This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in a patient with features overlapping cardiofaciocutaneous and Costello syndromes [PMID 16804887] In addition, a different variant at this nucleotide position (c.1914T>G) resulting in the same amino acid residue change has been previously reported as disease causing in patients with cardiofaciocutaneous syndrome [PMID 19206169]
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu)
Variation ID: 13981 Accession: VCV000013981.17
- Type and length
-
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
-
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 Aug 22, 2016 Feb 14, 2024 Jun 8, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1914T>A 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>A 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>A NP_001341538.1:p.Asp638Glu missense NM_001374244.1:c.2034T>A NP_001361173.1:p.Asp678Glu missense NM_001378467.1:c.1923T>A NP_001365396.1:p.Asp641Glu missense NM_001378468.1:c.1914T>A NP_001365397.1:p.Asp638Glu missense NM_001378469.1:c.1848T>A NP_001365398.1:p.Asp616Glu missense NM_001378470.1:c.1812T>A NP_001365399.1:p.Asp604Glu missense NM_001378471.1:c.1803T>A NP_001365400.1:p.Asp601Glu missense NM_001378472.1:c.1758T>A NP_001365401.1:p.Asp586Glu missense NM_001378473.1:c.1758T>A NP_001365402.1:p.Asp586Glu missense NM_001378474.1:c.1914T>A NP_001365403.1:p.Asp638Glu missense NM_001378475.1:c.1650T>A NP_001365404.1:p.Asp550Glu missense NC_000007.14:g.140749365A>T NC_000007.13:g.140449165A>T NG_007873.3:g.180400T>A LRG_299:g.180400T>A LRG_299t1:c.1914T>A P15056:p.Asp638Glu - Protein change
- D638E, D550E, D586E, D601E, D604E, D616E, D641E, D678E
- Other names
- -
- Canonical SPDI
- NC_000007.14:140749364:A:T
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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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1254 | 1368 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV000015015.36 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 8, 2023 | RCV000033337.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763164.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2017 | RCV000622900.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 16, 2021 | RCV001851863.5 |
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
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
Help
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Noonan syndrome 1 Lung cancer Noonan syndrome 7 LEOPARD syndrome 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893751.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV001528180.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in a patient … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in a patient with features overlapping cardiofaciocutaneous and Costello syndromes [PMID 16804887] In addition, a different variant at this nucleotide position (c.1914T>G) resulting in the same amino acid residue change has been previously reported as disease causing in patients with cardiofaciocutaneous syndrome [PMID 19206169] (less)
|
|
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Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742861.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian/European/Scandinavian
|
|
|
Likely pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003925531.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
A heterozygous missense variation in exon 16 of the BRAF gene that results in the amino acid substitution of glutamic acid for aspartic acid at … (more)
A heterozygous missense variation in exon 16 of the BRAF gene that results in the amino acid substitution of glutamic acid for aspartic acid at codon 638 was detected. The observed variant c.1914T>A (p.Asp638Glu) variant has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT. In summary, the variant meets our criteria to be classified as a likely pathogenic. (less)
Clinical Features:
Nystagmus (present)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Jun 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057242.13
First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); The majority of missense … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 18039235, 32506834, 29493581, 36448195, 16804887, 19376813, 24803665, 18413255, 19206169, 22495831, 35524774, 34573299, 31217210, 33753861, 32005694) (less)
|
|
|
Pathogenic
(Sep 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680155.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781088.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965743.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
|
|
|
Pathogenic
(Jun 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002227991.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16804887, 18039235, 22495831, 19206169). ClinVar contains an entry for this variant (Variation ID: 13981). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 638 of the BRAF protein (p.Asp638Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. (less)
|
|
|
Pathogenic
(Aug 01, 2006)
|
no assertion criteria provided
Method: literature only
|
CARDIOFACIOCUTANEOUS SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035271.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a 13-year-old girl with phenotypic features overlapping cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et … (more)
In a 13-year-old girl with phenotypic features overlapping cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et al., 2006), Rauen (2006) identified a 1914T-A transversion in exon 16 of the BRAF gene, resulting in an asp638-to-glu (D638E) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 16. (less)
|
Comment:
Comment:
A heterozygous missense variation in exon 16 of the BRAF gene that results in the amino acid substitution of glutamic acid for aspartic acid at codon 638 was detected. The observed variant c.1914T>A (p.Asp638Glu) variant has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT. In summary, the variant meets our criteria to be classified as a likely pathogenic.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 18039235, 32506834, 29493581, 36448195, 16804887, 19376813, 24803665, 18413255, 19206169, 22495831, 35524774, 34573299, 31217210, 33753861, 32005694)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16804887, 18039235, 22495831, 19206169). ClinVar contains an entry for this variant (Variation ID: 13981). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 638 of the BRAF protein (p.Asp638Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.
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. |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in a patient with features overlapping cardiofaciocutaneous and Costello syndromes [PMID 16804887] In addition, a different variant at this nucleotide position (c.1914T>G) resulting in the same amino acid residue change has been previously reported as disease causing in patients with cardiofaciocutaneous syndrome [PMID 19206169]
Comment:
A heterozygous missense variation in exon 16 of the BRAF gene that results in the amino acid substitution of glutamic acid for aspartic acid at codon 638 was detected. The observed variant c.1914T>A (p.Asp638Glu) variant has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT. In summary, the variant meets our criteria to be classified as a likely pathogenic.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 18039235, 32506834, 29493581, 36448195, 16804887, 19376813, 24803665, 18413255, 19206169, 22495831, 35524774, 34573299, 31217210, 33753861, 32005694)
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16804887, 18039235, 22495831, 19206169). ClinVar contains an entry for this variant (Variation ID: 13981). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glutamic acid at codon 638 of the BRAF protein (p.Asp638Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole exome sequencing diagnosis of inborn errors of metabolism and other disorders in United Arab Emirates. | Al-Shamsi A | Orphanet journal of rare diseases | 2016 | PMID: 27391121 |
| The RASopathies. | Rauen KA | Annual review of genomics and human genetics | 2013 | PMID: 23875798 |
| 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 |
| Cardio-facio-cutaneous syndrome: phenotypic variability and differential diagnosis in 3 cases with de novo BRAF mutations. | Demir E | Neuropediatrics | 2010 | PMID: 20859831 |
| 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 |
| HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. | Estep AL | American journal of medical genetics. Part A | 2006 | PMID: 16372351 |
| Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
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Text-mined citations for rs180177042 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.