VCV000044634.13 - ClinVar

NM_002880.4(RAF1):c.786T>A (p.Asn262Lys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002880.4(RAF1):c.786T>A (p.Asn262Lys)

Variation ID: 44634 Accession: VCV000044634.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.2 3: 12604184 (GRCh38) [ NCBI UCSC ] 3: 12645683 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 27, 2015	Sep 16, 2024	Apr 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002880.4:c.786T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002871.1:p.Asn262Lys	missense
NM_001354689.3:c.786T>A	NP_001341618.1:p.Asn262Lys	missense
NM_001354690.3:c.786T>A	NP_001341619.1:p.Asn262Lys	missense
NM_001354691.3:c.543T>A	NP_001341620.1:p.Asn181Lys	missense
NM_001354692.3:c.543T>A	NP_001341621.1:p.Asn181Lys	missense
NM_001354693.3:c.687T>A	NP_001341622.1:p.Asn229Lys	missense
NM_001354694.3:c.543T>A	NP_001341623.1:p.Asn181Lys	missense
NM_001354695.3:c.444T>A	NP_001341624.1:p.Asn148Lys	missense
NR_148940.3:n.1117T>A		non-coding transcript variant
NR_148941.3:n.1117T>A		non-coding transcript variant
NR_148942.3:n.1117T>A		non-coding transcript variant
NC_000003.12:g.12604184A>T
NC_000003.11:g.12645683A>T
NG_007467.1:g.64996T>A
LRG_413:g.64996T>A
LRG_413t1:c.786T>A	LRG_413p1:p.Asn262Lys
LRG_413t2:c.786T>A	LRG_413p2:p.Asn262Lys

... more HGVS ... less HGVS

Protein change

N262K, N148K, N229K, N181K

Other names

Canonical SPDI

NC_000003.12:12604183:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA261628 dbSNP: rs397516829 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAF1		No evidence available	No evidence available	GRCh38 GRCh37	1235	1290

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Noonan syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 24, 2014	RCV000037707.6
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 17, 2023	RCV000388842.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 24, 2014) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Noonan syndrome Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061369.6 First in ClinVar: May 03, 2013 Last updated: May 27, 2015	Publications: PubMed (2) PubMed: 11933072‚ 20052757 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) Number of individuals with the variant: 1

Pathogenic (May 13, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen RASopathy ACMG Specifications v1) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714080.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (3) PubMed: 11933072‚ 30732632‚ 20052757 Comment: PM1, PM2, PM5, PM6_Strong, PS3_Moderate Number of individuals with the variant: 1

Likely pathogenic (Jul 13, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198034.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024

Pathogenic (Apr 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329734.8 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect with enhanced ELK transactivation and activated downstream ERK phosphorylation (PMID: 20052757); In silico analysis supports that this missense … (more) Published functional studies demonstrate a damaging effect with enhanced ELK transactivation and activated downstream ERK phosphorylation (PMID: 20052757); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30732632, 32870709, 29493581, 20052757, 24957944, 9689060, 15520807, 17603483, 17603482, 19020799) (less)

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 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).

Comment:

Published functional studies demonstrate a damaging effect with enhanced ELK transactivation and activated downstream ERK phosphorylation (PMID: 20052757); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30732632, 32870709, 29493581, 20052757, 24957944, 9689060, 15520807, 17603483, 17603482, 19020799)

Germline Functional Evidence

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.

Comment:

Citations for germline classification of this variant

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 ...

These 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 Mar 22, 2025

ClinVar Genomic variation as it relates to human health

NM_002880.4(RAF1):c.786T>A (p.Asn262Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397516829 ...