ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.927_954dup (p.Gly319fs) (rs398124542)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239656 SCV000298065 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082645 SCV000331101 pathogenic not provided 2015-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000082645 SCV000565007 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing This duplication of 28 nucleotides in FLCN is denoted c.927_954dup28 at the cDNA level and p.Gly319SerfsX80 (G319SfsX80) at the protein level. Using alternate nomenclature, this variant would be defined as FLCN 1378_1405dup. The surrounding sequence is AGAA[dup28]GGGC. The duplication causes a frameshift which changes a Glycine to a Serine at codon 319, and creates a premature stop codon at position 80 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. FLCN c.927_954dup28 has been reported in several individuals with Birt-Hogg-Dub? syndrome, segregating with disease in affected kindreds (Nickerson 2002, Schmidt 2005, Toro 2008, Wang 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000492117 SCV000580733 pathogenic Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000239656 SCV000756986 pathogenic Multiple fibrofolliculomas 2019-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly319Serfs*80) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Birt-Hogg-Dub (BHD) syndrome in a single family. It has also been observed in unrelated individuals with BHD (PMID: 12204536, 19802896), and an individual with multiple fibrofolliculomas (PMID: 26402642). This variant is also known as c.923_950dup and 1378-1405dup in the literature. ClinVar contains an entry for this variant (Variation ID: 96493). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781384 SCV000919363 pathogenic Pneumothorax, primary spontaneous 2018-03-16 criteria provided, single submitter clinical testing Variant summary: FLCN c.927_954dup28 (p.Gly319SerfsX80) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.1389C>G (p.Tyr463X) has been classified as pathogenic by our laboratory. The variant was absent in 121372 control chromosomes (ExAC). The variant, c.927_954dup28, also known as c.1378_1405dup, has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (Schmidt_2005). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (PMS2 c.2186_2187delTC, p.Leu729fsX6). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000239656 SCV000023691 pathogenic Multiple fibrofolliculomas 2009-09-01 no assertion criteria provided literature only

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