Submissions for variant NM_002880.4(RAF1):c.124_125delinsAT (p.Ala42Ile)

dbSNP: rs876657965

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000461796	SCV001192867	likely benign	RASopathy	2019-09-24	reviewed by expert panel	curation	The c.124_125delinsAT (p.Ala42Ile) variant in RAF1 is reported in population databases as two contiguous missense variants: c.124G>A and c.125C>T in cis in 27/64,595 (0.03%) European individuals in gnomAD. This meets the cut off set by the ClinGen RASopathy Variant Curation Expert Panel to apply BS1. This variant has been observed in at least 22 individuals (SCV000858114.1, SCV000698121.1, SCV000272341.3, SCV000552093.5, GeneDx internal data). This variant was observed in an individual with an alternate molecular basis for disease (BP5; SCV000698121.1 ). Computational prediction tools and conservation analysis suggest that the p.Ala42Ile variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5, BP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219930	SCV000272341	uncertain significance	not specified	2015-11-03	criteria provided, single submitter	clinical testing	The p.Ala42Ile variant in RAF1 has not been previously reported in individuals w ith a RASopathy, but has been identified by our laboratory in 1 Caucasian adult with LNVC. This variant represents two adjacent base pair changes that are prese nt on the same copy of the RAF1 gene and result in the substitution of a single alanine (Ala) residue at position 42 with an isoleucine (Ile). These are reporte d as 2 separate changes in the ExAC database (c.124G>A and c.125C>T), each prese nt in 25/66738 European chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs115499992 and rs200856000) but have been confirmed to be present in cis (pers onal communication). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala42Ile variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461796	SCV000552093	uncertain significance	RASopathy	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 42 of the RAF1 protein (p.Ala42Ile). This variant is present in population databases (no rsID available, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with RAF1-related conditions (PMID: 26656175, 33500567). ClinVar contains an entry for this variant (Variation ID: 229175). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219930	SCV000698121	benign	not specified	2019-09-05	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.124_125delinsAT (p.Ala42Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 277244 control chromosomes. The observed variant frequency is approximately 12-fold over 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 benign. c.124_125delinsAT has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Bottillo_2016). This report does not provide an unequivocal conclusion about association of the variant with Noonan Syndrome and Related Conditions. A co-occurrence with another pathogenic variant has been internally reported (PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Eurofins Ntd Llc (ga)	RCV000589194	SCV000858114	uncertain significance	not provided	2017-11-26	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845521	SCV000987624	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
GeneDx	RCV000589194	SCV001871429	benign	not provided	2016-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381745	SCV002671550	likely benign	Cardiovascular phenotype	2018-03-30	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.
Revvity Omics, Revvity	RCV000589194	SCV003813689	uncertain significance	not provided	2019-04-05	criteria provided, single submitter	clinical testing