FLCN NM_144997.7:c.1333G>A, Ala445Thr

p.Ala445Thr in exon 12 of FLCN: This variant is not expected to have clinical si gnificance because it has been identified in 0.37% (246/66324) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs41419545). Additionally, 47 species including 27 mammals have a threon ine (Thr) at this position.

Variant summary: FLCN c.1333G>A (p.Ala445Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 251048 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency greatly exceeds the estimated maximal expected allele frequency for a pathogenic variant in FLCN causing Birt-Hogg-Dube Syndrome phenotype (1.3e-06), strongly suggesting that the variant is benign. c.1333G>A has been reported in the literature in individuals affected with Birt-Hogg-Dube Syndrome (Kahnoski_2003), without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Birt-Hogg-Dube Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, 10 classify as likely benign/benign while 2 classify as VUS. Based on the evidence outlined above, the variant was classified as likely benign.