ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1391G>T (p.Gly464Val)
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.1391G>T (p.Gly464Val)
Variation ID: 40364 Accession: VCV000040364.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140781617 (GRCh38) [ NCBI UCSC ] 7: 140481417 (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 Jan 31, 2015 Feb 14, 2024 May 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6:c.1391G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Gly464Val missense NM_001374258.1:c.1511G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Gly504Val missense NM_001354609.2:c.1391G>T NP_001341538.1:p.Gly464Val missense NM_001374244.1:c.1511G>T NP_001361173.1:p.Gly504Val missense NM_001378467.1:c.1400G>T NP_001365396.1:p.Gly467Val missense NM_001378468.1:c.1391G>T NP_001365397.1:p.Gly464Val missense NM_001378469.1:c.1325G>T NP_001365398.1:p.Gly442Val missense NM_001378470.1:c.1289G>T NP_001365399.1:p.Gly430Val missense NM_001378471.1:c.1280G>T NP_001365400.1:p.Gly427Val missense NM_001378472.1:c.1235G>T NP_001365401.1:p.Gly412Val missense NM_001378473.1:c.1235G>T NP_001365402.1:p.Gly412Val missense NM_001378474.1:c.1391G>T NP_001365403.1:p.Gly464Val missense NM_001378475.1:c.1127G>T NP_001365404.1:p.Gly376Val missense NC_000007.14:g.140781617C>A NC_000007.13:g.140481417C>A NG_007873.3:g.148148G>T LRG_299:g.148148G>T LRG_299t1:c.1391G>T P15056:p.Gly464Val - Protein change
- G464V, G427V, G376V, G442V, G412V, G430V, G467V, G504V
- Other names
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- Canonical SPDI
- NC_000007.14:140781616:C:A
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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
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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 (1) |
criteria provided, single submitter
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Oct 27, 2021 | RCV000033302.15 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2011 | RCV000037914.13 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000442182.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000426199.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2018 | RCV001813221.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2022 | RCV002250499.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2020 | RCV001811232.13 |
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
(Feb 28, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471782.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The BRAF c.1391G>T; p.Gly464Val variant (rs121913348) is reported in the literature in individuals affected with cardio-facio-cutaneous syndrome (Rodriguez-Viciana 2008, Yoon 2007). This variant is reported … (more)
The BRAF c.1391G>T; p.Gly464Val variant (rs121913348) is reported in the literature in individuals affected with cardio-facio-cutaneous syndrome (Rodriguez-Viciana 2008, Yoon 2007). This variant is reported in ClinVar (Variation ID: 40364), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 464 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show increased kinase activation consistent with a gain of function mechanism (Hollestelle 2007, Wan 2004). Based on available information, this variant is considered to be likely pathogenic. References: Hollestelle A et al. Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res. 2007 Feb;5(2):195-201. Rodriguez-Viciana P and Rauen KA. Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. Methods Enzymol. 2008;438:277-89. Wan PT et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004 Mar 19;116(6):855-67. Yoon G et al. Neurological complications of cardio-facio-cutaneous syndrome. Dev Med Child Neurol. 2007 Dec;49(12):894-9. (less)
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Likely pathogenic
(Apr 01, 2018)
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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: SCV002060473.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Oct 27, 2021)
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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: SCV000288405.5
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 40364). This missense change has been observed in individuals with cardio‚Äêfacio‚Äêcutaneous syndrome (PMID: 2102266, 18039235, 18413255). … (more)
ClinVar contains an entry for this variant (Variation ID: 40364). This missense change has been observed in individuals with cardio‚Äêfacio‚Äêcutaneous syndrome (PMID: 2102266, 18039235, 18413255). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, a(n) neutral and non-polar amino acid, with valine, a(n) neutral and non-polar amino acid, at codon 464 of the BRAF protein (p.Gly464Val). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 19376813, 23680146, 23907581, 25155755). (less)
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Pathogenic
(May 03, 2011)
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criteria provided, single submitter
Method: clinical testing
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Non-small cell lung carcinoma
Affected status: not provided
Allele origin:
somatic
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061576.4
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
Somatic BRAF variants have been identified in up to 3% of cases of lung adenocar cinoma (Davies 2002).
Number of individuals with the variant: 3
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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: SCV002521451.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 3CNET). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040364). Different missense changes at the same codon (p.Gly504Arg, p.Gly504Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013964, VCV000279992, VCV000372572). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Polyhydramnios (present) , Abnormal facial shape (present) , Macrocephaly (present) , Anteverted nares (present) , Hypertelorism (present) , Overfolded helix (present) , Long fingers (present) … (more)
Polyhydramnios (present) , Abnormal facial shape (present) , Macrocephaly (present) , Anteverted nares (present) , Hypertelorism (present) , Overfolded helix (present) , Long fingers (present) , Long toe (present) , Short chin (present) , Low-set ears (present) , Depressed nasal bridge (present) , Poor suck (present) , Dysphagia (present) , Hypocalcemia (present) , Curly hair (present) , Skin rash (present) , Hyperkeratosis (present) (less)
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505049.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505048.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling. | Haling JR | Cancer cell | 2014 | PMID: 25155755 |
Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling. | An L | Scientific reports | 2013 | PMID: 23907581 |
RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. | Holderfield M | Cancer cell | 2013 | PMID: 23680146 |
Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. | Santarpia L | Breast cancer research and treatment | 2012 | PMID: 22538770 |
Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. | Hollestelle A | Breast cancer research and treatment | 2010 | PMID: 19593635 |
Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. | Anastasaki C | Human molecular genetics | 2009 | PMID: 19376813 |
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 |
Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. | Hollestelle A | Molecular cancer research : MCR | 2007 | PMID: 17314276 |
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
Mutations of the BRAF gene in human cancer. | Davies H | Nature | 2002 | PMID: 12068308 |
Dissolution studies on ampicillin embonate and amoxycillin embonate. | Saesmaa T | Journal of pharmaceutical and biomedical analysis | 1990 | PMID: 2102266 |
http://docm.genome.wustl.edu/variants/ENST00000288602:c.1391G>T | - | - | - | - |
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Text-mined citations for rs121913348 ...
HelpRecord last updated Apr 20, 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.