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

Clinical significance:Pathogenic (Last evaluated: Dec 31, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000469440.3

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:
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
SCV000553831Invitaecriteria provided, single submitter
Pathogenic
(Dec 31, 2019)
germlineclinical testing

PubMed (5)
[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

RASopathies: Clinical Diagnosis in the First Year of Life.

Digilio MC, Lepri F, Baban A, Dentici ML, Versacci P, Capolino R, Ferese R, De Luca A, Tartaglia M, Marino B, Dallapiccola B.

Mol Syndromol. 2011 Sep;1(6):282-289. Epub 2011 Sep 14.

PubMed [citation]
PMID:
22190897
PMCID:
PMC3214957
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000553831.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces leucine with phenylalanine at codon 245 of the BRAF protein (p.Leu245Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This missense change and a different variant (c.735A>T) giving rise to the same protein effect observed here (p.Leu245Phe) have been observed in individuals affected with BRAF-related conditions (PMID: 19206169, 22190897, 30290804), including one individual in whom the variant was de novo (PMID: 19416762). ClinVar contains an entry for this variant (Variation ID: 40347). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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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