ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.94A>G (p.Ile32Val) (rs372738063)

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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 RCV000788000 SCV000927032 benign Noonan syndrome and Noonan-related syndrome 2019-06-27 reviewed by expert panel curation The c.94A>G (p.Ile32Val) variant in the RAF1 gene has been identified in patients who underwent testing for a RASopathy, however it has also been identified in multiple adults who did not have clinical features of a RASopathy (BS2, BP5; Invitae, EGL Diagnostics, GeneDx internal data; GTR Lab ID: 500031, 500060; SCV000287747.4, SCV000227277.5, SCV000209002.14). The filtering allele frequency of the p.Ile32Val variant is 0.017% for European (non-Finnish) genomes in the gnomAD database (8/31404 with 95% CI) which is a high enough frequency to be considered strong evidence that the variant is benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1). Computational prediction tools and conservation analysis suggest that the p.Ile32Val variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP5, BS1, BP4.
GeneDx RCV000680302 SCV000209002 likely benign not provided 2018-08-09 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000159060 SCV000227277 likely benign not specified 2015-08-21 criteria provided, single submitter clinical testing
Invitae RCV000229182 SCV000287747 uncertain significance Rasopathy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 32 of the RAF1 protein (p.Ile32Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs372738063, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000159060 SCV000966503 likely benign not specified 2018-03-19 criteria provided, single submitter clinical testing p.Ile32Val in exon2 of RAF1: This variant has been identified in 0.02% (22/12673 0) of European chromosomes and 0.03% (6/24036) of African chromosomes by the Gen ome Aggregation Database (gnomAD,; dbSNP rs3727 38063) and was found in a case with an alternate explanation for disease. In add ition, computational prediction tools do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria applied: BS1; BP5; BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159060 SCV001339226 likely benign not specified 2020-03-30 criteria provided, single submitter clinical testing Variant summary: RAF1 c.94A>G (p.Ile32Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251484 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of 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.94A>G has been reported in the literature in individuals affected with T-cell ALL (Zhang_2016). This report however, does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) including one expert panel (ClinGen RASopathy Variant Curation Expert Panel) cite the variant as likely benign/benign (n=4) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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