Submissions for variant NM_002880.4(RAF1):c.1770G>C (p.Lys590Asn)

dbSNP: rs773583951

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607962	SCV000731576	uncertain significance	not specified	2017-03-28	criteria provided, single submitter	clinical testing	The p.Lys590Asn variant in RAF1 has not been previously reported in individuals with a Rasopathy, but has been identified in 1/66734 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs773 583951). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinica l significance of the p.Lys590Asn variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV002506489	SCV002812756	uncertain significance	LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN	2021-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531680	SCV002983551	uncertain significance	RASopathy	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 590 of the RAF1 protein (p.Lys590Asn). This variant is present in population databases (rs773583951, gnomAD 0.0009%). 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: 517341). 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579580	SCV001807790	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579580	SCV001957116	uncertain significance	not provided		no assertion criteria provided	clinical testing