Submissions for variant NM_144997.7(FLCN):c.780-2A>G

dbSNP: rs1555609514

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519471	SCV000618088	pathogenic	not provided	2019-07-25	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29157599, 30533232)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386655	SCV001586968	pathogenic	Birt-Hogg-Dube syndrome	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the FLCN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Birt-Hogg-Dube syndrome (PMID: 29157599, 30533232). ClinVar contains an entry for this variant (Variation ID: 449726). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and retention of intron 7, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002413404	SCV002674743	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The c.780-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 5 in the FLCN gene. This variant was reported in multiple individuals with features consistent with Birt-Hogg-Dube syndrome (Volk C et al. Case Rep Genet, 2018 Nov;2018:4173704; Iwabuchi C et al. J Dermatol Sci, 2018 Jan;89:77-84; Sattler EC et al. Eur J Cancer, 2021 Jul;151:168-174; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000519471	SCV004227695	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000519471	SCV005872504	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	RCV001386655	SCV004032406	pathogenic	Birt-Hogg-Dube syndrome	2023-07-01	no assertion criteria provided	clinical testing