Submissions for variant NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)

dbSNP: rs397516813

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000473341	SCV000616425	pathogenic	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.1082G>C (p.Gly361Ala) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381 ClinVar SCV000209024.9). The p.Gly361Ala variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000209024.9, SCV000061333.5). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly361Ala variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PP2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037671	SCV000061333	likely pathogenic	Noonan syndrome	2016-02-17	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000159081	SCV000209024	pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: substantially reduced kinase activity and reduced binding of RAF1 to Cdc37 (Zhao et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34758253, 29493581, 35770001, 14701845, 29271604, 29051493)
Invitae	RCV000473341	SCV000552086	pathogenic	RASopathy	2022-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAF1 function (PMID: 14701845, 23737487). 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. ClinVar contains an entry for this variant (Variation ID: 40613). This missense change has been observed in individual(s) with clinical features of RAF1-related conditions (PMID: 29271604; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 361 of the RAF1 protein (p.Gly361Ala).
Mendelics	RCV000987116	SCV001136321	likely pathogenic	LEOPARD syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542563	SCV001760104	pathogenic	Noonan syndrome 5		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159081	SCV001979345	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159081	SCV001980434	likely pathogenic	not provided		no assertion criteria provided	clinical testing