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

dbSNP: rs180177039

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000207518	SCV000057222	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 16439621, 18413255, 17366577, 16474404, 24803665, 32959227, 30732632, 30141192, 30094826, 17704260, 17483702)
Laboratory for Molecular Medicine, Mass General Brigham 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 Children's Health, Delaware	RCV000207518	SCV000263066	pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing
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
Invitae	RCV000808147	SCV000948240	pathogenic	RASopathy	2023-05-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu501 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169, 20186801, 25463315). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 13978). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 16474404, 17483702). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 501 of the BRAF protein (p.Glu501Gly).
3billion	RCV000015012	SCV002012061	pathogenic	Cardiofaciocutaneous syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 1647440, 17366577, 17704260, PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu501Lys and pGlu501Ala) has been reported as pathogenic (VCV000013977.4, VCV000040373.5, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000015012	SCV000035268	pathogenic	Cardiofaciocutaneous syndrome 1	2006-03-01	no assertion criteria provided	literature only
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	RCV000015012	SCV000143823	not provided	Cardiofaciocutaneous syndrome 1		no assertion provided	not provided
Natera, Inc.	RCV001273349	SCV001456324	pathogenic	Familial cardiofaciocutaneous syndrome	2020-09-16	no assertion criteria provided	clinical testing