ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp) (rs180177040)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624854 SCV000742141 pathogenic Inborn genetic diseases 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Human Genetics, Inc RCV000015013 SCV000781086 pathogenic Cardiofaciocutaneous syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
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 2018-12-21 criteria provided, single submitter clinical testing The N581D pathogenic variant in the BRAF gene has been reported previously in multiple unrelated individuals with cardio-facio-cutaneous (CFC) syndrome (Rodriguez-Viciana et al., 2006; Niihori et al., 2006; Ciara et al., 2015). Functional studies demonstrated N581D shows impaired ability to induce phosphorylation of ERK and MEK (Niihori et al., 2006). The N581D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N581D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the protein kinase catalytic loop at a position that is conserved across species.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000474979 SCV000553829 pathogenic Rasopathy 2017-01-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 581 of the BRAF protein (p.Asn581Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in numerous individuals with features of cardio-facio-cutaneous (CFC) syndrome (PMID: 16474404, 18042262, 17366577, 16439621, 24037001) and was observed to have occurred de novo in at least four affected individuals (PMID: 16439621, 22876591, 25463315). ClinVar contains an entry for this variant (Variation ID: 13979). An experimental study in zebrafish has shown that BRAF protein with this variant behaves differently than wild-type protein, although the specific effect on protein function is unclear (PMID: 19376813). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000015013 SCV000035269 pathogenic Cardiofaciocutaneous syndrome 1 2006-03-01 no assertion criteria provided literature only

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