ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1432+1G>A (rs755959303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492464 SCV000580723 pathogenic Hereditary cancer-predisposing syndrome 2016-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239711 SCV000298084 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000254996 SCV000321668 likely pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The c.1432+1G>A splice site variant in the FLCN gene has been previously reported in association with Birt-Hogg-Dube syndrome (Toro et al., 2008). This variant destroys the canonical splice donor site in intron 12, and is expected to cause abnormal gene splicing. The c.1432+1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000239711 SCV000632843 likely pathogenic Multiple fibrofolliculomas 2018-04-17 criteria provided, single submitter clinical testing This sequence change affects a donor 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 been reported in the literature in an individual affected with Birt-Hogg-Dubé syndrome (PMID: 18234728) and an individual affected with familial colorectal cancer (PMID: 27356891). This variant is also known as IVS12+1G>A. ClinVar contains an entry for this variant (Variation ID: 253252). 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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