ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)
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.1495A>G (p.Lys499Glu)
Variation ID: 13976 Accession: VCV000013976.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140778013 (GRCh38) [ NCBI UCSC ] 7: 140477813 (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 Feb 20, 2016 Jul 23, 2024 Dec 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6:c.1495A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Lys499Glu missense NM_001374258.1:c.1615A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Lys539Glu missense NM_001354609.2:c.1495A>G NP_001341538.1:p.Lys499Glu missense NM_001374244.1:c.1615A>G NP_001361173.1:p.Lys539Glu missense NM_001378467.1:c.1504A>G NP_001365396.1:p.Lys502Glu missense NM_001378468.1:c.1495A>G NP_001365397.1:p.Lys499Glu missense NM_001378469.1:c.1429A>G NP_001365398.1:p.Lys477Glu missense NM_001378470.1:c.1393A>G NP_001365399.1:p.Lys465Glu missense NM_001378471.1:c.1384A>G NP_001365400.1:p.Lys462Glu missense NM_001378472.1:c.1339A>G NP_001365401.1:p.Lys447Glu missense NM_001378473.1:c.1339A>G NP_001365402.1:p.Lys447Glu missense NM_001378474.1:c.1495A>G NP_001365403.1:p.Lys499Glu missense NM_001378475.1:c.1231A>G NP_001365404.1:p.Lys411Glu missense NC_000007.14:g.140778013T>C NC_000007.13:g.140477813T>C NG_007873.3:g.151752A>G LRG_299:g.151752A>G LRG_299t1:c.1495A>G P15056:p.Lys499Glu - Protein change
- K499E, K411E, K447E, K462E, K465E, K477E, K502E, K539E
- Other names
- p.K499E:AAA>GAA
- Canonical SPDI
- NC_000007.14:140778012:T: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
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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
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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 |
1239 | 1350 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (4) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000015010.30 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV000207517.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 9, 2018 | RCV000779848.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2016 | RCV001813210.3 |
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
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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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Likely pathogenic
(Jul 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000263063.1
First in ClinVar: Feb 20, 2016 Last updated: Feb 20, 2016 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
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Likely pathogenic
(Apr 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rasopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916701.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: BRAF c.1495A>G (p.Lys499Glu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: BRAF c.1495A>G (p.Lys499Glu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246384 control chromosomes (in gnomAD and publication data). c.1495A>G has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008). These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, and both of them demonstrated an increased kinase activity for the variant protein (Rodriguez-Viciana 2006, Niihori 2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Dec 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060606.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521581.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
Amino acid change identical t o known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000013976, PMID:16474404). Different pathogenic amino acid change … (more)
Amino acid change identical t o known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000013976, PMID:16474404). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000040371,VCV000040372, PMID:18042262). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported. In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.829>=0.6). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome. It is absent from the gnomAD v2.1.1 dataset. ATherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Absent speech (present) , Growth delay (present) , Global developmental delay (present) , Short neck (present) , Skin tags (present)
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Pathogenic
(Dec 02, 2023)
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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: SCV000057217.15
First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22824468, 23505473, 18456719, 34184824, 18413255, 23093928, 16474404, 18042262, 19376813, 24803665, 16439621, 30462361, 31560489, 32369273, 28404629) (less)
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Pathogenic
(Nov 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577539.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
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Pathogenic
(Mar 01, 2006)
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no assertion criteria provided
Method: literature only
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CARDIOFACIOCUTANEOUS SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035266.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a patient with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1495A-G transition in exon 12 of the BRAF gene, predicting … (more)
In a patient with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1495A-G transition in exon 12 of the BRAF gene, predicting a lys499-to-glu (K499E) amino acid change. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
de novo
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GenomeConnect - CFC International
Accession: SCV001156341.1
First in ClinVar: Feb 06, 2020 Last updated: Feb 06, 2020 |
Comment:
Variant interpreted as Pathogenic and reported on 02-12-2018 by Lab or GTR ID Kaizer Franz Josef Hospital. GenomeConnect-CFC International assertions are reported exactly as they … (more)
Variant interpreted as Pathogenic and reported on 02-12-2018 by Lab or GTR ID Kaizer Franz Josef Hospital. 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. (less)
Clinical Features:
Abnormality of eye movement (present) , Hypermetropia (present) , Abnormality iris morphology (present) , Feeding difficulties (present) , Abnormality of the liver (present) , Abnormal … (more)
Abnormality of eye movement (present) , Hypermetropia (present) , Abnormality iris morphology (present) , Feeding difficulties (present) , Abnormality of the liver (present) , Abnormal renal morphology (present) , Abnormality of the ureter (present) , Abnormality of urine homeostasis (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Atrophic scars (present) , Hyperpigmentation of the skin (present) , Cutis laxa (present) , Morphological abnormality of the central nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Growth hormone deficiency (present) , Autoimmunity (present) , Anxiety (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Kaizer Franz Josef Hospital
Date variant was reported to submitter: 2018-02-12
Testing laboratory interpretation: Pathogenic
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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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Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. | Pierpont EI | American journal of medical genetics. Part A | 2010 | PMID: 20186801 |
Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. | Niihori T | Nature genetics | 2006 | PMID: 16474404 |
Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
Text-mined citations for rs180177037 ...
HelpRecord last updated Jul 23, 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.