Submissions for variant NM_002880.4(RAF1):c.909A>C (p.Thr303=)

gnomAD frequency: 0.00025  dbSNP: rs5746219

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000233051	SCV000616487	likely benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.909A>C (p.Thr303=) variant in the RAF1 gene is 0.0285% (27/66658) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037710	SCV000061372	likely benign	not specified	2015-06-09	criteria provided, single submitter	clinical testing	p.Thr303Thr in exon 9 of RAF1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 27/66658 European c hromosomes and 8/16512 South Asian chromosomes by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs5746219).
Invitae	RCV000233051	SCV000287745	likely benign	RASopathy	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000266115	SCV000440627	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	RCV000318996	SCV000440628	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	RCV000590617	SCV000698133	benign	not provided	2016-11-21	criteria provided, single submitter	clinical testing	Variant summary: The RAF1 c.909A>C (p.Thr303Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 36/121308 control chromosomes at a frequency of 0.0002968, which is approximately 12 times the estimated maximal expected allele frequency of a pathogenic RAF1 variant (0.000025), suggesting this variant is very likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign.
GeneDx	RCV000590617	SCV001904557	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813269	SCV002060613	likely benign	Noonan syndrome and Noonan-related syndrome	2020-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371809	SCV002688562	likely benign	Cardiovascular phenotype	2018-06-29	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.
CeGaT Center for Human Genetics Tuebingen	RCV000590617	SCV004146973	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RAF1: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV004541064	SCV004759710	likely benign	RAF1-related disorder	2021-03-15	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).
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590617	SCV001957384	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590617	SCV001973606	likely benign	not provided		no assertion criteria provided	clinical testing