ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs748878853
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Total submissions: 9
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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)
Invitae 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: 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.

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