ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1062+2T>G (rs886039370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254745 SCV000321659 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing The c.1062+2 T>G splice site variant in the FLCN gene has been previously reported in association with Birt-Hogg-Dube syndrome (Schmidt et al., 2005; Gad et al., 2007; Toro et al., 2008; Benusiglio et al., 2014). This mutation destroys the canonical splice donor site in intron 9, and is expected to cause abnormal gene splicing.
Invitae RCV000812531 SCV000952848 pathogenic Multiple fibrofolliculomas 2019-04-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the FLCN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in many families affected with Birt-Hogg-Dub syndrome (PMID: 15852235, 19802896, 27734835). The c.1062+2T>G variant has been reported as a founder mutation in the Danish population (PMID: 27734835), and is also known as IVS9_x0001_+2T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 265154). Experimental studies have shown that this variant results in the generation of two aberrant transcripts, one that leads to out-of-frame skipping of exon 9, and another that also leads to the out-of-frame activation of a cryptic donor splice site, located 130 nucleotides downstream of the natural splice site in intron 9 (PMID: 27734835). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001009818 SCV001169932 pathogenic Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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