ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.124_125delinsAT (p.Ala42Ile) (rs876657965)

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Total submissions: 6
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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,Partners HealthCare 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.
Invitae RCV000461796 SCV000552093 uncertain significance Rasopathy 2020-10-13 criteria provided, single submitter clinical testing This variant, c.124_125delGCinsAT, is a complex sequence change that results in a missense change substituting alanine for isoleucine at codon 42 of the RAF1 protein (p.Ala42Ile). This variant is reported in population databases as two contiguous missense variants c.124G>A and c.125C>T reported in cis in 27 individuals in population databases (ExAC, 0.04%). ClinVar contains an entry for this variant (Variation ID: 229175). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of this substitution is currently unknown. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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

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