ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680805 SCV000808250 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing The L485F variant has been published previously in association with cardio-facio-cutaneous (CFC) syndrome, including apparently de novo occurrences (Niihori et al., 2006; Sarkozy et al., 2009; Carcavilla et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies have shown L485F acts as a gain-of-function variant and stimulates the MAPK pathway (Niihori et al., 2006; Hu et al., 2015). Missense variants in the same residue (L485S) and in nearby residues (A481E, V487G) have been reported in the Human Gene Mutation Database in association with CFC syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
OMIM RCV000015009 SCV000035265 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211749 SCV000197149 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-10-21 no assertion criteria provided clinical testing The c.1455G>C (p.Leu485Phe) variant in BRAF has been previously identified in fo ur individuals with clinical features of a RASopathy (Niihori 2006, Rodriguez-Vi ciana 2006, LMM unpublished data). It was absent from large population studies ( http://evs.gs.washington.edu/EVS/; dbSNP rs180177036). In addition, a different variant with the same amino acid change (c.1455G>T) was identified by our labora tory in one individual with Cardio-facio-cutaneous syndrome (CFC). In vitro func tional studies provide some evidence that the p.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).
GeneReviews RCV000208764 SCV000264633 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only

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