ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.716G>A (p.Arg239His)

gnomAD frequency: 0.00004  dbSNP: rs753948488
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239701 SCV000298055 uncertain significance Birt-Hogg-Dube syndrome 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000239701 SCV000549432 uncertain significance Birt-Hogg-Dube syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 239 of the FLCN protein (p.Arg239His). This variant is present in population databases (rs753948488, gnomAD 0.006%). 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: 253233). 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 expected to disrupt FLCN protein function with a positive predictive value of 80%. 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.
Ambry Genetics RCV000561577 SCV000673404 likely benign Hereditary cancer-predisposing syndrome 2023-03-27 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
GeneDx RCV001527887 SCV001739031 uncertain significance not provided 2023-10-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not segregate with the disorder in affected individuals from a family with Birt-Hogg-Dube disease in published literature (PMID: 37331486); This variant is associated with the following publications: (PMID: 26489445, 19562744, 18794106, 30083234, 37331486)
Fulgent Genetics, Fulgent Genetics RCV002487112 SCV002787150 uncertain significance Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Nonpapillary renal cell carcinoma; Colorectal cancer 2021-12-27 criteria provided, single submitter clinical testing

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