ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.788T>G (p.Val263Gly) (rs397516830)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000523845 SCV000616423 likely pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.788T>G (p.Val263Gly) variant in RAF1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR ID: 26957; ClinVar SCV000061370.9). The p.Val263Gly variant has been identified in 6 other independent occurrences in patients with a RASopathy (PS4 not met; Partners LMM, Blueprint genetics, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 500188, 506381, 28338; ClinVar SCV000209021.9, SCV000207170.1). This variant was absent from large population studies (PM2; ExAC, A different pathogenic missense variant has been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 496189, 40608). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). 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). Computational prediction tools and conservation analysis suggest that the p.Val263Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PM1, PP3, PP2.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037708 SCV000061370 likely pathogenic Noonan syndrome 2013-11-19 criteria provided, single submitter clinical testing The Val263Gly variant has now been identified by our laboratory in three individ uals with clinical features of Noonan syndrome. In addition, a different amino a cid change at the same position (Val263Ala) has also been associated with the cl inical features of Noonan syndrome (Razzaque 2007). This variant has not been i dentified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that thi s variant may impact the protein. Of note, individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80 -95%, Razzaque 2007). In summary, the Val263Gly variant is likely to be pathogen ic, although additional information is needed to fully establish its clinical si gnificance.
GeneDx RCV000159078 SCV000209021 pathogenic not provided 2012-03-18 criteria provided, single submitter clinical testing The V263G missense mutation has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This mutation has been seen before at GeneDx and another missense mutation at this codon (V263A) was previously reported in a patient diagnosed with Noonan syndrome and hypertrophic cardiomyopathy (Razzaque et al., 2007). Furthermore, this mutation is located in a highly conserved portion of the RAF1 gene, where many other gain-of function mutations (P261A, P261S and P261L) have also been reported in association with Noonan syndrome (Pandit et al., 2007 and Razzaque et al., 2007). Therefore, V263G is considered to be a disease-causing mutation. The variant is found in NOONAN panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000523845 SCV000920144 pathogenic Rasopathy 2020-04-01 criteria provided, single submitter clinical testing RAF1 c.788T>G (p.Val263Gly) results in a non-conservative amino acid change located in a region of the CR2 functional domain of the encoded protein sequence supporting pathogenicity, as defined by the ClinGen RASopathy Expert Panel (PM1; PMID 29493581). Five of five in-silico tools predict a damaging effect of the variant on protein function (PP3). The variant was absent in 251466 control chromosomes in the gnomAD database (PM2). c.788T>G has been reported in the literature in at least 5 individuals affected with Noonan Syndrome and Related Conditions (e.g. Chen_2019, Clinton_2019, Ghedira_2018, Rodriguez_2019, Schulz_2012) (PS4). The variant was reported as a de novo occurrence (confirmed via parental testing) in at least 3 of the documented patients (e.g. Chen_2019, Ghedira_2018, Schulz_2012) (PS2). Additional patients with clinical features of a RASopathy or specifically Noonan syndrome have been reported in the ClinVar database (SCV000616423.3, SCV000061370.6). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same amino acid, p.Val263Ala, has been functionally assessed and showed increased in vitro kinase and ERK activation, behaving as a gain-of-function mutant (PMID 17603482). Kobayashi et al (2010) (PMID 20052757) report in their study that mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (S259). Functional studies suggest that dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain. The ClinGen RASopathy Variant Curation Expert Panel cites the variant in ClinVar (evaluation after 2014) as likely pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic.
Invitae RCV000523845 SCV001234889 pathogenic Rasopathy 2019-02-18 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 263 of the RAF1 protein (p.Val263Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with Noonan syndrome (PMID: 30157809, 30732632). ClinVar contains an entry for this variant (Variation ID: 40607). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Val263 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been observed in individuals with RAF1-related conditions (PMID: 17603482, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000037708 SCV000207170 pathogenic Noonan syndrome 2014-07-07 no assertion criteria provided clinical testing

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