NM_002880.4(RAF1):c.1837C>G (p.Leu613Val) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 2, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000254689.17

Allele description [Variation Report for NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)]

NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)

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_002880.4(RAF1):c.1837C>G (p.Leu613Val)

Other names:

p.L613V:CTA>GTA; NM_002880.3(RAF1):c.1837C>G; NM_002880.4(RAF1):c.1837C>G

HGVS:

NC_000003.12:g.12584624G>C
NG_007467.1:g.84556C>G
NM_001354689.3:c.1897C>G
NM_001354690.3:c.1837C>G
NM_001354691.3:c.1594C>G
NM_001354692.3:c.1594C>G
NM_001354693.3:c.1738C>G
NM_001354694.3:c.1654C>G
NM_001354695.3:c.1495C>G
NM_002880.4:c.1837C>GMANE SELECT
NP_001341618.1:p.Leu633Val
NP_001341619.1:p.Leu613Val
NP_001341620.1:p.Leu532Val
NP_001341621.1:p.Leu532Val
NP_001341622.1:p.Leu580Val
NP_001341623.1:p.Leu552Val
NP_001341624.1:p.Leu499Val
NP_002871.1:p.Leu613Val
NP_002871.1:p.Leu613Val
LRG_413t1:c.1837C>G
LRG_413t2:c.1897C>G
LRG_413:g.84556C>G
LRG_413p1:p.Leu613Val
LRG_413p2:p.Leu633Val
NC_000003.11:g.12626123G>C
NM_002880.3:c.1837C>G
NR_148940.3:n.2281C>G
NR_148941.3:n.2227C>G
NR_148942.3:n.2166C>G
P04049:p.Leu613Val
c.1837C>G

Protein change:

L499V; LEU613VAL

Links:

UniProtKB: P04049#VAR_037821; OMIM: 164760.0004; dbSNP: rs80338797

NCBI 1000 Genomes Browser:

rs80338797

Molecular consequence:

NM_001354689.3:c.1897C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354690.3:c.1837C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.1594C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.1594C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.1738C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.1654C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.1495C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.1837C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.2281C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.2227C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3:n.2166C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209032	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 2, 2021)	germline	clinical testing	Citation Link,
SCV002048615	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (May 12, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209032

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 2, 2021)

germline

clinical testing

Citation Link,

SCV002048615

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Pathogenic
(May 12, 2021)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000209032.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in ClinVar as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (SCV000616381.3; ClinVar Variant ID# 13960; Lanrum et al., 2016); Functional studies of L613V-transfected cells indicate higher levels of RAF1 kinase activity, which results in higher levels of MEK and ERK activation compared to wild type (Razzaque et al., 2007; Pandit et al., 2007); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17603483, 23093928, 17603482, 24803665, 30050098, 31017896, 30417923, 30732632, 29948256, 29907801, 31219622, 31560489, 34006472, 24957944, 9689060, 15520807, 29493581, 19020799)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048615.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The RAF1, c.1837C>G; p.Leu613Val variant (rs80338797) is reported in the literature in multiple patients affected with familial and sporadic Noonan syndrome (Razzaque 2007, Kobayashi 2010, Denayer 2010) and LEOPARD syndrome (Pandit 2007), and is classified as pathogenic in ClinVar (Variation ID: 13960). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Functional characterization of the p.Leu613Val protein indicates a constitutive heterodimerization with endogenous BRAF (Ritt 2010). This leads to an over-activation of basal MEK and ERK signaling, which increases further upon growth factor stimulation (Razzaque 2007, Pandit 2007), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Denayer E et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010 Mar;49(3):242-52. PMID: 19953625. Kobayashi T et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010 Mar;31(3):284-94. PMID: 20052757. Pandit B et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. PMID: 17603483. Razzaque MA et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7. PMID: 17603482. Ritt DA et al. Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling. Mol Cell Biol. 2010 Feb;30(3):806-19. PMID: 19933846

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 13, 2025

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