ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg) (rs1131690833)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492176 SCV000580742 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-23 criteria provided, single submitter clinical testing The p.W553R variant (also known as c.1657T>C), located in coding exon 11 of the FLCN gene, results from a T to C substitution at nucleotide position 1657. The tryptophan at codon 553 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals who has a personal or family history that is consistent with FLCN-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural assessment, this alteration disrupts the C-terminal DENN-like domain, which is a guanine nucleotide exchange factor implicated in FLCN’s role in membrane trafficking (Ambry internal data; Nookala RK et al. Open Biol, 2012 Aug;2:120071; Dodding MP. Small GTPases, 2017 04;8:100-105; Schmidt LS et al. Gene, 2018 Jan;640:28-42). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000690635 SCV000818332 pathogenic Multiple fibrofolliculomas 2020-05-03 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 553 of the FLCN protein (p.Trp553Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome (Invitae, external communications). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428647). 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. For these reasons, this variant has been classified as Pathogenic.

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