rs397516828
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_002880.4(RAF1):c.782C>T(p.Pro261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P261S) has been classified as Pathogenic.
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.782C>T | p.Pro261Leu | missense_variant | 7/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.782C>T | p.Pro261Leu | missense_variant | 7/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Noonan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 19, 2013 | The Pro261Leu variant in RAF1 has been reported as a de novo variant in one indi vidual with clinical features of Noonan syndrome (Pandit 2007). Recurrent missen se variants at this amino acid position (Pro261Leu, Pro261Ser, Pro261Thr, Pro261 Ala, and Pro261Arg) have been identified by our laboratory in individuals with c linical features associated with Noonan syndrome. Of note, individuals with path ogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic ca rdiomyopathy (80-95%, Razzaque 2007, Pandit 2007). In summary, this variant meet s our criteria to be classified as pathogenic based on its de novo occurrence (h ttp://pcpgm.partners.org/LMM). - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Dilated cardiomyopathy 1NN Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2017 | The P261L variant in the RAF1 gene has been reported previously in an individual with Noonan syndrome with clinical features including short stature, hypertrophic cardiomyopathy, and pectus anomaly (Pandit et al., 2007). The P261L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P261L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is not within a known functional domain and occurs at a position that is conserved across species. Functional studies have shown that P261L leads to increased activity of the RAF1 protein (Molzan et al., 2010). Missense variants in the same residue (P261A, P261T, P261S, P261H, P261R) and in nearby residues (R256S, S257L, S259P, S259T, S259F, T260I, T260R, N262I, N262K, V263D, V263A) have been reported in association with RAF1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P261L as a pathogenic variant. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2023 | The p.P261L pathogenic mutation (also known as c.782C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 782. The proline at codon 261 is replaced by leucine, an amino acid with similar properties. This alteration has been reported as de novo in a subject with features of Noonan syndrome (Pandit B et al. Nat Genet, 2007 Aug;39:1007-12). This alteration has also been reported in subjects with features of Noonan syndrome and overlapping disorders (Kobayashi T et al. Hum Mutat, 2010 Mar;31:284-94; Justino A et al. Eur J Hum Genet, 2015 Mar;23:347-53; Lazzaro G et al. Mol Genet Genomic Med, 2020 Apr;8:e1069). Two other alterations at the same codon, p.P261A (c.781C>G) and p.P261S (c.781C>T), have been described in association with Noonan syndrome (Razzaque MA, Nat. Genet. 2007 Aug; 39(8):1013-7; Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the RAF1 protein (p.Pro261Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17603483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 120246). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAF1 function (PMID: 20679480). 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, 20052757, 21784453, 22465605, 23885229, 29084544). 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. - |
Noonan syndrome 5 Other:1
not provided, no classification provided | literature only | Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at