Submissions for variant NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)

dbSNP: rs180177037

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000207517	SCV000057217	pathogenic	not provided	2023-12-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22824468, 23505473, 18456719, 34184824, 18413255, 23093928, 16474404, 18042262, 19376813, 24803665, 16439621, 30462361, 31560489, 32369273, 28404629)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207517	SCV000263063	likely pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779848	SCV000916701	likely pathogenic	RASopathy	2018-04-09	criteria provided, single submitter	clinical testing	Variant summary: BRAF c.1495A>G (p.Lys499Glu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246384 control chromosomes (in gnomAD and publication data). c.1495A>G has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008). These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, and both of them demonstrated an increased kinase activity for the variant protein (Rodriguez-Viciana 2006, Niihori 2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813210	SCV002060606	pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
3billion	RCV000015010	SCV002521581	pathogenic	Cardiofaciocutaneous syndrome 1	2022-05-22	criteria provided, single submitter	clinical testing	Amino acid change identical t o known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000013976, PMID:16474404). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000040371,VCV000040372, PMID:18042262). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported. In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.829>=0.6). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome. It is absent from the gnomAD v2.1.1 dataset. ATherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000015010	SCV002577539	pathogenic	Cardiofaciocutaneous syndrome 1	2021-11-22	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP2, PP3, PP5
OMIM	RCV000015010	SCV000035266	pathogenic	Cardiofaciocutaneous syndrome 1	2006-03-01	no assertion criteria provided	literature only
GenomeConnect - CFC International	RCV000015010	SCV001156341	not provided	Cardiofaciocutaneous syndrome 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-12-2018 by Lab or GTR ID Kaizer Franz Josef Hospital. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.