ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.507A>G (p.Arg169=)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV004695274 SCV005196475 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-07-17 reviewed by expert panel curation NM_001754.5(RUNX1):c.507A>G (p.Arg169_Gly170=) is a synonymous variant that is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). It alters the last three bases of an exon preceding a splice donor site or the first three bases of an exon following an acceptor splice site, with a predicted decrease in the score of the canonical splice site (measured by both MES and SSF) of at least 75%, regardless of the predicted creation/presence of a putative cryptic splice site (Splice AI score: 0.59) (PP3). This variant was reported in ClinVar in 2022 by Invitae, but the affected status of the proband is unknown (Variation ID 2071711). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria have been applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV002975794 SCV003282900 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2022-03-08 criteria provided, single submitter clinical testing This sequence change affects codon 169 of the RUNX1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RUNX1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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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