ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.489+2T>C (rs397508732)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000577437 SCV000790974 likely pathogenic Cystic fibrosis 2017-04-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000577437 SCV000919189 likely pathogenic Cystic fibrosis 2021-07-07 criteria provided, single submitter clinical testing Variant summary: CFTR c.489+2T>C 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: Three predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245226 control chromosomes. c.489+2T>C has been reported in the primary literature as a homozygous genotype in at-least one individual affected with Cystic Fibrosis (example, Malone_1998) and has been subsequently cited by others (example, Bobadilla_2002, Kabra_2007, Wachter_2017). Additionally, at-least one patient who was reportedly compound heterozygous with the p.F508del variant on the other allele has been reported as an unpublished personal correspondence in the Sick kids database. 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. Two clinical diagnostic laboratories and the CFTR-France database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, pending the identification of additional well phenotyped and extensively genotyped CF patients with this variant and/or a study describing an unequivocal functional outcome, this splice site variant was classified as likely pathogenic.
CFTR-France RCV000577437 SCV001169314 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000577437 SCV001587013 pathogenic Cystic fibrosis 2019-02-22 criteria provided, single submitter clinical testing This sequence change affects a donor 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 not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual affected with cystic fibrosis (PMID: 9482579, 15371902, 23974870). This variant is also known as 621+2T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 53969). 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577437 SCV000679160 not provided Cystic fibrosis no assertion provided literature only

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