Submissions for variant NM_002880.4(RAF1):c.1655A>G (p.Asn552Ser)

dbSNP: rs775817988

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654939	SCV000776845	uncertain significance	RASopathy	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 552 of the RAF1 protein (p.Asn552Ser). This variant is present in population databases (rs775817988, gnomAD 0.006%). This missense change has been observed in individual(s) with RAF1-related conditions (PMID: 35352813). ClinVar contains an entry for this variant (Variation ID: 40622). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt RAF1 function with a negative predictive value of 80%. 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.
GeneDx	RCV000680628	SCV000808071	uncertain significance	not provided	2018-02-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the RAF1 gene. The N552S variant has not been published as pathogenic or been reported as benign to our knowledge. The N552S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, the majority of missense variants in the RAF1 gene are pathogenic (Stenson et al., 2014). However, the N552S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV002399358	SCV002707082	uncertain significance	Cardiovascular phenotype	2023-08-04	criteria provided, single submitter	clinical testing	The p.N552S variant (also known as c.1655A>G), located in coding exon 14 of the RAF1 gene, results from an A to G substitution at nucleotide position 1655. The asparagine at codon 552 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.