Submissions for variant NM_144997.7(FLCN):c.763C>T (p.His255Tyr) (rs879255664)

Total submissions: 2

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	Multiple fibrofolliculomas	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.