Submissions for variant NM_002880.4(RAF1):c.1850A>C (p.Asn617Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003338135	SCV004047080	uncertain significance	Noonan syndrome 5		criteria provided, single submitter	clinical testing	The missense variant c.1910A>C (p.Asn637Thr) in RAF1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn637Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Asn at position 637 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Asn637Thr in RAF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005061287	SCV005696565	uncertain significance	RASopathy	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 617 of the RAF1 protein (p.Asn617Thr). This variant is not present in population databases (gnomAD no frequency). 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: 2585519). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) did not meet the statistical confidence thresholds required to predict the impact of this variant on RAF1 function. 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.