ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The 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.

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