ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1501G>A (p.Glu501Lys) (rs180177038)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000207513 SCV000338452 pathogenic not provided 2015-12-29 criteria provided, single submitter clinical testing
Invitae RCV000033315 SCV000948576 pathogenic Rasopathy 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 501 of the BRAF protein (p.Glu501Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with cardio-facio-cutaneous syndrome (PMID: 19206169). ClinVar contains an entry for this variant (Variation ID: 13977). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.501 amino acid residue in BRAF have been observed in affected individuals (PMID: 16474404, 20186801, 25463315). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844616 SCV000197148 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-05-23 no assertion criteria provided clinical testing The Glu501Lys variant in BRAF has been previously identified in four patients wi th clinical features of the Noonan spectrum (Razzaque 2007, LMM unpublished data ) and reportedly occurred de novo in two patients with Cardio-facio-cutaneous sy ndrome (CFC; Niihori 2006, Rodriguez-Viciana 2006). In addition, this variant wa s absent from large population studies. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207513 SCV000263065 likely pathogenic not provided 2015-07-22 criteria provided, single submitter clinical testing
OMIM RCV000015011 SCV000035267 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

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