Submissions for variant NM_002880.4(RAF1):c.122G>A (p.Arg41Gln)

gnomAD frequency: 0.00016  dbSNP: rs145611571

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037673	SCV000061335	likely benign	not specified	2018-10-10	criteria provided, single submitter	clinical testing	The p.Arg41Gln variant in RAF1 has been identified by our laboratory in 2 indivi duals with clinical features of a RASopathy and segregated with disease in 1 aff ected relative; however, this variant has also been identified in 0.05% (17/3442 0) of Latino chromosomes and 0.03% (44/126734) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and, therefore, it is classified as likely b enign. ACMG/AMP Criteria applied: BS1.
GeneDx	RCV000680304	SCV000209003	benign	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000253580	SCV000320377	likely benign	Cardiovascular phenotype	2020-03-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000463359	SCV000552090	likely benign	RASopathy	2024-02-01	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624707	SCV000740652	uncertain significance	Primary familial dilated cardiomyopathy	2016-10-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000680304	SCV000861761	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680304	SCV000884443	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing	The RAF1 c.122G>A; p.Arg41Gln variant (rs145611571), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03% (identified on 75 out of 277,246 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 279925). The arginine at position 41 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg41Gln variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Arg41Gln variant cannot be determined with certainty.
Mendelics	RCV000987120	SCV001136325	benign	LEOPARD syndrome 2	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001149006	SCV001309930	uncertain significance	Noonan syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000987120	SCV001309931	benign	LEOPARD syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037673	SCV001426962	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.122G>A (p.Arg41Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 252090 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome And Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.122G>A has been reported in the literature in at least one individual with autism (Kelleher_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22558107). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=6; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813264	SCV002060600	likely benign	Noonan syndrome and Noonan-related syndrome	2019-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541062	SCV004788117	likely benign	RAF1-related disorder	2020-07-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261025	SCV001438423	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing