NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp) AND Cardio-facio-cutaneous syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000211751.7

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:: Cardio-facio-cutaneous syndrome
Synonyms:: Cardiofaciocutaneous syndrome; CFC syndrome
Identifiers:: MONDO: MONDO:0015280; MedGen: C1275081; Orphanet: 1340; OMIM: PS115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061593	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 12, 2013)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16474404, 16439621, 18039235, 18042262, 22876591, 24033266
SCV000616362	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	Citation Link,
SCV000698333	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 4, 2016)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 18042262, 19206169, 24037001, 22876591, 16474404, 20186801, 17704260, 16439621, 17366577, 19376813, 18470943 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV003761515	GenomeConnect - CFC International	no classification provided	not provided	unknown	phenotyping only

Help

Summary from all submissions

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

Citations

PubMed

Neurological complications of cardio-facio-cutaneous syndrome.

Yoon G, Rosenberg J, Blaser S, Rauen KA.

Dev Med Child Neurol. 2007 Dec;49(12):894-9.

PubMed [citation]

PMID:: 18039235

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061593.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least 180 control chromosomes (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008 , Yoon 2007, Hazan 2012). This variant was observed to have occurred de novo in at least three of these individuals (Rodriguez-Viciana 2006, Hazan 2012). The As n581Asp variant has also been identified by our laboratory in one individual wit h Cardio-facio-cutaneous syndrome (LMM unpublished data), and was not identified in this individual's parents. Additionally, the Asparagine (Asn) residue at pos ition 581 is highly conserved across evolutionarily distant species, and the var iant was not identified in large population studies. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrence, and absence from controls.

#	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		2	not provided	2	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616362.4

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

Description

The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6_Strong, PS3.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase domain (InterPro, Niihori_2006). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 121424 control chromosomes. In literature, this variant is reported as a pathogenic variant found in several patients with cardio-facio-cutaneous syndrome, including reported de novo occurrences (Niihori_2006, Rodriguez-Viciana_2006, Narumi_2007, Nava_2007, Schulz_2008, Pierpont _2010, Hazan_2012, Quaio_2013). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Functional studies in zebra fish have shown that the N581D variant results in developmental defects that can be rescued by FGF-MAPK pathway inhibitors (Anastasaki_2009). Taken together, this variant is classified as Pathogenic.

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

From GenomeConnect - CFC International, SCV003761515.1

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

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

Last Updated: Nov 18, 2024

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