Submissions for variant NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys)

gnomAD frequency: 0.00002  dbSNP: rs557336321

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564803	SCV000673422	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	clinical testing	The p.R362C variant (also known as c.1084C>T), located in coding exon 7 of the FLCN gene, results from a C to T substitution at nucleotide position 1084. The arginine at codon 362 is replaced by cysteine, an amino acid with highly dissimilar properties. In vitro analyses indicated that this variant led to a significantly less stable protein when compared to wildtype (p<0.05) (Nahorski MS et al. Hum. Mutat. 2011 Aug;32:921-9). This amino acid position is highly conserved in available vertebrate species. In another study, structural analysis indicates that this alteration is destabilizing and functional analyses demonstrated that p.R362C results in reduced protein production, reduced colony formation, and reduced solubility; function was stabilized at a lower temperature (Clausen L et al. PLoS Genet 2020 11;16(11):e1009187). In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000691604	SCV000819390	uncertain significance	Birt-Hogg-Dube syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 362 of the FLCN protein (p.Arg362Cys). This variant is present in population databases (rs557336321, gnomAD 0.003%). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 35441217). ClinVar contains an entry for this variant (Variation ID: 485585). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLCN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FLCN function (PMID: 21538689, 33137092). 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.
Illumina Laboratory Services, Illumina	RCV001127833	SCV001287182	uncertain significance	Familial spontaneous pneumothorax	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000691604	SCV001287183	uncertain significance	Birt-Hogg-Dube syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000691604	SCV002030098	uncertain significance	Birt-Hogg-Dube syndrome	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV002483536	SCV002783063	uncertain significance	Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Nonpapillary renal cell carcinoma; Colorectal cancer	2021-11-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321681	SCV004026705	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409849	SCV004116445	uncertain significance	FLCN-related condition	2023-01-26	criteria provided, single submitter	clinical testing	The FLCN c.1084C>T variant is predicted to result in the amino acid substitution p.Arg362Cys. This variant has been reported in an individual with breast cancer (Chen et al. 2020. PubMed ID: 32091409). In silico structural analyese and experimental studies using a yeast based assay suggest this variant may impact protein function (Clausen et al. 2020. PubMed ID: 33137092). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17120475-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/485585/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000691604	SCV004195329	uncertain significance	Birt-Hogg-Dube syndrome	2023-08-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478283	SCV004218907	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with renal cell carcinoma (PMID: 35441217 (2022)). Functional studies have reported this variant has a damaging effect on protein function (PMID: 21538689 (2011), 33137092 (2020)). The frequency of this variant in the general population, 0.000027 (3/113102 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.