ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.136G>A (p.Ala46Thr)

dbSNP: rs2058005288
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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 RCV004692437 SCV005196575 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2024-08-01 reviewed by expert panel curation NM_001754.5(RUNX1):c.136G>A (p.Ala46Thr) is a missense variant which 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). This missense variant has a REVEL score <0.50 (0.387) and a SpliceAI score ≤0.20 (0) (BP4). ClinVar has one entry (Invitae, variation ID 1003215) for this variant, but the affected status is unknown. To our knowledge, this variant has not been reported in the literature in individuals affected with RUNX1-related conditions. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, BP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV001299743 SCV001488850 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2024-02-29 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the RUNX1 protein (p.Ala46Thr). 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. ClinVar contains an entry for this variant (Variation ID: 1003215). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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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