NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys) AND Noonan syndrome

Clinical significance:Pathogenic (Last evaluated: Sep 24, 2014)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000037707.3

Allele description [Variation Report for NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys)]

NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys)
HGVS:
  • NC_000003.12:g.12604184A>T
  • NG_007467.1:g.64996T>A
  • NM_001354689.3:c.786T>AMANE SELECT
  • NM_001354690.2:c.786T>A
  • NM_001354691.2:c.543T>A
  • NM_001354692.2:c.543T>A
  • NM_001354693.2:c.687T>A
  • NM_001354694.2:c.543T>A
  • NM_001354695.2:c.444T>A
  • NM_002880.3:c.786T>A
  • NP_001341618.1:p.Asn262Lys
  • NP_001341619.1:p.Asn262Lys
  • NP_001341620.1:p.Asn181Lys
  • NP_001341621.1:p.Asn181Lys
  • NP_001341622.1:p.Asn229Lys
  • NP_001341623.1:p.Asn181Lys
  • NP_001341624.1:p.Asn148Lys
  • NP_002871.1:p.Asn262Lys
  • LRG_413t1:c.786T>A
  • LRG_413t2:c.786T>A
  • LRG_413:g.64996T>A
  • LRG_413p1:p.Asn262Lys
  • LRG_413p2:p.Asn262Lys
  • NC_000003.11:g.12645683A>T
  • NR_148940.2:n.1117T>A
  • NR_148941.2:n.1117T>A
  • NR_148942.2:n.1117T>A
  • c.786T>A
Protein change:
N148K
Links:
dbSNP: rs397516829
NCBI 1000 Genomes Browser:
rs397516829
Molecular consequence:
  • NM_001354689.3:c.786T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.786T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.2:c.543T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.2:c.543T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.687T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.2:c.543T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.2:c.444T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.786T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.1117T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.1117T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.1117T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Noonan syndrome (NS)
Synonyms:
Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:
MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061369Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Sep 24, 2014)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Mutations in conserved regions 1, 2, and 3 of Raf-1 that activate transforming activity.

Chan EY, Stang SL, Bottorff DA, Stone JC.

Mol Carcinog. 2002 Apr;33(4):189-97.

PubMed [citation]
PMID:
11933072

Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation.

Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, Kawame H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N, Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kurosawa K, Mizuno S, Ohashi H, David A, Philip N, et al.

Hum Mutat. 2010 Mar;31(3):284-94. doi: 10.1002/humu.21187.

PubMed [citation]
PMID:
20052757
See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000061369.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The Asn262Lys variant has been reported in two individuals with clinical feature s of a RASopathy and was identified to occur de novo in both individuals (Kobaya shi 2010, LMM unpublished). It was absent from large population studies. Computa tional prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In vitro functional studies provide some evidence that the Asn2 62Lys variant may impact protein function (Chan 2002, Kobayashi 2010). However, these types of assays may not accurately represent biological function. Individu als with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hy pertrophic cardiomyopathy (80-95%, Chan 2002). In summary, this variant meets ou r criteria to be classified as pathogenic (http://pcpgmwww.partners.org/personal izedmedicince/LMM).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Jul 7, 2021

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