ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.319_320delinsCAC (p.Val107fs) (rs398124535)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082635 SCV000114677 pathogenic not provided 2012-12-18 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239674 SCV000298043 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492373 SCV000580737 pathogenic Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing The c.319_320delGTinsCAC pathogenic mutation, located in coding exon 2 of the FLCN gene, results from the deletion of two nucleotides and insertion of three nucleotides at positions 319 to 320, causing a translational frameshift with a predicted alternate stop codon (p.V107Hfs*26). This mutation has been reported in multiple families with Birt-Hogg-Dubé syndrome (Toro JR et al J. Med. Genet. 2008 Jun; 45(6):321-31; Houweling AC et al. Br. J. Cancer 2011 Dec;105(12):1912-9; Gijezen LM et al. PLoS ONE 2014 Jun;9(6):e99071). Of note, this alteration is also designated as c.774-5delGTinsCAC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000082635 SCV000617547 pathogenic not provided 2017-07-07 criteria provided, single submitter clinical testing The c.319_320delGTinsCAC variant in the FLCN gene has been reported previously in at least two families with features of Birt-Hogg-Dube syndrome (Toro et al., 2008; Gijezen et al., 2014). This variant causes a frameshift starting with codon Valine 107, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Val107HisfsX26. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.319_320delGTinsCAC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Based on currently available evidence, we consider c.319_320delGTinsCAC to be pathogenic.
Invitae RCV000239674 SCV000756946 pathogenic Multiple fibrofolliculomas 2019-09-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val107Hisfs*26)) 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 observed in individuals affected with Birt-Hogg-Dub syndrome (PMID: 18234728, 22146830, 24910976). It is also known as c.774-5delGTinsCAC in the literature. ClinVar contains an entry for this variant (Variation ID: 96483). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.

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