NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser) AND RASopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 27, 2020
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:: RCV001172275.1

Allele description [Variation Report for NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)]

NM_004333.6(BRAF):c.1454T>C (p.Leu485Ser)

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.1454T>C (p.Leu485Ser)

Other names:

p.L485S:TTG>TCG

HGVS:

NC_000007.14:g.140778054A>G
NG_007873.3:g.151711T>C
NM_001354609.2:c.1454T>C
NM_001374244.1:c.1574T>C
NM_001374258.1:c.1574T>C
NM_001378467.1:c.1463T>C
NM_001378468.1:c.1454T>C
NM_001378469.1:c.1388T>C
NM_001378470.1:c.1352T>C
NM_001378471.1:c.1343T>C
NM_001378472.1:c.1298T>C
NM_001378473.1:c.1298T>C
NM_001378474.1:c.1454T>C
NM_001378475.1:c.1190T>C
NM_004333.6(BRAF):c.1454T>C
NM_004333.6:c.1454T>CMANE SELECT
NP_001341538.1:p.Leu485Ser
NP_001361173.1:p.Leu525Ser
NP_001361187.1:p.Leu525Ser
NP_001365396.1:p.Leu488Ser
NP_001365397.1:p.Leu485Ser
NP_001365398.1:p.Leu463Ser
NP_001365399.1:p.Leu451Ser
NP_001365400.1:p.Leu448Ser
NP_001365401.1:p.Leu433Ser
NP_001365402.1:p.Leu433Ser
NP_001365403.1:p.Leu485Ser
NP_001365404.1:p.Leu397Ser
NP_004324.2:p.Leu485Ser
LRG_299t1:c.1454T>C
LRG_299:g.151711T>C
NC_000007.13:g.140477854A>G
NM_004333.4:c.1454T>C
NM_004333.6(BRAF):c.1454T>CMANE SELECT
NM_004333.6:c.1454T>C

Protein change:

L397S

Links:

dbSNP: rs397507475

NCBI 1000 Genomes Browser:

rs397507475

Molecular consequence:

NM_001354609.2:c.1454T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1574T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1574T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1463T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1454T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1388T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1352T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1343T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1298T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1298T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1454T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1190T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1454T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001335322	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Likely pathogenic (Feb 27, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 20395089, 21871821, 18039235 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001335322

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Likely pathogenic
(Feb 27, 2020)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Cardio-facio-cutaneous syndrome with infantile spasms and delayed myelination.

Aizaki K, Sugai K, Saito Y, Nakagawa E, Sasaki M, Aoki Y, Matsubara Y.

Brain Dev. 2011 Feb;33(2):166-9. doi: 10.1016/j.braindev.2010.03.008. Epub 2010 Apr 14.

PubMed [citation]

PMID:: 20395089

Epilepsy in RAS/MAPK syndrome: two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review.

Adachi M, Abe Y, Aoki Y, Matsubara Y.

Seizure. 2012 Jan;21(1):55-60. doi: 10.1016/j.seizure.2011.07.013. Epub 2011 Aug 25. Review.

PubMed [citation]

PMID:: 21871821

See all PubMed Citations (3)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV001335322.1

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

Description

The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). 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). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PP2, PP3, PM5.

#	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

Last Updated: Apr 6, 2024

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