ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1286dup (p.His429fs) (rs879255675)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239666 SCV000298077 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000413427 SCV000490529 pathogenic not provided 2017-07-18 criteria provided, single submitter clinical testing The c.1286dupA variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dube syndrome (Toro et al., 2008; Maffe et al., 2011). The duplication causes a frameshift starting with codon Histidine 429, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.His429GlufsX27. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.1286dupA to be pathogenic, and its presence consistent with a diagnosis of Birt-Hogg-Dube syndrome.
Invitae RCV000239666 SCV000549466 pathogenic Multiple fibrofolliculomas 2017-06-06 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 11 of the FLCN mRNA (c.1286dupA), causing a frameshift at codon 429. This creates a premature translational stop signal (p.His429Glnfs*27) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic. This particular variant has been reported in the literature in an individual with Birt-Hogg-Dubé (BHD) syndrome (PMID: 18234728). This variant is also known as c.1741insA in the literature. A different variant, c.1285dupC (p.His429Profs*27), which results in the same truncated protein as the one observed here, has been reported in individuals affected with BHD syndrome (PMID: 18234728). It has been shown to affect the protein stability and tumor suppressor activity of the FLCN protein in cell culture (PMID: 21538689). For these reasons, this variant has been classified as Pathogenic.

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