NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly) AND Cardiofaciocutaneous syndrome 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 2, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000015012.28

Allele description [Variation Report for NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly)]

NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly)

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.1502A>G (p.Glu501Gly)

Other names:

p.E501G:GAA>GGA

HGVS:

NC_000007.14:g.140778006T>C
NG_007873.3:g.151759A>G
NM_001354609.2:c.1502A>G
NM_001374244.1:c.1622A>G
NM_001374258.1:c.1622A>G
NM_001378467.1:c.1511A>G
NM_001378468.1:c.1502A>G
NM_001378469.1:c.1436A>G
NM_001378470.1:c.1400A>G
NM_001378471.1:c.1391A>G
NM_001378472.1:c.1346A>G
NM_001378473.1:c.1346A>G
NM_001378474.1:c.1502A>G
NM_001378475.1:c.1238A>G
NM_004333.6:c.1502A>GMANE SELECT
NP_001341538.1:p.Glu501Gly
NP_001361173.1:p.Glu541Gly
NP_001361187.1:p.Glu541Gly
NP_001365396.1:p.Glu504Gly
NP_001365397.1:p.Glu501Gly
NP_001365398.1:p.Glu479Gly
NP_001365399.1:p.Glu467Gly
NP_001365400.1:p.Glu464Gly
NP_001365401.1:p.Glu449Gly
NP_001365402.1:p.Glu449Gly
NP_001365403.1:p.Glu501Gly
NP_001365404.1:p.Glu413Gly
NP_004324.2:p.Glu501Gly
LRG_299t1:c.1502A>G
LRG_299:g.151759A>G
NC_000007.13:g.140477806T>C
NM_004333.4:c.1502A>G
P15056:p.Glu501Gly
c.1502A>G

Protein change:

E413G; GLU501GLY

Links:

UniProtKB: P15056#VAR_026117; OMIM: 164757.0018; dbSNP: rs180177039

NCBI 1000 Genomes Browser:

rs180177039

Molecular consequence:

NM_001354609.2:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1622A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1622A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1511A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1436A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1400A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1391A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1346A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1346A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1238A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1502A>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

Recent activity

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Rattus norvegicus ATP binding cassette subfamily A member 4 (Abca4), mRNA
Rattus norvegicus ATP binding cassette subfamily A member 4 (Abca4), mRNA
gi|157819512|ref|NM_001107721.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035268	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000143823	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV002012061	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16474404, 17366577, 17704260, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035268

OMIM

no assertion criteria provided

Pathogenic
(Mar 1, 2006)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000143823

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)

no classification provided

not provided

germline

not provided

PubMed (1)
[See all records that cite this PMID]

SCV002012061

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2021)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.

Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA.

Science. 2006 Mar 3;311(5765):1287-90. Epub 2006 Jan 26.

PubMed [citation]

PMID:: 16439621

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.

Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, et al.

Nat Genet. 2006 Mar;38(3):294-6. Epub 2006 Feb 12.

PubMed [citation]

PMID:: 16474404

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000035268.3

#	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 1502A-G transition in exon 12 of the BRAF gene, predicting a glu501-to-gly (E501G) 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 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), SCV000143823.1

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

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

From 3billion, SCV002012061.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 1647440, 17366577, 17704260, PS2, PS4). 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). A different missense change at the same codon (p.Glu501Lys and pGlu501Ala) has been reported as pathogenic (VCV000013977.4, VCV000040373.5, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992, 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

Last Updated: Sep 29, 2024

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