NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp) AND Cardiofaciocutaneous syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000015013.33

Allele description [Variation Report for NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)]

NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)

Gene:

BRAF:B-Raf proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)

Other names:

p.N581D:AAT>GAT; NM_004333.4(BRAF):c.1741A>G

HGVS:

NC_000007.14:g.140754187T>C
NG_007873.3:g.175578A>G
NM_001354609.2:c.1741A>G
NM_001374244.1:c.1861A>G
NM_001374258.1:c.1861A>G
NM_001378467.1:c.1750A>G
NM_001378468.1:c.1741A>G
NM_001378469.1:c.1675A>G
NM_001378470.1:c.1639A>G
NM_001378471.1:c.1630A>G
NM_001378472.1:c.1585A>G
NM_001378473.1:c.1585A>G
NM_001378474.1:c.1741A>G
NM_001378475.1:c.1477A>G
NM_004333.6:c.1741A>GMANE SELECT
NP_001341538.1:p.Asn581Asp
NP_001361173.1:p.Asn621Asp
NP_001361187.1:p.Asn621Asp
NP_001365396.1:p.Asn584Asp
NP_001365397.1:p.Asn581Asp
NP_001365398.1:p.Asn559Asp
NP_001365399.1:p.Asn547Asp
NP_001365400.1:p.Asn544Asp
NP_001365401.1:p.Asn529Asp
NP_001365402.1:p.Asn529Asp
NP_001365403.1:p.Asn581Asp
NP_001365404.1:p.Asn493Asp
NP_004324.2:p.Asn581Asp
LRG_299t1:c.1741A>G
LRG_299:g.175578A>G
NC_000007.13:g.140453987T>C
NM_004333.4:c.1741A>G
c.1741A>G

Protein change:

N493D; ASN581ASP

Links:

OMIM: 164757.0019; dbSNP: rs180177040

NCBI 1000 Genomes Browser:

rs180177040

Molecular consequence:

NM_001354609.2:c.1741A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1861A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1861A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1750A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1741A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1675A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1639A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1630A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1585A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1585A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1741A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1477A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1741A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiofaciocutaneous syndrome 1 (CFC1)
Synonyms:: Congenital heart defects characteristic facial appearance ectodermal abnormalities and growth failure
Identifiers:: MONDO: MONDO:0007265; MedGen: CN029449; Orphanet: 1340; OMIM: 115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035269	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000781086	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002012143	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19376813, 16474404, 25741868
SCV003840148	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	no assertion criteria provided	Pathogenic	unknown	research
SCV005086386	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28783719, 29540830, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	2	not provided	not provided	2	not provided	research, clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Nothing to display

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000035269.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1741A-G transition in exon 14 of the BRAF gene, predicting an asn581-to-asp (N581D) amino acid change.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781086.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002012143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, PM6_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19376813, 16474404). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn621Lys) has been reported as pathogenic (ClinVar ID: VCV000044811.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.932, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV003840148.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086386.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150) and Noonan syndrome 7 (MIM#613706) (PMID: 28783719, PMID: 29540830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with cardiofaciocutaneous syndrome. One of these reports is by an expert panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 18, 2024

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