ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1253T>C (p.Leu418Pro)

dbSNP: rs879255674
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239663 SCV000298074 uncertain significance Birt-Hogg-Dube syndrome 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000493637 SCV000582854 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing The L418P variant in the FLCN gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L418P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether L418P is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000239663 SCV001512354 uncertain significance Birt-Hogg-Dube syndrome 2023-03-21 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLCN protein function. ClinVar contains an entry for this variant (Variation ID: 253246). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 418 of the FLCN protein (p.Leu418Pro).

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