Submissions for variant NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)

dbSNP: rs180177040

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000211751	SCV000616362	pathogenic	Cardio-facio-cutaneous syndrome	2017-04-03	reviewed by expert panel	curation	The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6_Strong, PS3.
GeneDx	RCV000033329	SCV000057234	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate N581D shows impaired ability to induce phosphorylation of ERK and MEK (Niihori et al., 2006); 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, 34573299, 30141192, 33040082, 22876591, 19376813, 24803665, 30050098, 29907801, 33967092, 34643321, 16474404, 25463315)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211751	SCV000061593	pathogenic	Cardio-facio-cutaneous syndrome	2013-07-12	criteria provided, single submitter	clinical testing	The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least 180 control chromosomes (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008 , Yoon 2007, Hazan 2012). This variant was observed to have occurred de novo in at least three of these individuals (Rodriguez-Viciana 2006, Hazan 2012). The As n581Asp variant has also been identified by our laboratory in one individual wit h Cardio-facio-cutaneous syndrome (LMM unpublished data), and was not identified in this individual's parents. Additionally, the Asparagine (Asn) residue at pos ition 581 is highly conserved across evolutionarily distant species, and the var iant was not identified in large population studies. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrence, and absence from controls.
Invitae	RCV000474979	SCV000553829	pathogenic	RASopathy	2022-07-25	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 581 of the BRAF protein (p.Asn581Asp). This missense change has been observed in individual(s) with features of cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 16474404, 17366577, 18042262, 22876591, 24037001, 25463315). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 19376813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 13979).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211751	SCV000698333	pathogenic	Cardio-facio-cutaneous syndrome	2016-11-04	criteria provided, single submitter	clinical testing	Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase domain (InterPro, Niihori_2006). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 121424 control chromosomes. In literature, this variant is reported as a pathogenic variant found in several patients with cardio-facio-cutaneous syndrome, including reported de novo occurrences (Niihori_2006, Rodriguez-Viciana_2006, Narumi_2007, Nava_2007, Schulz_2008, Pierpont _2010, Hazan_2012, Quaio_2013). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Functional studies in zebra fish have shown that the N581D variant results in developmental defects that can be rescued by FGF-MAPK pathway inhibitors (Anastasaki_2009). Taken together, this variant is classified as Pathogenic.
Ambry Genetics	RCV004018631	SCV000742141	pathogenic	Cardiovascular phenotype	2023-05-25	criteria provided, single submitter	clinical testing	The c.1741A>G (p.N581D) alteration is located in exon 14 (coding exon 14) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 1741. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including multiple cases with reported de novo occurrences (Niihori, 2006; Rodriguez-Viciana, 2006; Yoon, 2007; Hazan, 2012; Ciara, 2014; Battaglia, 2021; Pierpont, 2022). Another alteration at the same codon, c.1741A>C (p.N581H), has been reported de novo in an individual with features of BRAF-related RASopathy (Sparks, 2020). This amino acid position is highly conserved in available vertebrate species. The p.N581D amino acid is located in the catalytic loop of BRAF (Niihori, 2006). Experimental studies on the effect of cardiofaciocutaneous syndrome mutant alleles in an in vivo zebrafish model system showed that the p.N581D alteration can result in developmental abnormalities in zebrafish when expressed during early development. The mutant embryos were shown to respond to treatment with inhibitors of the FGF-MAPK pathway (Anastasaki, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000015013	SCV000781086	pathogenic	Cardiofaciocutaneous syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000033329	SCV001446714	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion	RCV000015013	SCV002012143	pathogenic	Cardiofaciocutaneous syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, PM6_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19376813, 16474404). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn621Lys) has been reported as pathogenic (ClinVar ID: VCV000044811.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.932, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000033329	SCV002022065	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing
OMIM	RCV000015013	SCV000035269	pathogenic	Cardiofaciocutaneous syndrome 1	2006-03-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000033329	SCV001807094	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000033329	SCV001951112	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - CFC International	RCV000211751	SCV003761515	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	phenotyping only
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000015013	SCV003840148	pathogenic	Cardiofaciocutaneous syndrome 1		no assertion criteria provided	research
Molecular Genetics, Centre for Human Genetics	RCV003450642	SCV004190104	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing