Submissions for variant NM_002880.4(RAF1):c.639T>C (p.Thr213=)

gnomAD frequency: 0.00002  dbSNP: rs397516823

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001030082	SCV001192874	benign	RASopathy	2019-11-04	reviewed by expert panel	curation	The c.639T>C (p.Thr213Thr) variant in RAF1 is classified as benign because it has been identified in 0.05616% (lower bound of the 95% CI of 28/35434) of Latino alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). It was observed in an individual with an alternate molecular basis for disease (BP5; SCV000061357.6). It does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact to splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037695	SCV000061357	likely benign	not specified	2012-02-15	criteria provided, single submitter	clinical testing	Thr213Thr in exon 6 of RAF1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and it is not located wi thin the splice consensus sequence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030082	SCV000659062	likely benign	RASopathy	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621888	SCV000740149	likely benign	Cardiovascular phenotype	2017-05-05	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.
Eurofins Ntd Llc (ga)	RCV000727917	SCV000855426	uncertain significance	not provided	2017-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037695	SCV000920139	benign	not specified	2018-04-02	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.639T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.0001 in 246250 control chromosomes (gnomAD). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 28-fold higher than 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. To our knowledge, no occurrence of c.639T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000727917	SCV001844371	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541112	SCV004776881	likely benign	RAF1-related disorder	2023-03-14	no assertion criteria provided	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).