Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781383 | SCV000919362 | likely pathogenic | Familial spontaneous pneumothorax | 2018-02-22 | criteria provided, single submitter | clinical testing | Variant summary: FLCN c.1432+2T>C 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 abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246180 control chromosomes. To our knowledge, no occurrence of c.1432+2T>C in individuals affected with Birt-Hogg-Dube Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Invitae | RCV003500601 | SCV004310083 | pathogenic | Birt-Hogg-Dube syndrome | 2023-07-26 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 12 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 633219). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |