ClinVar Genomic variation as it relates to human health

Variant summary: FLCN c.619-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 3'- acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251398 control chromosomes. c.619-1G>A has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (examples- Leter_2008, Houweling_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is not present in population databases (gnomAD no frequency). 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: 428657). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 17611575, 27652079). This sequence change affects an acceptor splice site in intron 6 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).

The c.619-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 4 of the FLCN gene. This alteration, referred to as c.1074-1G>A, was previously identified in two unrelated families with Birt-Hogg-Dube syndrome (Leter EM et al. J. Invest. Dermatol. 2008 Jan;128(1):45-9). 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 pathogenic.

The FLCN c.619-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with Birt-Hogg-Dube syndrome (Table 1, Referred to as c.1074-1G>A, Leter et al. 2008. PubMed ID: 17611575; Tables S4 and S7, Hartman et al. 2020. PubMed ID: 32782288; Table 2, Houweling et al. 2011. PubMed ID: 22146830; Table 2, Johannesma et al. 2016. PubMed ID: 27652079). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/428657/). Variants that disrupt the consensus splice acceptor site in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.