ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1433-2A>G

gnomAD frequency: 0.00001  dbSNP: rs398124528
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000082628 SCV000114670 pathogenic not provided 2012-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166694 SCV000217502 likely pathogenic Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing The c.1433-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 10 in the FLCN gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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.
GeneDx RCV000082628 SCV000321669 pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing The c.1433-2A>G splice site variant in the FLCN gene destroys the canonical splice acceptor site in intron 12. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. This pathogenic variant has not been previously reported to our knowledge.
Labcorp Genetics (formerly Invitae), Labcorp RCV000796649 SCV000936170 likely pathogenic Birt-Hogg-Dube syndrome 2019-12-16 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). 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. This variant has not been reported in the literature in individuals with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 96476). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 12 of the FLCN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Myriad Genetics, Inc. RCV000796649 SCV004042955 likely pathogenic Birt-Hogg-Dube syndrome 2023-04-27 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

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