ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.739T>G (p.Phe247Val) (rs397516903)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788008 SCV000927040 likely pathogenic Noonan syndrome and Noonan-related syndrome 2019-05-10 reviewed by expert panel curation The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.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, 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037958 SCV000061624 uncertain significance not specified 2013-01-10 criteria provided, single submitter clinical testing The Phe247Val variant in BRAF has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. In summary, additional inform ation is needed to fully asses the clinical significance of the Phe247Val varian t.
GeneDx RCV000339233 SCV000330320 likely pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing The F247V variant in the BRAF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This 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 F247V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (T244P, L245F, A246P) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous (CFC) syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The F247V variant is a strong candidate for a pathogenic variant
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000824912 SCV000965943 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome no assertion criteria provided clinical testing

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