ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.649C>T (p.Gln217Ter)

dbSNP: rs1555609899
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519187 SCV000617531 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing The Q217X nonsense variant in the FLCN gene has been reported previously in at least one individual with features consistent with Birt-Hogg-Dube syndrome (Kluger et al., 2010). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q217X 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 Q217X to be pathogenic.
Ambry Genetics RCV002367730 SCV002659246 pathogenic Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing The p.Q217* pathogenic mutation (also known as c.649C>T), located in coding exon 4 of the FLCN gene, results from a C to T substitution at nucleotide position 649. This changes the amino acid from a glutamine to a stop codon within coding exon 4. This alteration was reported in a cohort of 22 French individuals with Birt-Hogg-Dube syndrome in an individual with skin findings including fibrofolliculomas, epidermoid cysts and acrochordons; multiple lung cysts; a Bosniak renal cyst; and nodules and cysts in the thyroid (Kluger N et al. Br. J. Dermatol., 2010 Mar;162:527-37). In addition to the information 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.
Invitae RCV003500542 SCV004297084 pathogenic Birt-Hogg-Dube syndrome 2023-07-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 449402). This premature translational stop signal has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome (PMID: 19785621, 29357828). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln217*) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235).

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