Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM2PP2BP4_Strong
The NM_002880.4(RAF1):c.934G>C(p.Val312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
In a region_of_interest Disordered (size 114) in uniprot entity RAF1_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_002880.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the RAF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 2.4628 (below the threshold of 3.09). Trascript score misZ: 3.4185 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome 5, dilated cardiomyopathy 1NN, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome, familial isolated dilated cardiomyopathy, LEOPARD syndrome 2, Costello syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.057960004).
Review Status: criteria provided, single submitter
Collection Method: clinical testing
A novel variant of uncertain significance has been identified in the RAF1 gene. The V312L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where only amino acids with similar properties to Valine are tolerated across species. However, the V312L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, only one missense variant in a nearby residue (T310A) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -