rs80338797

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PS2PS3

This summary comes from the ClinGen Evidence Repository: The c.1837C>G (p.Leu613Val) variant in RAF1 has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2; PMID 17603483). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM2, PS3, PS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA257066/MONDO:0018997/004

Frequency

Genomes: not found (cov: 32)

Consequence

RAF1
NM_002880.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 3.76

Variant links:

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]

RAF1 links:

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]

MKRN2 links:

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ACMG classification

Classification made for transcript

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.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4 linkuse as main transcript	c.1837C>G	p.Leu613Val	missense_variant	17/17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 linkuse as main transcript	c.1837C>G	p.Leu613Val	missense_variant	17/17	1	NM_002880.4	ENSP00000251849	P3	P04049-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2021	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 -

Noonan syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.1837C>G (p.Leu613Val) variant in RAF1 has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2; PMID 17603483). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PM2, PS3, PS2. -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -

Noonan syndrome 5

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2007	- -
Likely pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 17603483). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 13960). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

LEOPARD syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2013

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). -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Dec 30, 2019

- -

RAF1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2023

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. -

Noonan syndrome with multiple lentigines

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

-0.087

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.81

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over