ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.619-1G>A (rs1131690840)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492185 SCV000580759 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000815117 SCV000955562 pathogenic Multiple fibrofolliculomas 2018-11-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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). This variant has been observed in individuals affected with Birt-Hogg-Dubé syndrome (PMID: 17611575, 27652079). ClinVar contains an entry for this variant (Variation ID: 428657). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Integrated Genetics/Laboratory Corporation of America RCV001174973 SCV001338456 pathogenic Birt-Hogg-Dubé Syndrome 2020-04-09 criteria provided, single submitter clinical testing 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.

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