Submissions for variant NM_002880.4(RAF1):c.1688G>A (p.Arg563Gln)

gnomAD frequency: 0.00001  dbSNP: rs727504827

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156167	SCV000205883	uncertain significance	not specified	2014-03-06	criteria provided, single submitter	clinical testing	The Arg563Gln variant in SOS1 has now been identified by our laboratory in one a ffected individual and his reportedly unaffected mother. Computational predictio n tools and conservation analyses do not provide strong support for or against a n impact to the normal function of the protein. In summary, additional informati on is needed to assess the clinical significance of the Arg563Gln variant.
GeneDx	RCV000680316	SCV000490892	uncertain significance	not provided	2020-01-30	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819687	SCV000960362	uncertain significance	RASopathy	2024-07-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 563 of the RAF1 protein (p.Arg563Gln). This variant is present in population databases (rs727504827, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179378). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680316	SCV004562747	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	The RAF1 c.1688G>A; p.Arg563Gln variant (rs727504827), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 179378). This variant is found in the general population with an overall allele frequency of 0.002 % (5/251250 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.777). Due to limited information, the clinical significance of this variant is uncertain at this time.
Ambry Genetics	RCV004984692	SCV005485521	uncertain significance	Cardiovascular phenotype	2024-07-23	criteria provided, single submitter	clinical testing	The p.R563Q variant (also known as c.1688G>A), located in coding exon 15 of the RAF1 gene, results from a G to A substitution at nucleotide position 1688. The arginine at codon 563 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a cardiomyopathy cohort (Akinrinade O et al. J Cardiovasc Transl Res, 2023 Dec;16:1287-1302). 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 available evidence, the clinical significance of this variant remains unclear.