The p.Gly534Arg variant in BRAF has been previously identified in one individual with clinical features of a RASopathy and occurred de novo (Rauen 2006, Gripp 2 007). It is absent from large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, although additional studies are required to fully establish its clinical significance, the p.Gly534Arg variant is likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1600G>C (p.Gly534Arg)
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.
(8)
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
8
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.1600G>C (p.Gly534Arg)
Variation ID: 13980 Accession: VCV000013980.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140777006 (GRCh38) [ NCBI UCSC ] 7: 140476806 (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 Mar 5, 2016 Jan 7, 2023 Oct 2, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1600G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Gly534Arg missense NM_001374258.1:c.1720G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Gly574Arg missense NM_001354609.2:c.1600G>C NP_001341538.1:p.Gly534Arg missense NM_001374244.1:c.1720G>C NP_001361173.1:p.Gly574Arg missense NM_001378467.1:c.1609G>C NP_001365396.1:p.Gly537Arg missense NM_001378468.1:c.1600G>C NP_001365397.1:p.Gly534Arg missense NM_001378469.1:c.1534G>C NP_001365398.1:p.Gly512Arg missense NM_001378470.1:c.1498G>C NP_001365399.1:p.Gly500Arg missense NM_001378471.1:c.1489G>C NP_001365400.1:p.Gly497Arg missense NM_001378472.1:c.1444G>C NP_001365401.1:p.Gly482Arg missense NM_001378473.1:c.1444G>C NP_001365402.1:p.Gly482Arg missense NM_001378474.1:c.1600G>C NP_001365403.1:p.Gly534Arg missense NM_001378475.1:c.1336G>C NP_001365404.1:p.Gly446Arg missense NC_000007.14:g.140777006C>G NC_000007.13:g.140476806C>G NG_007873.3:g.152759G>C LRG_299:g.152759G>C LRG_299t1:c.1600G>C LRG_299p1:p.Gly534Arg - Protein change
- G534R, G446R, G500R, G512R, G537R, G574R, G482R, G497R
- Other names
- -
- Canonical SPDI
- NC_000007.14:140777005:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2021 | RCV000015014.41 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Jul 1, 2016 | RCV000208775.15 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 11, 2017 | RCV000623633.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 18, 2019 | RCV000779634.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001257953.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680156.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Sex: female
Tissue: blood
|
|
|
Likely pathogenic
(Jul 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710865.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly534Arg variant in BRAF has been previously identified in one individual with clinical features of a RASopathy and occurred de novo (Rauen 2006, Gripp … (more)
The p.Gly534Arg variant in BRAF has been previously identified in one individual with clinical features of a RASopathy and occurred de novo (Rauen 2006, Gripp 2 007). It is absent from large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, although additional studies are required to fully establish its clinical significance, the p.Gly534Arg variant is likely pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jul 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742637.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Hispanic
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012051.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected individual (PMID:23875798, 17551924, PS2). The missense … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected individual (PMID:23875798, 17551924, PS2). 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). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3Cnet: 0.998, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Full cheeks (present) , Global developmental delay (present) , Abnormal facial shape (present) , Failure to thrive (present) , Delayed gross motor development (present) , … (more)
Full cheeks (present) , Global developmental delay (present) , Abnormal facial shape (present) , Failure to thrive (present) , Delayed gross motor development (present) , Growth delay (present) , Generalized hypotonia (present) , Immunodeficiency (present) , Macrotia (present) , Relative macrocephaly (present) , Delayed speech and language development (present) , Preauricular pit (present) , Fever (present) (less)
|
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Pathogenic
(Aug 01, 2006)
|
no assertion criteria provided
Method: literature only
|
CARDIOFACIOCUTANEOUS SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035270.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a 7-year-old boy with craniofacial features overlapping both cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep … (more)
In a 7-year-old boy with craniofacial features overlapping both cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et al., 2006), Rauen (2006) identified a 1600G-C transversion in exon 13 of the BRAF gene, resulting in a gly534-to-arg (G534R) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 13. (less)
|
|
|
Pathogenic
(Feb 18, 2019)
|
no assertion criteria provided
Method: research
|
PHACE syndrome
Genetic syndrome with a Dandy-Walker malformation as major feature Tethered cord
Affected status: yes
Allele origin:
germline
|
Dobyns Lab, Seattle Children's Research Institute
Accession: SCV000916311.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Dandy-Walker malformation
Affected status: yes
Allele origin:
de novo
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434766.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Cardio-facio-cutaneous syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000264634.2
First in ClinVar: Mar 05, 2016 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected individual (PMID:23875798, 17551924, PS2). 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). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3Cnet: 0.998, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
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:
The p.Gly534Arg variant in BRAF has been previously identified in one individual with clinical features of a RASopathy and occurred de novo (Rauen 2006, Gripp 2 007). It is absent from large population studies. Computational prediction too ls and conservation analysis suggest that this variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, although additional studies are required to fully establish its clinical significance, the p.Gly534Arg variant is likely pathogenic.
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected individual (PMID:23875798, 17551924, PS2). 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). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3Cnet: 0.998, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cardiofaciocutaneous Syndrome. | Adam MP | - | 2023 | PMID: 20301365 |
| Redefining the Etiologic Landscape of Cerebellar Malformations. | Aldinger KA | American journal of human genetics | 2019 | PMID: 31474318 |
| Cutaneous manifestations in Costello and cardiofaciocutaneous syndrome: report of 18 cases and literature review. | Morice-Picard F | Pediatric dermatology | 2013 | PMID: 24283439 |
| The RASopathies. | Rauen KA | Annual review of genomics and human genetics | 2013 | PMID: 23875798 |
| 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 |
| Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. | Gripp KW | American journal of medical genetics. Part A | 2007 | PMID: 17551924 |
| The cardiofaciocutaneous syndrome. | Roberts A | Journal of medical genetics | 2006 | PMID: 16825433 |
| 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 |
| LEOPARD syndrome: clinical diagnosis in the first year of life. | Digilio MC | American journal of medical genetics. Part A | 2006 | PMID: 16523510 |
| 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 |
| Multiple lentigenes syndrome. | Gorlin RJ | American journal of diseases of children (1960) | 1969 | PMID: 5771505 |
| Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. | Noonan JA | American journal of diseases of children (1960) | 1968 | PMID: 4386970 |
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Text-mined citations for rs180177041 ...
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 Nov 10, 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.