Submissions for variant NM_144997.7(FLCN):c.250-1G>A

dbSNP: rs786202081

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164717	SCV000215388	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-22	criteria provided, single submitter	clinical testing	The c.250-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 2 of the FLCN gene. This alteration has been identified in multiple family members diagnosed with Birt-Hogg-Dube (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). Of note, this alteration is also known as IVS4-1G>A in published literature. 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. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239714	SCV000298041	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000490144	SCV000576551	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of the adjacent exon; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19802896, 21937013, 15852235, 28152038, 29357828)
MGZ Medical Genetics Center	RCV000239714	SCV002581026	pathogenic	Birt-Hogg-Dube syndrome	2022-07-15	criteria provided, single submitter	clinical testing
Invitae	RCV000239714	SCV003248775	pathogenic	Birt-Hogg-Dube syndrome	2022-09-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 185318). This variant is also known as IVS4-1G>A. Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 18234728). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the FLCN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235).
Myriad Genetics, Inc.	RCV000239714	SCV004043888	likely pathogenic	Birt-Hogg-Dube syndrome	2023-05-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.