ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.33C>G (p.Cys11Trp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286124 SCV001472650 likely pathogenic none provided 2020-06-15 criteria provided, single submitter clinical testing The FLCN c.33C>G; p.Cys11Trp variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.31C>T, p.Cys11Arg) have been reported in individuals with Birt-Hogg-Dube syndrome (Lee 2019). The cysteine at codon 11 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Lee et al. Birt-Hogg-Dubé Syndrome in Korean: Clinicoradiologic Features and Long Term Follow-Up. Korean J Intern Med. 2019 Jul;34(4):830-840.
Invitae RCV001297304 SCV001486312 uncertain significance Multiple fibrofolliculomas 2020-05-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 11 of the FLCN protein (p.Cys11Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Cys11 amino acid residue in FLCN. Other variant(s) that disrupt this residue have been observed in individuals with FLCN-related conditions (PMID: 30360018, Invitae), which suggests that this may be a clinically significant amino acid residue. 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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