Submissions for variant NM_144997.7(FLCN):c.1430G>A (p.Arg477Gln)

gnomAD frequency: 0.00003  dbSNP: rs748878853

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000379332	SCV000400984	uncertain significance	Spontaneous pneumothorax	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000266163	SCV000400985	uncertain significance	Birt-Hogg-Dube syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000414396	SCV000491087	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17028174)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000266163	SCV000632842	uncertain significance	Birt-Hogg-Dube syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 477 of the FLCN protein (p.Arg477Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 322061). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765332	SCV000896595	uncertain significance	Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Carcinoma of colon; Nonpapillary renal cell carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011546	SCV001171879	benign	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000414396	SCV002009909	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001011546	SCV002530119	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000414396	SCV004219702	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000085 (11/129108 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.