ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.967A>G (p.Thr323Ala) (rs775898894)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522356 SCV000616488 likely benign Rasopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.907A>G (p.Thr303Ala) variant in the RAF1 gene is 0.0284% (7/11568) of Latino 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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588644 SCV000698132 benign not provided 2016-03-21 criteria provided, single submitter clinical testing
Invitae RCV000522356 SCV000939042 uncertain significance Rasopathy 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 303 of the RAF1 protein (p.Thr303Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs775898894, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 448928). 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. 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.

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