ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.247G>A (p.Glu83Lys) (rs757060348)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563799 SCV000673439 likely benign Hereditary cancer-predisposing syndrome 2016-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
GeneDx RCV000421206 SCV000532954 uncertain significance not provided 2016-10-26 criteria provided, single submitter clinical testing The E83K variant in the FLCN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The E83K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider E83K a variant of uncertain significance.
Invitae RCV000540761 SCV000632864 uncertain significance Multiple fibrofolliculomas 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 83 of the FLCN protein (p.Glu83Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs757060348, ExAC 0.01%). This variant has not been reported in the literature in individuals with FLCN-related disease. ClinVar contains an entry for this variant (Variation ID: 390184). 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 tolerated, 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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