ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.250-2A>G (rs398124533)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082633 SCV000114675 pathogenic not provided 2012-08-02 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239670 SCV000298040 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000082633 SCV000321650 pathogenic not provided 2021-01-21 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (Stenson 2014); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31958439, 29357828, 25525159, 21937013, 19802896, 25610687, 18234728)
Ambry Genetics RCV000492149 SCV000580730 pathogenic Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing The c.250-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the FLCN gene. This alteration was previously identified in 13 individuals from 4 unrelated families affected with perifollicular fibromas, trichodiscomas, renal tumors, lung cysts and spontaneous pneumothorax (Toro J et al. J Med Genet. 2008 Jun;45(6):321-31). In addition to the clinical data presented in the literature, 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 a disease-causing mutation.
Invitae RCV000239670 SCV000632865 pathogenic Multiple fibrofolliculomas 2020-09-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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 been reported in in individuals and a family affected with Birt-Hogg-Dubé syndrome (PMID: 18234728). This variant is also known as IVS4-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 96481). 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). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000239670 SCV000023701 pathogenic Multiple fibrofolliculomas 2009-09-01 no assertion criteria provided literature only

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