ClinVar Genomic variation as it relates to human health

The c.782C>G;p.(Pro261Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40606; PMID: 28777121; 26266034; 25862627; 22824796; 22465605) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PMID: 22824796; 22465605) - PM1. This variant is not present in population databases (rs397516828- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 120246) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 26266034) - PM6. Missense variant in RAF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic

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; Observed in an individual with Noonan syndrome in the published literature (van Trier et al., 2015); This variant is associated with the following publications: (PMID: 30692697, 24803665, 28777121, 25862627, 26266034, 30384889, 32668031, 32981126, 24957944, 9689060, 15520807, 29493581, 19020799)

Variant summary: The RAF1 c.782C>G (p.Pro261Arg) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121388 control chromosomes and has been reported in the literature in at least 2 Noonan Syndrome patients, one in whom the variant was absent in both parents (assumed de novo [Ratola_2015, VanTrier_2015]). Other variants affecting the same codon (Pro261Ala, Pro261Leu) have been classified as pathogenic/likely pathogenic by our lab, indicating the variant to be located in a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.

proposed classification - variant undergoing re-assessment, contact laboratory

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro261 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603482, 17603483, 20683980, 21784453, 22465605). 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: 40606). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 25862627, 26266034, 28777121). 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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 261 of the RAF1 protein (p.Pro261Arg).