ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe) (rs180177036)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844617 SCV000204150 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-10-21 criteria provided, single submitter clinical testing The c.1455G>T (Leu485Phe) variant in BRAF has been previously identified in one individual with clinical features of a Cardio-facio-cutaneous syndrome (LMM unpu blished data). It was absent from large population studies (http://evs.gs.washin gton.edu/EVS/). In addition, a different variant with the same amino acid change (c.1455G>C) was identified in four individuals with clinical features of a RASo pathy (Niihori 2006, Rodriguez-Viciana 2006, LMM unpublished data). In vitro fu nctional studies provide some evidence that the Leu485Phe variant may impact pro tein function by increasing its kinase activity (Rodriguez-Viciana 2008). Howeve r, these types of assays may not accurately represent biological function. In s ummary, this variant meets our criteria to be classified as pathogenic (http://p cpgmwww.partners.org/personalizedmedicince/LMM).
Invitae RCV000154481 SCV000832735 likely pathogenic Rasopathy 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 485 of the BRAF protein (p.Leu485Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with cardio-facio-cutaneous syndrome (PMID: 28524057). ClinVar contains an entry for this variant (Variation ID: 177844). Experimental studies have shown that this missense change results in a BRAF protein with significantly increased kinase activity (PMID: 18413255, 16474404, 16439621). A different variant (c.1455G>C) giving rise to the same protein effect observed here (p.Leu485Phe) has been reported in individuals affected with cardio-facio-cutaneous syndrome and determined to be Likely pathogenic (PMID: 16474404, 16439621, 18039235, 19206169). In addition, another different missense substitution at this codon (p.Leu485Ser) has been reported in individuals affected with cardio-facio-cutaneous syndrome (PMID: 18039235, 21871821, 20395089). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824921 SCV000965953 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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