ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1522_1524del (p.Lys508del) (rs398124529)

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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 RCV000082629 SCV000114671 pathogenic not provided 2013-07-11 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239713 SCV000298087 likely pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000082629 SCV000321670 pathogenic not provided 2015-08-29 criteria provided, single submitter clinical testing The c.1522_1524delAAG variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dubé syndrome (So, 2009). It 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. This variant causes an in-frame deletion of codon Lysine 508, denoted p.Lys508del. Functional studies have shown that c.1522_1524delAAG significantly impairs the stability of the protein product, folliculin (Nahorski et al., 2011). We interpret c.1522_1524delAAG as a pathogenic variant.
Invitae RCV000239713 SCV000937134 pathogenic Multiple fibrofolliculomas 2019-09-18 criteria provided, single submitter clinical testing This variant, c.1522_1524delAAG, results in the deletion of 1 amino acid of the FLCN protein (p.Lys508del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Birt-Hogg-Dub syndrome in one family (PMID: 19659657). It has also been observed in unrelated individuals with Birt-Hogg-Dub syndrome (PMID: 23364595, Invitae). ClinVar contains an entry for this variant (Variation ID: 96477). Experimental studies have shown that this deletion of 1 amino acid results in an unstable FLCN protein (PMID: 21538689). For these reasons, this variant has been classified as Pathogenic.

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