ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.249+1G>T

dbSNP: rs1060502369
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000473630 SCV000549448 likely pathogenic Birt-Hogg-Dube syndrome 2016-05-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the FLCN gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an FLCN-related disease. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in FLCN are known to be pathogenic (PMID: 15852235). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV004022726 SCV005030724 pathogenic Hereditary cancer-predisposing syndrome 2022-05-05 criteria provided, single submitter clinical testing The c.249+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the FLCN gene. This variant has been reported in family with Birt-Hogg-Dube syndrome (BHDS) (Liu Y et al. Orphanet J Rare Dis. 2017 05;12:104. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor 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.

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