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.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 3 (Most recent: May 26, 2021)
- Last evaluated:
- May 13, 2019
- Accession:
- VCV000044634.4
- Variation ID:
- 44634
- Description:
- single nucleotide variant
Help
NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys)
- Allele ID
- 53801
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 3p25.2
- Genomic location
- 3: 12604184 (GRCh38) GRCh38 UCSC
- 3: 12645683 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNC_000003.11:g.12645683A>T NC_000003.12:g.12604184A>T NM_001354689.3:c.786T>A MANE Select NP_001341618.1:p.Asn262Lys missense NM_001354690.2:c.786T>A NP_001341619.1:p.Asn262Lys missense NM_001354691.2:c.543T>A NP_001341620.1:p.Asn181Lys missense NM_001354694.2:c.543T>A NP_001341623.1:p.Asn181Lys missense NM_001354695.2:c.444T>A NP_001341624.1:p.Asn148Lys missense NM_002880.3:c.786T>A NP_002871.1:p.Asn262Lys missense NM_001354692.2:c.543T>A NP_001341621.1:p.Asn181Lys missense NM_001354693.2:c.687T>A NP_001341622.1:p.Asn229Lys missense LRG_413t2:c.786T>A LRG_413p2:p.Asn262Lys LRG_413t1:c.786T>A LRG_413p1:p.Asn262Lys NR_148940.2:n.1117T>A NR_148941.2:n.1117T>A NR_148942.2:n.1117T>A NG_007467.1:g.64996T>A LRG_413:g.64996T>A - Protein change
- N262K, N148K, N229K, N181K
- Other names
- -
- Canonical SPDI
- NC_000003.12:12604183:A:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA261628
- dbSNP: rs397516829
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | May 13, 2019 | RCV000388842.2 | |
| Pathogenic | 1 | criteria provided, single submitter | Sep 24, 2014 | RCV000037707.3 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| RAF1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
566 | 619 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | Supporting information
(See all) |
|---|---|---|---|---|
|
Pathogenic
(Mar 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Allele origin:
germline
|
GeneDx
Accession: SCV000329734.7
Submitted: (Jan 29, 2019) |
Comment:
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 … (more)
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. (less)
|
|
Pathogenic
(Sep 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
Allele origin:
germline
|
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000061369.6
Submitted: (Mar 21, 2019) |
Comment:
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 … (more)
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). (less)
|
|
Pathogenic
(May 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714080.1
Submitted: (May 26, 2021) |
Comment:
PM1, PM2, PM5, PM6_Strong, PS3_Moderate
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. | Chen H | Orphanet journal of rare diseases | 2019 | PMID: 30732632 |
| 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 | Human mutation | 2010 | PMID: 20052757 |
| Mutations in conserved regions 1, 2, and 3 of Raf-1 that activate transforming activity. | Chan EY | Molecular carcinogenesis | 2002 | PMID: 11933072 |
Text-mined citations for rs397516829...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jul 07, 2021