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 2021-03-12 criteria provided, single submitter clinical testing Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Rossing 2017); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 15852235, 26659639, 20522427, 18234728, 17133269, 25519458, 29720200, 29357828, 27734835)
Invitae RCV000812531 SCV000952848 pathogenic Multiple fibrofolliculomas 2020-09-11 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-Dubé 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 The c.1062+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the FLCN gene. This mutation has been detected in numerous individuals meeting clinical diagnostic criteria for Birt-Hogg-Dube syndrome (BHD) (Schmidt LS et al. Am J Hum Genet. 2005 Jun;76(6):1023-33; Gad S et al. Br J Cancer. 2007 Jan 29;96(2):336-40; ​Toro JR et al. J Med Genet. 2008 Jun;45(6):321-31; Benusiglio PR et al. Orphanet J Rare Dis. 2014 Oct 29;9:163; Whitworth J et al. JAMA Oncol. 2016 Mar;2(3):373-9; Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). While this mutation has been identified in BHD patients of various ethnicities, it has been reported to be especially prevalent in the Danish population and haplotype analysis revealed that it is a Danish founder mutation (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). Finally, a mini-gene splicing assay has shown that this mutation causes aberrant splicing (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). 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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