Submissions for variant NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)

dbSNP: rs180177035

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000208766	SCV000616360	pathogenic	Cardio-facio-cutaneous syndrome	2017-04-03	reviewed by expert panel	curation	The c.770A>G (p.Gln257Arg) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID:18042262, PMID:17551924, PMID:16474404). In vitro functional studies provide some evidence that the p.Q257R variant may impact protein function (PS3; PMID:18413255; PMID:19376813). 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 exon 6, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Q257R variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for cardio-facio-cutaneous syndrome in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong.
GeneDx	RCV000080904	SCV000057194	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Functional in vitro studies have demonstrated that the p.(Q257R) variant results in increased kinase activity and activation of downstream effectors (MEK and ERK) (Rodriguez-Viciana et al., 2008), and in vivo studies have demostrated developmental defects and CFC-like features in animal models (Anastasaki et al., 2009; Moriya et al., 2015); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17551924, 29778030, 29704308, 34573299, 17703371, 23312806, 16474404, 18042262, 19376813, 26472072, 26242988, 28809097, 27799561, 28650561, 29084544, 23340054, 30050098, 32005694, 32369273, 29907801, 33482860, 31130284, 27322245, 24719372, 24803665, 24775816, 33795686, 33040082, 33726816, 31785789, 33860439, 18413255, 29493581, 17603483, 15520807, 16439621, 15488754, 24957944)
Eurofins Ntd Llc (ga)	RCV000080904	SCV000112811	pathogenic	not provided	2013-04-26	criteria provided, single submitter	clinical testing
Invitae	RCV000033289	SCV000218757	pathogenic	RASopathy	2023-09-19	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 13973). This missense change has been observed in individuals with Noonan spectrum disorders (PMID: 16474404, 17703371, 24719372, 24775816). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 257 of the BRAF protein (p.Gln257Arg). Experimental studies have shown that this missense change affects BRAF function (PMID: 16474404, 18413255). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000015007	SCV000236532	pathogenic	Cardiofaciocutaneous syndrome 1	2015-01-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000033289	SCV000245458	pathogenic	RASopathy	2013-07-11	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 24-year-old female with intellectual disability, epilepsy, coarse facial features, short stature, microcephaly, and severe brain ischemia and hemiparesis following cardiac arrest at age 8y.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000080904	SCV000263061	pathogenic	not provided	2015-07-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000080904	SCV000602655	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing	The BRAF c.770A>G, p.Gln257Arg variant (rs180177035) has been reported in multiple patients diagnosed with LEOPARD syndrome, cardio-facial-cutaneous syndrome or other RASopathies (Niihori 2006, Rodriguez-Viciana 2006, Gripp 2007, Narumi 2007, Nystrom 2008, Neumann 2009, Sarkozy 2009, Carcavilla 2013, Wong Ramsey 2014). The variant is located in the cysteine-rich domain of the BRAF conserved region 1 (Niihori 2006, Rodriguez-Viciana 2006), and several additional variants in neighboring codons have also been identified in cardio-facial-cutaneous syndrome (Kiel 2014). Functional analyses of the p.Gln257Arg variant protein indicates over-activation of phospho-MEK and phospho-ERK (Rodriguez-Viciana 2006, Rodriguez-Viciana 2008) and downstream transcriptional activity (Niihori 2006), consistent with the established disease mechanisms of BRAF-related disorders. This variant is reported in ClinVar (Variation ID: 13973) and is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamine at codon 257 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.838). Based on available information, this variant is considered to be pathogenic. References: Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. PMID: 24775816. Gripp KW et al. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007 Jul 1;143A(13):1472-80. PMID: 17551924.. Kiel C et al. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10(5):727. PMID: 24803665. Narumi Y et al. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. Am J Med Genet A. 2007 Apr 15;143A(8):799-807. PMID: 17366577. Niihori T et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006 Mar;38(3):294-6. PMID: 16474404. Nystrom AM et al. Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet. 2008 Aug;45(8):500-6. PMID: 18456719. Rodriguez-Viciana P et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006 Mar 3;311(5765):1287-90. PMID: 16439621. Rodriguez-Viciana P et al. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. PMID: 18413255. Sarkozy A et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009 Apr;30(4):695-702. PMID: 19206169.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208766	SCV000698346	pathogenic	Cardio-facio-cutaneous syndrome	2017-04-17	criteria provided, single submitter	clinical testing	Variant summary: The BRAF c.770A>G (p.Gln257Arg) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index) and is located in acylglycerol/phorbol-ester binding domain of the protein (InterPro). This variant is absent from 118580 control chromosomes from ExAC dataset. The variant is widely accepted to be pathogenic in the literature with concordant clinical and functional data. It is frequently reported in patients with CFC including evidence of de novo occurrences. In vitro as well as in vivo functional evidences are consistent with pathogenic outcome. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Ambry Genetics	RCV000623239	SCV000742125	pathogenic	Inborn genetic diseases	2023-02-03	criteria provided, single submitter	clinical testing	The c.770A>G (p.Q257R) alteration is located in exon 6 (coding exon 6) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 770, causing the glutamine (Q) at amino acid position 257 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This common mutation has been reported in individuals with clinical features of cardiofaciocutaneous (CFC) syndrome (Gripp, 2007; Joyce, 2016; Niihori, 2006; Mucciolo, 2016; Wong Ramsey, 2014). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.Q257R alteration has significantly increased kinase activity compare to wildtype (Rodriguez-Viciana, 2008). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Blueprint Genetics	RCV000080904	SCV000927948	pathogenic	not provided	2018-09-21	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000015007	SCV000999368	pathogenic	Cardiofaciocutaneous syndrome 1		criteria provided, single submitter	clinical testing
Mendelics	RCV000015007	SCV001137523	pathogenic	Cardiofaciocutaneous syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027771	SCV001190375	pathogenic	Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7	2019-08-13	criteria provided, single submitter	clinical testing	BRAF NM_004333.4 exon 6 p.Gln257Arg (c.770A>G): This variant is considered to be a common disease variant and has been reported in the literature in several individuals with cardiofaciocutaneous syndrome (CFC) and other Noonan-spectrum disorders, including several de novo occurrences (Niihori 2006 PMID:16474404, Gripp 2007 PMID:17551924, Schulz 2008 PMID:18042262, Sarkozy 2009 PMID:19206169, Neumann 2009 PMID:18854871, Carcavilla 2013 PMID:24775816, Wong Ramsey 2014 PMID:24719372, Joyce 2016 PMID:26242988, Xu 2017 PMID:29084544). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including an entry from the ClinGen RASopathies Expert Panel (Variation ID:13973). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, both in vitro and in vivo functional studies support that this variant will impact the protein (Niihori 2006 PMID:16474404, Rodriguez-Viciana 2008 PMID:18403255, Anastasaki 2009 PMID:19376813, Inoue 2014 PMID:25035421). In summary, this variant is classified as pathogenic based on the data above.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001261967	SCV001439323	pathogenic	Noonan syndrome 7	2020-07-22	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000080904	SCV001449679	pathogenic	not provided	2017-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000080904	SCV001502611	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001329219	SCV001520594	pathogenic	LEOPARD syndrome 3	2019-08-02	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813208	SCV002060974	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-04-01	criteria provided, single submitter	clinical testing
DASA	RCV001813744	SCV002061271	pathogenic	Noonan syndrome 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.770A>G;p.(Gln257Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13973; OMIM: 164757.0013; PMID:18042262; 17551924; 16474404; 17703371; 24719372; 24775816) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:18413255; 19376813; 16474404) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (C1_1; PMID: 29493581) - PM1. This variant is not present in population databases (rs180177035, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 40351) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID:18042262; 17551924) - PM6_strong. Missense variant in BRAF that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001261967	SCV003807319	pathogenic	Noonan syndrome 7	2022-03-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2 strong, PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PP1 supporting, PP3 supporting
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224098	SCV003920481	pathogenic	Cardiofaciocutaneous syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7; Melanoma, cutaneous malignant, susceptibility to, 1; Colorectal cancer; Lung cancer	2021-03-30	criteria provided, single submitter	clinical testing	BRAF NM_004333.4 exon 6 p.Gln257Arg (c.770A>G): This variant is considered to be a common disease variant and has been reported in the literature in several individuals with cardiofaciocutaneous syndrome (CFC) and other Noonan-spectrum disorders, including several de novo occurrences (Niihori 2006 PMID:16474404, Gripp 2007 PMID:17551924, Schulz 2008 PMID:18042262, Sarkozy 2009 PMID:19206169, Neumann 2009 PMID:18854871, Carcavilla 2013 PMID:24775816, Wong Ramsey 2014 PMID:24719372, Joyce 2016 PMID:26242988, Xu 2017 PMID:29084544). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including an entry from the ClinGen RASopathies Expert Panel (Variation ID:13973). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, both in vitro and in vivo functional studies support that this variant will impact the protein (Niihori 2006 PMID:16474404, Rodriguez-Viciana 2008 PMID:18403255, Anastasaki 2009 PMID:19376813, Inoue 2014 PMID:25035421). In summary, this variant is classified as pathogenic based on the data above.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001261967	SCV003932627	pathogenic	Noonan syndrome 7	2023-06-16	criteria provided, single submitter	clinical testing	ACMG criteria used: PS3, PS4, PM2
OMIM	RCV000015007	SCV000035263	pathogenic	Cardiofaciocutaneous syndrome 1	2006-03-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208766	SCV000203920	pathogenic	Cardio-facio-cutaneous syndrome	2015-07-01	no assertion criteria provided	clinical testing	The p.Gln257Arg variant in BRAF is an established pathogenic variant for Cardiof aciocutaneous syndrome (CFC) and is absent from large population studies. The p. Gln257Arg variant is one of the most commonly identified variants in BRAF and ha s been reported in >30 individuals with CFC syndrome (Rodriguez-Viciana 2008, Sa rkozy 2009, Neumann 2009, Abe 2012 Luk 2013, Wong Ramsey 2014, LMM unpublished d ata) and in 1 individual with LEOPARD syndrome (Carcavilla 2013). De novo occurr ences have been described for several individuals (Gripp 2007, Sarkozy 2009, Luk 2013, Neumann 2009, Niihori 2006). In addition, in vitro and in vivo functional studies support that this variant impacts protein function (Anastaski 2009, Ana stasaki 2012, Wen 2013, Inoue 2014). In summary, this variant meets our criteria to be classified as pathogenic for CFC syndrome in an autosomal dominant manner based upon de novo occurrence, absence from controls, and functional evidence.
GeneReviews	RCV000208766	SCV000264630	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	literature only
GenomeConnect - CFC International	RCV000208766	SCV001156334	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	phenotyping only	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported, most recently on 04-27-2016 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 09-25-2012 by lab or GTR ID Central Manchester University Hospitals Regional Genetics Laboratory Services. Variant interpreted as Pathogenic and reported on 04-30-2009 by lab or GTR ID Prevention Genetics. 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. Phenotypic details are available under supporting information.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV001261967	SCV002073930	pathogenic	Noonan syndrome 7	2022-02-08	no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV001813744	SCV003840166	pathogenic	Noonan syndrome 1		no assertion criteria provided	research
Molecular Genetics, Centre for Human Genetics	RCV001813744	SCV004190094	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing