an individual with CF, who had mild pulmonary disease and elevated sweat chloride levels (Krzyanowska P et al. Sci Rep, 2015 Jul;5:12000). This nucleotide position is highly conserved on sequence alignment. 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672764 SCV004038902 likely pathogenic Cystic fibrosis 2024-10-11 criteria provided, single submitter clinical testing Variant summary: CFTR c.490-1G>A 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: Four predict the variant abolishes a 3' acceptor site. Two predict the variant creates a 3' acceptor site. One predicts the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 249200 control chromosomes. c.490-1G>A has been reported in the literature in individuals affected with Cystic Fibrosis who were reported as presumed compound heterozygous with other pathogenic variants (Krzyzanowska_2015, Montgomery_2018). These data indicate that the variant is likely to be 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: 26160248, 29884450). ClinVar contains an entry for this variant (Variation ID: 53974). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV004566885 SCV005057444 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-01-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV001831793 SCV002080151 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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