ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1433-2A>G (rs398124528)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
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.
Invitae RCV000796649 SCV000936170 likely pathogenic Multiple fibrofolliculomas 2019-12-16 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). 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). 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 FLCN are known to be pathogenic (PMID: 15852235). 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.

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