Submissions for variant NM_002880.4(RAF1):c.1814C>T (p.Ser605Phe)

gnomAD frequency: 0.00006  dbSNP: rs730881004

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159088	SCV000209031	uncertain significance	not specified	2016-06-27	criteria provided, single submitter	clinical testing	The S605F variant in the RAF1 gene has been published previously as possibly associated with Noonan syndrome and inherited from a parent lacking clear clinical manifestations of Noonan syndrome (Kneitel et al., 2015). The 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. S605F is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV000253554	SCV000319670	uncertain significance	Cardiovascular phenotype	2023-04-06	criteria provided, single submitter	clinical testing	The p.S605F variant (also known as c.1814C>T), located in coding exon 16 of the RAF1 gene, results from a C to T substitution at nucleotide position 1814. The serine at codon 605 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been detected in one fetus with features suggestive, but not diagnostic, of Noonan syndrome (Kneitel AW et al. Fetal Pediatr Pathol, 2015 Oct;34:361-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654968	SCV000776878	uncertain significance	RASopathy	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 605 of the RAF1 protein (p.Ser605Phe). This variant is present in population databases (rs730881004, gnomAD 0.008%). This missense change has been observed in individual(s) with a RAF1-related disease (PMID: 26467173). ClinVar contains an entry for this variant (Variation ID: 181512). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765706	SCV000897067	uncertain significance	LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN	2018-10-31	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001838984	SCV002099402	uncertain significance	LEOPARD syndrome 2; Noonan syndrome 5	2021-02-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003129792	SCV003813691	uncertain significance	not provided	2019-06-10	criteria provided, single submitter	clinical testing