ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1253T>C (p.Leu418Pro) (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 Multiple fibrofolliculomas 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 Multiple fibrofolliculomas 2020-09-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 418 of the FLCN protein (p.Leu418Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 253246). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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