Submissions for variant NM_144997.7(FLCN):c.1193G>C (p.Gly398Ala)

gnomAD frequency: 0.00001  dbSNP: rs766801011

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530248	SCV000632829	uncertain significance	Birt-Hogg-Dube syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 398 of the FLCN protein (p.Gly398Ala). This variant is present in population databases (rs766801011, gnomAD 0.01%). 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: 460585). 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%. 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	RCV002350218	SCV002645586	likely benign	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Fulgent Genetics, Fulgent Genetics	RCV005004222	SCV002806162	uncertain significance	Familial spontaneous pneumothorax; Nonpapillary renal cell carcinoma; Colorectal cancer; Birt-Hogg-Dube syndrome 1	2024-05-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000530248	SCV004195366	uncertain significance	Birt-Hogg-Dube syndrome	2023-05-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004787855	SCV005406221	likely benign	Birt-Hogg-Dube syndrome 1	2024-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000150	SCV005623365	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	The FLCN c.1193G>C (p.Gly398Ala) variant has not been reported in individuals with FLCN-related conditions in the published literature. The frequency of this variant in the general population, 0.000016 (4/249082 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 deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.