rs80338797

Variant names:

• chr3-12584624-G-C
• rs80338797
• NM_002880.4:c.1837C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-12584624-G-C
• chr3-12584624-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS2 PM2_Supporting PS3_Moderate PS4

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA257066/MONDO:0021060/040

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 3.76

Genes affected

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.1837C>G	p.Leu613Val	missense_variant	Exon 17 of 17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.1837C>G	p.Leu613Val	missense_variant	Exon 17 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:3

Dec 11, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

May 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Dec 02, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Noonan syndrome 5 Pathogenic:2

Aug 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

LEOPARD syndrome 2 Pathogenic:1

Aug 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines Pathogenic:1

Mar 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu613Val variant in RAF1 has been associated with the clinical features of Noonan syndrome (Ciara 2009, Razzaque 2007, Denayer 2010, Kobayashi 2010) and LE OPARD syndrome (Pandit 2007). In addition, this variant has been reported to sho w familial segregation and to have occurred de novo. Individuals with pathogeni c variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiom yopathy (80-95%, Razzaque 2007, Pandit 2007, E. Ciara 2009, Denayer 2010, Kobaya shi 2010). However, one study identified this variant in two individuals with No onan syndrome who did not have HCM (Razzaque 2007). In summary, this variant me ets our criteria to be classified as pathogenic based on familial segregation co mbined with observations that the variant has been observed de novo (http://pcp gm.partners.org/LMM). -

RAF1-related disorder Pathogenic:1

Jan 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RAF1 c.1837C>G variant is predicted to result in the amino acid substitution p.Leu613Val. This variant was reported in multiple individuals with Noonan syndrome and in at least one individual it was reported to be de novo (see for example - Razzaque et al. 2007. PubMed ID: 17603482; Chen et al. 2019. PubMed ID: 30732632). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Razzaque et al. 2007. PubMed ID: 17603482). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Dec 30, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome with multiple lentigines Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.022	D;D;T
Polyphen		0.14	B;.;.
Vest4		0.57
MutPred		0.81		Loss of catalytic residue at L613 (P = 0.0273);.;.;
MVP		0.92
MPC		0.39
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338797; hg19: chr3-12626123; COSMIC: COSV50103946; COSMIC: COSV50103946;