ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1796C>G (p.Thr599Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004333.6(BRAF):c.1796C>G (p.Thr599Arg)
Variation ID: 280033 Accession: VCV000280033.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140753339 (GRCh38) [ NCBI UCSC ] 7: 140453139 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 21, 2018 Feb 4, 2024 Mar 24, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6(BRAF):c.1796C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
missense NM_004333.6:c.1796C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Thr599Arg missense NM_001374258.1:c.1916C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Thr639Arg missense NM_001354609.2:c.1796C>G NP_001341538.1:p.Thr599Arg missense NM_001374244.1:c.1916C>G NP_001361173.1:p.Thr639Arg missense NM_001378467.1:c.1805C>G NP_001365396.1:p.Thr602Arg missense NM_001378468.1:c.1796C>G NP_001365397.1:p.Thr599Arg missense NM_001378469.1:c.1730C>G NP_001365398.1:p.Thr577Arg missense NM_001378470.1:c.1694C>G NP_001365399.1:p.Thr565Arg missense NM_001378471.1:c.1685C>G NP_001365400.1:p.Thr562Arg missense NM_001378472.1:c.1640C>G NP_001365401.1:p.Thr547Arg missense NM_001378473.1:c.1640C>G NP_001365402.1:p.Thr547Arg missense NM_001378474.1:c.1796C>G NP_001365403.1:p.Thr599Arg missense NM_001378475.1:c.1532C>G NP_001365404.1:p.Thr511Arg missense NC_000007.14:g.140753339G>C NC_000007.13:g.140453139G>C NG_007873.3:g.176426C>G LRG_299:g.176426C>G LRG_299t1:c.1796C>G P15056:p.Thr599Arg - Protein change
- T599R, T511R, T547R, T562R, T565R, T577R, T602R, T639R
- Other names
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- Canonical SPDI
- NC_000007.14:140753338:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1230 | 1339 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 30, 2022 | RCV000291177.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2021 | RCV000856750.2 | |
Pathogenic (1) |
reviewed by expert panel
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Mar 24, 2020 | RCV001172278.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 24, 2020)
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reviewed by expert panel
Method: curation
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RASopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV001335327.1
First in ClinVar: Jun 12, 2020 Last updated: Jun 12, 2020 |
Comment:
The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; … (more)
The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID: 19206169). Additionally, the variant is located in BRAF, 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). 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): PS2_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2. (less)
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Pathogenic
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329761.7
First in ClinVar: Dec 06, 2016 Last updated: Sep 21, 2018 |
Comment:
The T599R pathogenic variant in the BRAF gene has been reported previously in association with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2008; Sarkozy et al., 2014). … (more)
The T599R pathogenic variant in the BRAF gene has been reported previously in association with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2008; Sarkozy et al., 2014). Functional studies indicate that the T599R variant results in increased foci formation and increased phosphorylation of the ERK and MEK proteins (Sarkozy et al., 2014). The T599R variant is not observed in large population cohorts (Lek et al., 2016). The T599R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (F595L, G596V, L597V, V600G, K601Q, K601I) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T599R as a pathogenic variant. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999298.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Hypertelorism (present) , Depressed nasal bridge (present)
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV002012139.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 19206169, 28650561, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19206169, PS3). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Thr599Ile) has been reported as pathogenic (VCV000040388.5, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Strabismus (present) , Low-set ears (present) , Long face (present) , Intellectual disability (present) , Seizure (present) , Premature birth (present) , Delayed speech and … (more)
Strabismus (present) , Low-set ears (present) , Long face (present) , Intellectual disability (present) , Seizure (present) , Premature birth (present) , Delayed speech and language development (present) , Seizure (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) (less)
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Pathogenic
(Aug 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022049.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. | Ueda K | American journal of medical genetics. Part A | 2017 | PMID: 28650561 |
Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/faecd415-c6bd-4898-b360-35d0ec408f2a | - | - | - | - |
Text-mined citations for rs121913375 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.