Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000522675 | SCV000616422 | pathogenic | RASopathy | 2024-12-03 | reviewed by expert panel | curation | The c.775T>A (p.Ser259Thr) variant in the RAF1 gene is a missense variant predicted to cause substitution of serine by threonine at amino acid 259. This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.753, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function (PP3). 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). The variant is also 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 p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The variant has also been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Zenker et al. internal data; ClinVar SCV000209017.9). Additionally, it has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). In vitro functional studies also provide some evidence that the p.Ser259Thr variant may impact protein function (PS3_Supporting; PMID: 21784453, 20052757). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM5_Strong, PM6_Strong, PS4, PM1, PP1, PP2, PP3, PM2_Supporting, PS3_Supporting. (RASopathy VCEP specifications version 2.3; 12/3/2024) |
| Revvity Omics, |
RCV000159074 | SCV003819033 | pathogenic | not provided | 2022-01-10 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000037698 | SCV002761577 | pathogenic | Noonan syndrome | 2022-06-21 | criteria provided, single submitter | clinical testing | The RAF1 c.775T>A variant is classified as a Pathogenic variant (PS4, PS3, PM5, PP3) This variant is a single nucleotide change in exon 7/18 of the RAF1 gene, which is predicted to change the amino acid serine at position 259 in the protein to threonine. The variant has been reported multiple times in patients with Noonan syndrome and with clinical features of a RASopathy (PMID: 19020799, 21784453, 33318624, 29493581). This variant is in dbSNP (rs3730271) but is absent from population databases (PS4). Functional studies have shown that this variant may impact protein function by increasing activation of MEK and ERK (PMID: 21784453) (PS3). Missense variants in the same residue (p.S259C, p.S259F, p.S259P, p.A259Y) have been previously reported as pathogenic in association with Noonan spectrum disorders (PM5).The variant has been reported in the ClinVar and HGMD as pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). |
| Mayo Clinic Laboratories, |
RCV000159074 | SCV001714081 | pathogenic | not provided | 2019-06-23 | criteria provided, single submitter | clinical testing | PM6_Strong, PS3, PS4_Supporting, PM1, PM2, PM5_Strong, PP2, PP3, PP1 |
| Labcorp Genetics |
RCV000522675 | SCV001379118 | pathogenic | RASopathy | 2022-11-19 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Ser259 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, 20052757, 21784453). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RAF1 function (PMID: 21784453). 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: 40601). This missense change has been observed in individuals with Noonan syndrome (PMID: 19020799; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 259 of the RAF1 protein (p.Ser259Thr). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000159074 | SCV000209017 | pathogenic | not provided | 2023-03-16 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate increased activation of MEK and ERK (Kobayashi et al., 2010; Lee et al., 2011); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20052757, 24957944, 9689060, 15520807, 17603483, 17603482, 29493581, 19020799, 33318624, 21784453) |
| Laboratory for Molecular Medicine, |
RCV000037698 | SCV000061360 | likely pathogenic | Noonan syndrome | 2010-09-09 | criteria provided, single submitter | clinical testing | The Ser259Thr variant in RAF1 has been previously identified in two individuals with clinical features of Noonan syndrome (Ko 2008, LMM unpublished data). In ad dition, two different amino acid changes at this location (Ser259Phe, Ser259Tyr) have been identified in individuals with Noonan spectrum features, suggesting a lterations at this amino acid are not tolerated (Pandit 2007, Kobayashi 2009; LM M unpublished data). Ser259 is also known to be of critical importance to the r egulation of the RAF1 protein (Kobayashi 2009). Therefore, it is likely that thi s variant is pathogenic. |
| Molecular Genetics, |
RCV003450656 | SCV004190087 | pathogenic | Noonan syndrome 1 | no assertion criteria provided | clinical testing |