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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 3, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000159089.18

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)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000616381	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications RAF1 V2.3.0)	Pathogenic (Dec 3, 2024)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 17603483, 17603482, 22826437 Citation Link,
SCV000918145	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 11, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18505544, 18241070, 19953625, 17603483, 17603482, 20052757, 21339642, 29948256 Citation Link,
SCV000951436	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18241070, 19953625, 17603482, 17603483, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616381

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications RAF1 V2.3.0)

Pathogenic
(Dec 3, 2024)

germline

curation

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

Citation Link,

SCV000918145

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 11, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000951436

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants.

Wu X, Yin J, Simpson J, Kim KH, Gu S, Hong JH, Bayliss P, Backx PH, Neel BG, Araki T.

Mol Cell Biol. 2012 Oct;32(19):3872-90. doi: 10.1128/MCB.00751-12. Epub 2012 Jul 23.

PubMed [citation]

PMID:: 22826437
PMCID:: PMC3457534

Leopard syndrome.

Sarkozy A, Digilio MC, Dallapiccola B.

Orphanet J Rare Dis. 2008 May 27;3:13. doi: 10.1186/1750-1172-3-13. Review.

PubMed [citation]

PMID:: 18505544
PMCID:: PMC2467408

See all PubMed Citations (10)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616381.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

The c.1837C>G (p.Leu613Val) variant in the RAF1 gene is a missense variant predicted to cause substitution of leucine by valine at amino acid 613. This variant is absent from gnomAD v2 (PM2_Supporting). The variant has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2_VeryStrong; PMID:17603483), and its prevalence in affecteds is statistically increased over controls (PS4). In vitro functional studies also provide some evidence that the p.Leu613Val variant may impact protein function (PS3; PMID: 7603482, 17603483, 22826437). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting. (Specification Version 2.3, 12/3/2024)

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: RAF1 c.1837C>G (p.Leu613Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 31346 control chromosomes (gnomAD and publications). The variant, c.1837C>G, has been reported in the literature in multiple individuals affected with Noonan Syndrome or Leopard Syndrome (Razzaque_2007, Pandit_2007, Denayer_2010, Kobayashi_2010, vanTrier_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing higher levels of MEK and ERK phosphorylation associated with this variant (Razzaque_2007, Pandit_2007). Two ClinVar submissions from a FDA recognized database and a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000951436.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 613 of the RAF1 protein (p.Leu613Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17603482, 17603483, 18241070, 19953625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13960). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt RAF1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 17603483). For these reasons, this variant has been classified as Pathogenic.

#	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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