Submissions for variant NM_144997.7(FLCN):c.1141G>A (p.Val381Met)

dbSNP: rs1347669124

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000805211	SCV000945159	uncertain significance	Birt-Hogg-Dube syndrome	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 381 of the FLCN protein (p.Val381Met). 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: 650120). 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	RCV002453795	SCV002617156	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	The p.V381M variant (also known as c.1141G>A), located in coding exon 7 of the FLCN gene, results from a G to A substitution at nucleotide position 1141. The valine at codon 381 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003117595	SCV003798914	uncertain significance	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153847	SCV003843337	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000805211	SCV004195325	uncertain significance	Birt-Hogg-Dube syndrome	2023-08-28	criteria provided, single submitter	clinical testing