NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys) AND not provided

Clinical significance:Pathogenic (Last evaluated: May 13, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000388842.2

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)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000329734GeneDxcriteria provided, single submitter
Pathogenic
(Mar 3, 2017)
germlineclinical testing

Citation Link,

SCV001714080Mayo Clinic Laboratories, Mayo Cliniccriteria provided, single submitter
Pathogenic
(May 13, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot 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

Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.

Chen H, Li X, Liu X, Wang J, Zhang Z, Wu J, Huang M, Guo Y, Li F, Wang X, Fu L.

Orphanet J Rare Dis. 2019 Feb 7;14(1):29. doi: 10.1186/s13023-019-1010-z.

PubMed [citation]
PMID:
30732632
PMCID:
PMC6367752
See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000329734.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The N262K variant has been reported previously as a de novo occurrence in a patient with Noonan spectrum disorder (Kobayashi et al., 2010). N262K is also reported as a pathogenic variant in ClinVar by a different clinical laboratory and apparently occurred de novo in a patient with Noonan syndrome (ClinVar SCV000061369.4; Landrum et al., 2015). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N262K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the CR2 domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (N262I) and in nearby residues (S257L, S259P/T/F, T260I/R, P261T/S/A/R/L/H, V263A/D) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the N262K variant show that it inhibits the phosphorylation of nearby codon serine-259, which is necessary for RAF1 activation, abolishes binding of 14-3-3 protein complex, and results in partial activation of ERK (Kobayashi et al., 2010). Therefore, we interpret N262K as a pathogenic variant.

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714080.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

PM1, PM2, PM5, PM6_Strong, PS3_Moderate

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

Last Updated: Jul 7, 2021

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