ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly) (rs180177039)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414915 SCV000492993 likely pathogenic Pulmonic stenosis; Webbed neck; Downslanted palpebral fissures; Premature birth; Wide intermamillary distance; High forehead; Low-set, posteriorly rotated ears; Ventricular hypertrophy; Neonatal respiratory distress; Ventricular septal defect 2014-10-08 criteria provided, single submitter clinical testing
GeneDx RCV000207518 SCV000057222 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing The E501G missense variant in the BRAF gene has been reported previously in association with Cardio-Facio-Cutaneous syndrome and with apparently de novo occurrences (Niihori et al., 2006; Narumi et al., 2007). E501G is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The E501G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (E501K/A/V) and a nearby residue (K499E/N) have been published in association with CFC syndrome (Niihori et al., 2006), supporting the functional importance of this region of the protein. Therefore, the presence this pathogenic variant is consistent with the diagnosis of a RASopathy.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000015012 SCV000143823 not provided Cardiofaciocutaneous syndrome 1 no assertion provided not provided
Invitae RCV000808147 SCV000948240 pathogenic Rasopathy 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 501 of the BRAF protein (p.Glu501Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cardio-facio-cutaneous syndrome, including at least one individual where the variant was reported de novo (PMID: 16474404, 16439621, 17483702). ClinVar contains an entry for this variant (Variation ID: 13978). 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. This variant disrupts the p.Glu501 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 25463315, 19206169, 20186801), suggesting that it is a clinically significant residue. As a result, 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 RCV000211750 SCV000061587 pathogenic Cardio-facio-cutaneous syndrome 2011-11-21 criteria provided, single submitter clinical testing The Glu501Gly variant has been reported in at least 7 individuals with clinical features of Cardio-facio-cutaneous syndrome and was absent from 280 control chro mosomes (Niihori 2006, Rodriguez-Viciana 2006, Narumi 2007, Rodriguez-Viciana 20 08). In addition, this variant was reported to have occurred de novo in two indi viduals, supporting a pathogenic role. Furthermore, glutamic acid (Glu) at posi tion 501 is highly conserved across evolutionarily distant species into C. elega ns and computational analyses (AlignGVGD, PolyPhen2, SIFT) predict that a change to a glycine (Gly) at this position may impact the protein. Based on this info rmation, this variant is highly likely to be pathogenic. The presence of a heter ozygous pathogenic variant in BRAF is consistent with a diagnosis of Cardio-faci o-cutaneous syndrome but this information should be reconciled with the complete clinical history of this individual.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207518 SCV000263066 pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
OMIM RCV000015012 SCV000035268 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.