ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.743+1G>C

dbSNP: rs397508791
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000047247 SCV000220603 likely pathogenic Cystic fibrosis 2014-08-20 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV000047247 SCV001590398 pathogenic Cystic fibrosis 2023-07-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 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 individuals with cystic fibrosis (PMID: 7472820, 12454843, 19481507, 22658665). This variant is also known as c.875+1G>C. ClinVar contains an entry for this variant (Variation ID: 54052). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001509316 SCV001715950 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing PVS1, PM2
Baylor Genetics RCV003474617 SCV004213359 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-09-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047247 SCV005380388 likely pathogenic Cystic fibrosis 2024-08-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.743+1G>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. 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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251316 control chromosomes. c.743+1G>C, also known under the legacy name 875+1G>C, has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Wilschanski_1995, Scotet_2003). 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: 12815607, 7472820). ClinVar contains an entry for this variant (Variation ID: 54052). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001831802 SCV002078134 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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