ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.770A>G (p.Gln257Arg) (rs180177035)

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Total submissions: 18
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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 2018-11-28 criteria provided, single submitter clinical testing The Q257R variant in the BRAF gene has been reported previously in association with Cardio-Facio- Cutaneous (CFC) syndrome (Niihori et al., 2006; Rodriguez-Viciana et al., 2006; Schulz et al., 2008; Gripp et al., 2007). This semi-conservative missense variant is the most common recurrent variant in CFC identified thus far and has been observed de novo multiple times in the literature and internally (Niihori et al., 2006; Schulz et al., 2008; Gripp et al., 2007). Functional in vitro studies have demonstrated that the Q257R variant results in increased kinase activity and activation of downstream effectors (MEK and ERK) (Rodriguez- Viciana et al., 2008). The Q257R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080904 SCV000112811 pathogenic not provided 2013-04-26 criteria provided, single submitter clinical testing
Invitae RCV000033289 SCV000218757 pathogenic Rasopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 257 of the BRAF protein (p.Gln257Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This sequence change was reported in several individuals affected with Noonan spectrum disorders (PMID: 16474404, 17703371, 24719372, 24775816). ClinVar contains an entry for this variant (Variation ID: 13973). Experimental studies have shown that this missense change significantly increases BRAF kinase activity in vitro (PMID: 16474404, 18413255). For these reasons, this variant has been classified as Pathogenic.
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 Alfred I. duPont Hospital for Children RCV000080904 SCV000263061 pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507717 SCV000602655 pathogenic not specified 2019-06-30 criteria provided, single submitter clinical testing The 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 characterization 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.
Integrated Genetics/Laboratory Corporation of America 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 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
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.
OMIM RCV000015007 SCV000035263 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare 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 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
GenomeConnect - CFC International RCV000208766 SCV001156334 not provided Cardio-facio-cutaneous syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 04-30-2009 by Lab or GTR ID 239772. 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.

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