ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1897C>G (p.Leu633Val) (rs80338797)

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Total submissions: 11
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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,Partners HealthCare 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 2018-02-02 criteria provided, single submitter clinical testing The L613V variant in the RAF1 gene has been reported previously in patients with Noonan syndrome, one of whom had an atrial septal defect and tetralogy of Fallot (Razzaque et al., 2007). L613V has also been reported as de novo in a patient with Noonan syndrome with multiple lentigines (NSML) (Pandit et al., 2007). The L613V variant is not observed in large population cohorts (Lek et al., 2016). Although L613V is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species. 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). In summary, we consider this variant to be pathogenic.Based on the high frequency of hypertrophic cardiomyopathy and other heart defects (>80%) in individuals with a RAF1 pathogenic variant, an appropriate cardiologic screening protocol is recommended.
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 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 613 of the RAF1 protein (p.Leu613Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with Noonan syndrome and Noonan syndrome with multiple lentigines and has been reported to be de novo in at least one affected individual (PMID: 17603482, 19953625, 18241070, 17603483). ClinVar contains an entry for this variant (Variation ID: 13960). Experimental studies have shown that this missense change increases the kinase activity of the RAF1 protein (PMID: 17603482, 17603483). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256891 SCV001433389 pathogenic Familial hypertrophic cardiomyopathy 1 2019-12-30 criteria provided, single submitter clinical testing
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 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
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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