NM_001374258.1(BRAF):c.1621G>A (p.Glu541Lys) AND Rasopathy

Clinical significance:Pathogenic (Last evaluated: Dec 21, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000033315.4

Allele description [Variation Report for NM_001374258.1(BRAF):c.1621G>A (p.Glu541Lys)]

NM_001374258.1(BRAF):c.1621G>A (p.Glu541Lys)

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_001374258.1(BRAF):c.1621G>A (p.Glu541Lys)
HGVS:
  • NC_000007.14:g.140778007C>T
  • NG_007873.3:g.151758G>A
  • NM_001354609.2:c.1501G>A
  • NM_001374244.1:c.1621G>A
  • NM_001374258.1:c.1621G>AMANE SELECT
  • NM_001378467.1:c.1510G>A
  • NM_001378468.1:c.1501G>A
  • NM_001378469.1:c.1435G>A
  • NM_001378470.1:c.1399G>A
  • NM_001378471.1:c.1390G>A
  • NM_001378472.1:c.1345G>A
  • NM_001378473.1:c.1345G>A
  • NM_001378474.1:c.1501G>A
  • NM_001378475.1:c.1237G>A
  • NM_004333.6:c.1501G>A
  • NP_001341538.1:p.Glu501Lys
  • NP_001361173.1:p.Glu541Lys
  • NP_001361187.1:p.Glu541Lys
  • NP_001365396.1:p.Glu504Lys
  • NP_001365397.1:p.Glu501Lys
  • NP_001365398.1:p.Glu479Lys
  • NP_001365399.1:p.Glu467Lys
  • NP_001365400.1:p.Glu464Lys
  • NP_001365401.1:p.Glu449Lys
  • NP_001365402.1:p.Glu449Lys
  • NP_001365403.1:p.Glu501Lys
  • NP_001365404.1:p.Glu413Lys
  • NP_004324.2:p.Glu501Lys
  • LRG_299t1:c.1501G>A
  • LRG_299:g.151758G>A
  • NC_000007.13:g.140477807C>T
  • NM_004333.4:c.1501G>A
  • P15056:p.Glu501Lys
  • p.Glu501Gln
Protein change:
E413K; GLU501LYS
Links:
UniProtKB: P15056#VAR_026118; OMIM: 164757.0017; dbSNP: rs180177038
NCBI 1000 Genomes Browser:
rs180177038
Molecular consequence:
  • NM_001354609.2:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374244.1:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374258.1:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378467.1:c.1510G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378468.1:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378469.1:c.1435G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378470.1:c.1399G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378471.1:c.1390G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378472.1:c.1345G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378473.1:c.1345G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378474.1:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378475.1:c.1237G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004333.6:c.1501G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000948576Invitaecriteria provided, single submitter
Pathogenic
(Dec 21, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, et al.

Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955.

PubMed [citation]
PMID:
19206169
PMCID:
PMC4028130

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 (3)

Details of each submission

From Invitae, SCV000948576.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glutamic acid with lysine at codon 501 of the BRAF protein (p.Glu501Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with cardio-facio-cutaneous syndrome (PMID: 19206169). ClinVar contains an entry for this variant (Variation ID: 13977). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.501 amino acid residue in BRAF have been observed in affected individuals (PMID: 16474404, 20186801, 25463315). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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