rs180177036
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001374258.1(BRAF):c.1575G>T(p.Leu525Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L525S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.1575G>T | p.Leu525Phe | missense_variant | 13/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1455G>T | p.Leu485Phe | missense_variant | 12/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1575G>T | p.Leu525Phe | missense_variant | 13/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1455G>T | p.Leu485Phe | missense_variant | 12/18 | NM_004333.6 | P4 | ||
ENST00000700122.1 | n.502+3185C>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RASopathy Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Feb 27, 2020 | The c.1455G>T (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 5 patients with clinical features of a RASopathy, 2 of which were reported as unconfirmed de novo cases (PS4; PM6_Strong; PMIDs: 18039235, 28524057, SCV000832735.1, SCV000204150.4, SCV000965953.1, Otto-von-Guericke-Universität Magdeburg internal communication). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). 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). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect 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): PS4, PM6_Strong, PS3, PM2, PP2, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2021 | ClinVar contains an entry for this variant (Variation ID: 177844). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 16439621, 16474404, 18413255, 25348715). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (PMID: 16439621, 16474404, 18039235, 19206169, 28524057). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 485 of the BRAF protein (p.Leu485Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. - |
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 21, 2014 | The c.1455G>T (Leu485Phe) variant in BRAF has been previously identified in one individual with clinical features of a Cardio-facio-cutaneous syndrome (LMM unpu blished data). It was absent from large population studies (http://evs.gs.washin gton.edu/EVS/). In addition, a different variant with the same amino acid change (c.1455G>C) was identified in four individuals with clinical features of a RASo pathy (Niihori 2006, Rodriguez-Viciana 2006, LMM unpublished data). In vitro fu nctional studies provide some evidence that the Leu485Phe variant may impact pro tein function by increasing its kinase activity (Rodriguez-Viciana 2008). Howeve r, these types of assays may not accurately represent biological function. In s ummary, this variant meets our criteria to be classified as pathogenic (http://p cpgmwww.partners.org/personalizedmedicince/LMM). - |
Cardio-facio-cutaneous syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2019 | Variant summary: BRAF c.1455G>T (p.Leu485Phe) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251326 control chromosomes (gnomAD). The variant, c.1455G>T, has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana_2006, Sato_2017). Another variant (c.1455G>C) leading to the same protein change (p.Leu485Phe) has also been observed in individuals affected with Cardiofaciocutaneous Syndrome including one de novo occurrence (Niihori_2006, Sarkozy_2009). These data indicate that the variant is likely to be associated with disease. At least two publications reported experimental evidence evaluating an impact on protein function and showed increased BRAF activity (Niihori_2006, Rodriguez-Viciana_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Another variant affecting the same codon, p.L485S, has been reported to associate with Cardiofaciocutaneous Syndrome too. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2023 | Reported in probands with clinical features of cardio-facio-cutaneous (CFC) syndrome (Yoon et al., 2007; Sato et al., 2017; Mohan et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34358384, 30406758, 18039235, 28524057) - |
Noonan syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at