Submissions for variant NM_144997.7(FLCN):c.1048C>T (p.Arg350Trp)

gnomAD frequency: 0.00002  dbSNP: rs1261069493

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567340	SCV000673434	likely benign	Hereditary cancer-predisposing syndrome	2021-05-17	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.
Invitae	RCV000635560	SCV000756977	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 tryptophan, which is neutral and slightly polar, at codon 350 of the FLCN protein (p.Arg350Trp). 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: 485589). 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.
GeneDx	RCV001548632	SCV001768577	uncertain significance	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000635560	SCV002584563	uncertain significance	Birt-Hogg-Dube syndrome	2022-08-17	criteria provided, single submitter	clinical testing	The FLCN c.1048C>T (p.Arg350Trp) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In addition, a computational saturation assay on protein structural destabilization showed that this variant would not change protein structure (PMID: 33137092). To our knowledge, this variant has not been reported in individuals with Birt-Hogg-Dubé syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.