Submissions for variant NM_002880.4(RAF1):c.119G>A (p.Arg40His)

gnomAD frequency: 0.00016  dbSNP: rs192632236

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000127704	SCV000616419	benign	RASopathy	2024-09-17	reviewed by expert panel	curation	The c.119G>A variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by histidine at amino acid 40 (p.Arg40His). The filtering allele frequency of this variant is 0.5265% for Admixed American chromosomes in gnomAD v4, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The computational predictor REVEL gives a score of 0.281, which is below the threshold of 0.3 and does not predict a damaging effect on RAF1 function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease and did not segregate with disease in affected family members (BP5, BS4; GeneDx internal data; GTR ID: 26957; SCV000171283.11). Additionally this variant was identified in multiple healthy individuals (BS2_P, Eurofins, SCV000227278.5; Illumina, SCV000440638.3; Ambry Genetics, SCV000736788.4). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BS4, BS2_supporting, BP4, BP5 (Specification Version 2.1, 9/17/2024)
GeneDx	RCV000680303	SCV000171283	benign	not provided	2018-08-28	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.
Eurofins Ntd Llc (ga)	RCV000175738	SCV000227278	benign	not specified	2015-06-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000127704	SCV000287736	benign	RASopathy	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000348082	SCV000440637	benign	LEOPARD syndrome 2	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV000390116	SCV000440638	likely benign	Noonan syndrome 5	2018-01-12	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV000617266	SCV000736788	benign	Cardiovascular phenotype	2018-07-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660242	SCV000782256	uncertain significance	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680303	SCV002049953	benign	not provided	2022-03-30	criteria provided, single submitter	clinical testing