ClinVar Miner

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

dbSNP: rs80338797
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000440827 SCV000616381 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824753 SCV000061345 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2013-03-26 criteria provided, single submitter 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).
GeneDx RCV000254689 SCV000209032 pathogenic not provided 2021-12-02 criteria provided, single submitter 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159089 SCV000918145 pathogenic RASopathy 2018-12-11 criteria provided, single submitter 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.
Invitae RCV000159089 SCV000951436 pathogenic RASopathy 2021-12-18 criteria provided, single submitter clinical testing 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).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256891 SCV001433389 pathogenic Hypertrophic cardiomyopathy 1 2019-12-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000254689 SCV002048615 pathogenic not provided 2021-05-12 criteria provided, single submitter 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
PreventionGenetics, part of Exact Sciences RCV004532353 SCV004116053 pathogenic RAF1-related disorder 2023-01-11 criteria provided, single submitter 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.
OMIM RCV000014989 SCV000035245 pathogenic LEOPARD syndrome 2 2007-08-01 no assertion criteria provided literature only
OMIM RCV000014990 SCV000035246 pathogenic Noonan syndrome 5 2007-08-01 no assertion criteria provided literature only
GeneReviews RCV000020508 SCV000040959 not provided Noonan syndrome with multiple lentigines no assertion provided literature only
Database of Curated Mutations (DoCM) RCV000440827 SCV000510512 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000014990 SCV001482323 likely pathogenic Noonan syndrome 5 2019-05-31 no assertion criteria provided research

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