ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.429C>G (p.Phe143Leu) (rs773792624)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432084 SCV000530831 uncertain significance not provided 2016-08-16 criteria provided, single submitter clinical testing This variant is denoted FLCN c.429C>G at the cDNA level, p.Phe143Leu (F143L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FLCN Phe143Leu 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. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. FLCN Phe143Leu occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether FLCN Phe143Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571995 SCV000673467 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-15 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000689693 SCV000817356 uncertain significance Multiple fibrofolliculomas 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 143 of the FLCN protein (p.Phe143Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 388510). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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