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NM_004333.6(BRAF):c.437G>A (p.Arg146Gln) AND RASopathy

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 6, 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:
RCV000654945.4

Allele description [Variation Report for NM_004333.6(BRAF):c.437G>A (p.Arg146Gln)]

NM_004333.6(BRAF):c.437G>A (p.Arg146Gln)

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.437G>A (p.Arg146Gln)
HGVS:
  • NC_000007.14:g.140834676C>T
  • NG_007873.3:g.95089G>A
  • NM_001354609.2:c.437G>A
  • NM_001374244.1:c.437G>A
  • NM_001374258.1:c.437G>A
  • NM_001378467.1:c.437G>A
  • NM_001378468.1:c.437G>A
  • NM_001378469.1:c.437G>A
  • NM_001378470.1:c.335G>A
  • NM_001378471.1:c.437G>A
  • NM_001378472.1:c.281G>A
  • NM_001378473.1:c.281G>A
  • NM_001378474.1:c.437G>A
  • NM_001378475.1:c.240+15435G>A
  • NM_004333.6:c.437G>AMANE SELECT
  • NP_001341538.1:p.Arg146Gln
  • NP_001361173.1:p.Arg146Gln
  • NP_001361187.1:p.Arg146Gln
  • NP_001365396.1:p.Arg146Gln
  • NP_001365397.1:p.Arg146Gln
  • NP_001365398.1:p.Arg146Gln
  • NP_001365399.1:p.Arg112Gln
  • NP_001365400.1:p.Arg146Gln
  • NP_001365401.1:p.Arg94Gln
  • NP_001365402.1:p.Arg94Gln
  • NP_001365403.1:p.Arg146Gln
  • NP_004324.2:p.Arg146Gln
  • LRG_299t1:c.437G>A
  • LRG_299:g.95089G>A
  • NC_000007.13:g.140534476C>T
  • NM_004333.4:c.437G>A
Protein change:
R112Q
Links:
dbSNP: rs557241012
NCBI 1000 Genomes Browser:
rs557241012
Molecular consequence:
  • NM_001378475.1:c.240+15435G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354609.2:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374244.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374258.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378467.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378468.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378469.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378470.1:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378471.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378472.1:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378473.1:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378474.1:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004333.6:c.437G>A - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000776853Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 6, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA.

Genet Med. 2019 Feb;21(2):417-425. doi: 10.1038/s41436-018-0062-0. Epub 2018 Jun 15. Erratum in: Genet Med. 2018 Jul 26;:.

PubMed [citation]
PMID:
29907801

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000776853.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the BRAF protein (p.Arg146Gln). This variant is present in population databases (rs557241012, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome and/or related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 372564). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BRAF function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Apr 6, 2024