Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_002880.4(RAF1):c.1082G>T(p.Gly361Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G361A) has been classified as Pathogenic.
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 Pathogenic. Variant got 11 ACMG points.
PM1
In a domain Protein kinase (size 260) in uniprot entity RAF1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_002880.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-12599717-C-G is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAF1. . Gene score misZ: 2.4628 (greater than the threshold 3.09). Trascript score misZ: 3.4185 (greater than threshold 3.09). The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. GenCC has associacion of the gene with Noonan syndrome 5, dilated cardiomyopathy 1NN, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome, familial isolated dilated cardiomyopathy, LEOPARD syndrome 2, Costello syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989