NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu) AND Noonan syndrome 7

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 7, 2023
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:: RCV004783752.1

Allele description [Variation Report for NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)]

NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)

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.1914T>G (p.Asp638Glu)

Other names:

p.D638E:GAT>GAG

HGVS:

NC_000007.14:g.140749365A>C
NG_007873.3:g.180400T>G
NM_001354609.2:c.1914T>G
NM_001374244.1:c.2034T>G
NM_001374258.1:c.2034T>G
NM_001378467.1:c.1923T>G
NM_001378468.1:c.1914T>G
NM_001378469.1:c.1848T>G
NM_001378470.1:c.1812T>G
NM_001378471.1:c.1803T>G
NM_001378472.1:c.1758T>G
NM_001378473.1:c.1758T>G
NM_001378474.1:c.1914T>G
NM_001378475.1:c.1650T>G
NM_004333.6:c.1914T>GMANE SELECT
NP_001341538.1:p.Asp638Glu
NP_001361173.1:p.Asp678Glu
NP_001361187.1:p.Asp678Glu
NP_001365396.1:p.Asp641Glu
NP_001365397.1:p.Asp638Glu
NP_001365398.1:p.Asp616Glu
NP_001365399.1:p.Asp604Glu
NP_001365400.1:p.Asp601Glu
NP_001365401.1:p.Asp586Glu
NP_001365402.1:p.Asp586Glu
NP_001365403.1:p.Asp638Glu
NP_001365404.1:p.Asp550Glu
NP_004324.2:p.Asp638Glu
LRG_299t1:c.1914T>G
LRG_299:g.180400T>G
NC_000007.13:g.140449165A>C
NM_004333.4:c.1914T>G
NM_004333.5:c.1914T>G
NM_004333.6:c.1914T>G
P15056:p.Asp638Glu

Protein change:

D550E

Links:

UniProtKB: P15056#VAR_058630; dbSNP: rs180177042

NCBI 1000 Genomes Browser:

rs180177042

Molecular consequence:

NM_001354609.2:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.2034T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.2034T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1923T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1848T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1812T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1803T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1758T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1758T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1650T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome 7 (NS7)
Identifiers:: MONDO: MONDO:0013379; MedGen: C3150970; Orphanet: 648; OMIM: 613706

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005397313	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 7, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 16804887, 21063443, 27391121, 27940666, 31217210, 29095811, 37510243, 19206169, 18413255, 22495831, 35524774, 32369273, 37138575, 18039235, 34573299, 31069529, 33040082, 20859831, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005397313

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 7, 2023)

germline

clinical testing

PubMed (19)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype.

Rauen KA.

Am J Med Genet A. 2006 Aug 1;140(15):1681-3. No abstract available.

PubMed [citation]

PMID:: 16804887

Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway.

Kleefstra T, Wortmann SB, Rodenburg RJ, Bongers EM, Hadzsiev K, Noordam C, van den Heuvel LP, Nillesen WM, Hollody K, Gillessen-Kaesbach G, Lammens M, Smeitink JA, van der Burgt I, Morava E.

Eur J Hum Genet. 2011 Feb;19(2):138-44. doi: 10.1038/ejhg.2010.171. Epub 2010 Nov 10.

PubMed [citation]

PMID:: 21063443
PMCID:: PMC3025797

See all PubMed Citations (19)

Details of each submission

From Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397313.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

This sequence variant is a single nucleotide substitution (T>G) at position 1914 of the coding sequence of the BRAF gene that results in a aspartic acid to glutamic acid amino acid change at residue 638 of the B-Raf proto-oncogene, serine/threonine kise protein. The 638 residue falls in the kise domain (PMID: 18413255) which plays a critical role in BRAF function. This is a previously reported variant (ClinVar 162797) that has been observed in individuals affected by Costello syndrome (PMID: 16804887, 31069529) and cardiofaciocutaneous syndrome (PMID: 19206169, 37138575, 20859831, 21063443, 33040082, 27391121, 29095811, 22495831, 18039235, 37510243, 27940666, 31217210, 35524774, 34573299, 32369273), several of which were confirmed de novo (PMID: 19206169, 37138575, 20859831, 21063443). This variant is absent from the gnomAD population database (0/~250,000 alleles). Multiple bioinformatic tools predict that this Asp to Glu amino acid change would be damaging, and the Asp638 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant demonstrate impaired kise activity (PMID: 18413255). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP2, PP3, PS1, PS3

#	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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