Submissions for variant NM_002880.4(RAF1):c.788T>A (p.Val263Asp)

dbSNP: rs397516830

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586507	SCV000698128	likely pathogenic	Noonan syndrome 3	2016-02-15	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.788T>A affects a conserved nucleotide, resulting in amino acid change from Val to Asp. 4/4 in-silico tools used predict this variant to be damaging. This variant was not found in approximately 121404 control chromosomes from the broad and large populations of ExAC. This variant was found as a de novo mutation in a patient with hypoplastic left heart syndrome associated with Noonan Syndrome (Schulz_2012). Additionally, another missense mutation at the same residue p.V263G has been classified as pathogenic/likely pathogenic by three labs in ClinVar. Furthermore, there are multiple variants in this region (such as p.S259F/P/T, p.T260R/I, p.P261A/R/H/S/T, p.N262I/K, etc.), reported in patients with NS, suggesting that the region is mutational hot-spot. At least one reputable database lists the variant as disease-causing. Taken together, this variant has currently been classified as a Probable Disease Variant/Likely Pathogenic.
GeneDx	RCV000680804	SCV000808248	pathogenic	not provided	2018-08-27	criteria provided, single submitter	clinical testing	The V263D variant in the RAF1 gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Schulz et al., 2012). The V263D variant is not observed in large population cohorts (Lek et al., 2016). The V263D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (V263A) and nearby residues (S259T/P/F, T260I/R, P261S/A/T/L/R/H, N262I/K) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V263D as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV000763093	SCV000893629	pathogenic	LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002530926	SCV003525043	pathogenic	RASopathy	2022-02-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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, 30157809, 30732632; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 496189). This missense change has been observed in individual(s) with clinical features of RAF1-related conditions (PMID: 22821648). 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 valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 263 of the RAF1 protein (p.Val263Asp).