Submissions for variant NM_002880.4(RAF1):c.788T>G (p.Val263Gly)

dbSNP: rs397516830

Total submissions: 7

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, http://exac.broadinstitute.org). 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, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523845	SCV001234889	pathogenic	RASopathy	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 263 of the RAF1 protein (p.Val263Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 30157809, 30732632). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40607). 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. This variant disrupts the p.Val263 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603482; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
Molecular Genetics, Centre for Human Genetics	RCV003450657	SCV004190089	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing