NM_001374258.1(BRAF):c.735A>C (p.Leu245Phe) AND Noonan syndrome and Noonan-related syndrome

Clinical significance:Pathogenic (Last evaluated: May 10, 2019)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000788013.1

Allele description [Variation Report for NM_001374258.1(BRAF):c.735A>C (p.Leu245Phe)]

NM_001374258.1(BRAF):c.735A>C (p.Leu245Phe)

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.735A>C (p.Leu245Phe)
Other names:
p.L245F:TTA>TTC; NM_004333.4(BRAF):c.735A>C
HGVS:
  • NC_000007.14:g.140801537T>G
  • NG_007873.3:g.128228A>C
  • NM_001354609.2:c.735A>C
  • NM_001374244.1:c.735A>C
  • NM_001374258.1:c.735A>CMANE SELECT
  • NM_001378467.1:c.744A>C
  • NM_001378468.1:c.735A>C
  • NM_001378469.1:c.735A>C
  • NM_001378470.1:c.633A>C
  • NM_001378471.1:c.735A>C
  • NM_001378472.1:c.579A>C
  • NM_001378473.1:c.579A>C
  • NM_001378474.1:c.735A>C
  • NM_001378475.1:c.471A>C
  • NM_004333.6:c.735A>C
  • NP_001341538.1:p.Leu245Phe
  • NP_001361173.1:p.Leu245Phe
  • NP_001361187.1:p.Leu245Phe
  • NP_001365396.1:p.Leu248Phe
  • NP_001365397.1:p.Leu245Phe
  • NP_001365398.1:p.Leu245Phe
  • NP_001365399.1:p.Leu211Phe
  • NP_001365400.1:p.Leu245Phe
  • NP_001365401.1:p.Leu193Phe
  • NP_001365402.1:p.Leu193Phe
  • NP_001365403.1:p.Leu245Phe
  • NP_001365404.1:p.Leu157Phe
  • NP_004324.2:p.Leu245Phe
  • LRG_299t1:c.735A>C
  • LRG_299:g.128228A>C
  • NC_000007.13:g.140501337T>G
  • NM_004333.4:c.735A>C
  • P15056:p.Leu245Phe
  • c.735A>C
Protein change:
L157F; LEU245PHE
Links:
UniProtKB: P15056#VAR_058623; OMIM: 164757.0027; dbSNP: rs397507466
NCBI 1000 Genomes Browser:
rs397507466
Molecular consequence:
  • NM_001354609.2:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374244.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374258.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378467.1:c.744A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378468.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378469.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378470.1:c.633A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378471.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378472.1:c.579A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378473.1:c.579A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378474.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378475.1:c.471A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004333.6:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Noonan syndrome and Noonan-related syndrome
Identifiers:
MONDO: MONDO:0020297; MedGen: CN260604; Orphanet: 98733

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000927045ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(May 10, 2019)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927045.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.735A>C (p.Leu245Phe) variant in BRAF has been reported as a a de novo occurrence, one of which was confirmed in at least 4 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx University Magdeburg GTR Lab ID's 21766, 26957, 506381; ClinVar SCV000061622.5, SCV000057188.16 PMID 19416762). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Leu245Phe variant may impact the protein (PP3). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PM2, PM1, PP2, PP3, PS4_Supporting.

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

Last Updated: Nov 27, 2021

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