ClinVar Genomic variation as it relates to human health
NM_001374258.1(BRAF):c.2034T>G (p.Asp678Glu)
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_001374258.1(BRAF):c.2034T>G (p.Asp678Glu)
Variation ID: 162797 Accession: VCV000162797.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140749365 (GRCh38) [ NCBI UCSC ] 7: 140449165 (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 2, 2015 Apr 15, 2024 Dec 28, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6:c.1914T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Asp638Glu missense NM_001374258.1:c.2034T>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Asp678Glu missense NM_001354609.2:c.1914T>G NP_001341538.1:p.Asp638Glu missense NM_001374244.1:c.2034T>G NP_001361173.1:p.Asp678Glu missense NM_001378467.1:c.1923T>G NP_001365396.1:p.Asp641Glu missense NM_001378468.1:c.1914T>G NP_001365397.1:p.Asp638Glu missense NM_001378469.1:c.1848T>G NP_001365398.1:p.Asp616Glu missense NM_001378470.1:c.1812T>G NP_001365399.1:p.Asp604Glu missense NM_001378471.1:c.1803T>G NP_001365400.1:p.Asp601Glu missense NM_001378472.1:c.1758T>G NP_001365401.1:p.Asp586Glu missense NM_001378473.1:c.1758T>G NP_001365402.1:p.Asp586Glu missense NM_001378474.1:c.1914T>G NP_001365403.1:p.Asp638Glu missense NM_001378475.1:c.1650T>G NP_001365404.1:p.Asp550Glu missense NC_000007.14:g.140749365A>C NC_000007.13:g.140449165A>C NG_007873.3:g.180400T>G LRG_299:g.180400T>G LRG_299t1:c.1914T>G P15056:p.Asp638Glu - Protein change
- D638E, D601E, D604E, D641E, D586E, D616E, D678E, D550E
- Other names
- p.D638E:GAT>GAG
- Canonical SPDI
- NC_000007.14:140749364:A: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
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 |
1224 | 1333 |
Conditions - Germline
Condition
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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 (1) |
criteria provided, single submitter
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Aug 27, 2013 | RCV000150199.5 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2022 | RCV000157831.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 5, 2017 | RCV000624589.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2022 | RCV000689333.7 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 16, 2018 | RCV000767527.3 | |
not provided (1) |
no classification provided
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- | RCV000999624.2 |
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
Help
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
(Aug 27, 2013)
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criteria provided, single submitter
Method: clinical testing
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Cardio-facio-cutaneous syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197128.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, … (more)
The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742118.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Infantile spasms (present) , Seizures (present) , Severe global developmental delay (present) , Intellectual disability, profound (present) , Hypertonia (present) , Microcephaly (present) , Cortical … (more)
Infantile spasms (present) , Seizures (present) , Severe global developmental delay (present) , Intellectual disability, profound (present) , Hypertonia (present) , Microcephaly (present) , Cortical visual impairment (present) , Exotropia (present) , Cerebral atrophy (present) , Infantile muscular hypotonia (present) , Hyperreflexia (present) , Functional abnormality of the gastrointestinal tract (present) , Failure to thrive (present) , Hypoplasia of the corpus callosum (present) , Abnormality of muscle fibers (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
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Pathogenic
(Dec 28, 2022)
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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: SCV000207761.13
First in ClinVar: Feb 24, 2015 Last updated: Jan 07, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic [(HGMD]; This variant is associated with the following publications: (PMID: 27171548, 30141192, 23093928, 25525159, 19206169, 18413255, 21063443, 30556322, 32369273, 33040082, 31069529, 34643321) (less)
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Pathogenic
(Aug 28, 2022)
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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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Invitae
Accession: SCV000816979.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 162797). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (PMID: 16804887, 18039235, 22495831). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 638 of the BRAF protein (p.Asp638Glu). (less)
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Pathogenic
(Nov 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247573.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Aug 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167600.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Sex: male
Secondary finding: no
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Pathogenic
(Sep 21, 2018)
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no assertion criteria provided
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
de novo
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000898145.1
First in ClinVar: Apr 21, 2019 Last updated: Apr 21, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809483.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932077.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959358.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect - CFC International
Accession: SCV001156331.1
First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020 |
Comment:
Variant interpreted as Pathogenic and reported on 10-13-2014 by Lab or GTR ID 26957. GenomeConnect-CFC International assertions are reported exactly as they appear on the … (more)
Variant interpreted as Pathogenic and reported on 10-13-2014 by Lab or GTR ID 26957. 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) , Abnormality of globe size (present) , Feeding difficulties (present) , Abnormality of the stomach (present) , Abnormality of the … (more)
Abnormality of eye movement (present) , Abnormality of globe size (present) , Feeding difficulties (present) , Abnormality of the stomach (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the pelvis (present) , Epidermal thickening (present) , Generalized hypotonia (present) , Seizures (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2014-10-13
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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Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. | Abe Y | American journal of medical genetics. Part A | 2012 | PMID: 22495831 |
Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. | Kleefstra T | European journal of human genetics : EJHG | 2011 | PMID: 21063443 |
Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Methods in enzymology | 2008 | PMID: 18413255 |
Neurological complications of cardio-facio-cutaneous syndrome. | Yoon G | Developmental medicine and child neurology | 2007 | PMID: 18039235 |
Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. | Rauen KA | American journal of medical genetics. Part A | 2006 | PMID: 16804887 |
Text-mined citations for rs180177042 ...
HelpRecord last updated Apr 15, 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.