ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.490-1G>A (rs397508734)

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Total submissions: 4
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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.
Invitae RCV000672764 SCV001589435 pathogenic Cystic fibrosis 2020-09-02 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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs397508734, ExAC 0.02%). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 23857699, 26160248). It is also known as c.622-1G>A in the literature. 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, but this prediction has not been confirmed by published transcriptional studies. 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). For these reasons, this variant has been classified as Pathogenic.

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