ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507717 SCV000602655 pathogenic not specified 2016-09-23 criteria provided, single submitter clinical testing
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
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.
Blueprint Genetics RCV000080904 SCV000927948 pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing
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.
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000015007 SCV000236532 pathogenic Cardiofaciocutaneous syndrome 1 2015-01-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080904 SCV000112811 pathogenic not provided 2013-04-26 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000208766 SCV000264630 pathogenic Cardio-facio-cutaneous syndrome 2016-03-03 no assertion criteria provided literature only
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.
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.
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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000080904 SCV000263061 pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing
OMIM RCV000015007 SCV000035263 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

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