ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
22146830 Houweling et al. 2011 presented the clinical data of 115 FLCN mutation carriers from 35 Birt?Hogg?Dub? (BDH) families. In two of the families with clinical BHD but without a mutation in the coding region of FLNC, a deletion of exon 1 was observed. Exon 1 is the first of three non-coding exons. The exact size and the effects of these deletions remain to be determined.
20413710 Kunogi et al. 2010 studied 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography and qPCR were applied for mutation screening. An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations, which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3'-end of the FLCN gene including exons 12 and 13 (13/25=52.0%).
21412933 Benhammou et al. 2011 identified six intragenic deletions and one intragenic duplication in 47% (7/15) of unrelated BHDS families and characterized 5 of 7 breakpoints. Data from this study confirm that, in addition to frameshift, missense, nonsense and splice-site mutations, BHDS can be caused by intragenic CNVs.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.