Submissions for variant NM_144997.7(FLCN):c.763C>T (p.His255Tyr)

dbSNP: rs879255664

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239703	SCV000298058	uncertain significance	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000489495	SCV000577487	pathogenic	not provided	2018-02-06	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted FLCN c.763C>T at the cDNA level, p.His255Tyr (H255Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has been reported in at least one individual with Birt-Hogg-Dub? syndrome (Hasumi 2016). FLCN His255Tyr demonstrated reduced FLCN protein compared to wild-type in a functional assay and, in a mouse model, FLCN His255Tyr led to the development of an oncocytic hybrid kidney tumor (Hasumi 2009, Hasumi 2016). A missense variant in the same residue (His255Pro) has been reported in association with Birt-Hogg-Dub? syndrome, supporting the functional importance of this region of the protein (Nahorski 2011). FLCN His255Tyr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV003165679	SCV003856230	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The p.H255Y pathogenic mutation (also known as c.763C>T), located in coding exon 4 of the FLCN gene, results from a C to T substitution at nucleotide position 763. The histidine at codon 255 is replaced by tyrosine, an amino acid with similar properties. This mutation has been identified in multiple individuals with clinical diagnoses of Birt-Hogg Dube syndrome (BHD) or major clinical features of the condition (Hasumi Y et al. Proc Natl Acad Sci U S A, 2009 Nov;106:18722-7; Al-Shinnag M et al. Front Oncol, 2021 Sep;11:738822) and segregated with disease in at least one family (Hasumi H et al. Hum Mol Genet, 2017 Jan;26:354-366). FLCN H255Y also demonstrated loss of tumor supressor function and did not reverse the multicystic kidney phenotype in transgenic, FLCN-deficient mice (Hasumi Y et al. Proc Natl Acad Sci U S A, 2009 Nov;106:18722-7; Hasumi H et al. Hum Mol Genet, 2017 Jan;26:354-366). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000239703	SCV004042923	likely pathogenic	Birt-Hogg-Dube syndrome	2023-04-21	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28007907]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34604083, 28007907].
Invitae	RCV000239703	SCV004285900	uncertain significance	Birt-Hogg-Dube syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 255 of the FLCN protein (p.His255Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 28007907). ClinVar contains an entry for this variant (Variation ID: 253236). 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. Experimental studies have shown that this missense change affects FLCN function (PMID: 28007907). This variant disrupts the p.His255 amino acid residue in FLCN. Other variant(s) that disrupt this residue have been observed in individuals with FLCN-related conditions (PMID: 19850877, 21538689), which suggests that this may be a clinically significant amino acid residue. 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.