Submissions for variant NM_144997.7(FLCN):c.1085G>A (p.Arg362His)

dbSNP: rs559055296

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000635556	SCV000756973	uncertain significance	Birt-Hogg-Dube syndrome	2023-12-01	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 362 of the FLCN protein (p.Arg362His). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 529995). 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.
Sema4, Sema4	RCV002258979	SCV002530093	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	curation
GeneDx	RCV002305520	SCV002599987	uncertain significance	not provided	2023-08-11	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
Ambry Genetics	RCV002258979	SCV002724943	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	The p.R362H variant (also known as c.1085G>A), located in coding exon 7 of the FLCN gene, results from a G to A substitution at nucleotide position 1085. The arginine at codon 362 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000635556	SCV004195361	uncertain significance	Birt-Hogg-Dube syndrome	2023-05-19	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000635556	SCV004228542	not provided	Birt-Hogg-Dube syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.