Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000033332 | SCV000616388 | pathogenic | Rasopathy | 2017-04-03 | reviewed by expert panel | curation | The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). 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). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). 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): PM6_Strong, PS3, PM2, PP2, PP3, PM1. |
Gene |
RCV000077865 | SCV000057237 | pathogenic | not provided | 2013-05-22 | criteria provided, single submitter | clinical testing | p.Gly596Val (GGT>GTT): c.1787 G>T in exon 15 of the BRAF gene (NM_004333.4). The G596V mutation in the BRAF gene has been previously reported in at least 4 unrelated patients with Cardio-Facio-Cutaneous syndrome (Rodriguez-Viciana et al., 2006). This mutation falls within the activation loop located within the third conserved region of the BRAF protein. The G596V mutation 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. The variant is found in NOONAN panel(s). |
EGL Genetic Diagnostics, |
RCV000077865 | SCV000058306 | pathogenic | not provided | 2013-03-18 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000844615 | SCV000197137 | pathogenic | Noonan syndrome; Cardio-facio-cutaneous syndrome | 2014-09-10 | criteria provided, single submitter | clinical testing | The Gly596Val variant has been identified in 7 individuals with clinical feature s of Cardio-facio-cutaneous syndrome (CFC) and 3 individuals with clinical featu res of Noonan syndrome (Rodriguez-Viciana 2006, Yoon 2007, Rodriguez-Viciana 200 8, LMM unpublished data). It was absent from large population studies. In-vitro functional studies provide some evidence that the Gly596Val variant may impact p rotein function (Rodrigues-Viciana 2006). Furthermore, animal models in zebrafis h have shown that this variant causes severe developmental abnormalities (Anasta saki 2009). In summary, this variant meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/). |
Invitae | RCV000033332 | SCV000936651 | pathogenic | Rasopathy | 2018-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with valine at codon 596 of the BRAF protein (p.Gly596Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cardio-facio-cutaneous syndrome, in some of whom it was found de novo (PMID: 16439621, 25463315). ClinVar contains an entry for this variant (Variation ID: 40387). Experimental studies have shown that this missense change causes a decrease in phosphorylation and kinase activity of downstream enzymes, as well as developmental changes in zebrafish embryos (PMID: 16439621, 18413255, 19376813); however, the clinical significance of these findings is unclear. For these reasons, this variant has been classified as Pathogenic. |
Institute for Genomic Statistics and Bioinformatics, |
RCV000856749 | SCV000999297 | pathogenic | Cardiofaciocutaneous syndrome 1 | criteria provided, single submitter | clinical testing | ||
Centre for Mendelian Genomics, |
RCV000856749 | SCV001369351 | pathogenic | Cardiofaciocutaneous syndrome 1 | 2019-08-20 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PM2,PM6_Strong,PP2,PP3,PP4. |
Ambry Genetics | RCV001265809 | SCV001443981 | likely pathogenic | Inborn genetic diseases | 2018-01-10 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000033332 | SCV000196671 | pathogenic | Rasopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
Gene |
RCV000208758 | SCV000264635 | pathogenic | Cardio-facio-cutaneous syndrome | 2016-03-03 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438697 | SCV000505826 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424067 | SCV000505827 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431311 | SCV000505828 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441123 | SCV000505829 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Genome |
RCV000844615 | SCV001156342 | not provided | Noonan syndrome; Cardio-facio-cutaneous syndrome | no assertion provided | phenotyping only | Variant interpreted as Pathogenic and reported on 12-03-2010 by Lab or GTR ID 21766. 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. |