ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1252A>G (p.Met418Val)

gnomAD frequency: 0.00010  dbSNP: rs578042376
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV002264698 SCV002546481 likely benign Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2022-07-07 reviewed by expert panel curation NM_001754.5(RUNX1):c.1252A>G (p.Met418Val) is a missense variant. It has a MAF of 0.0001747 (0.01747%, 3/17174, 17174 alleles) in the African/African American population of the gnomAD v2.1.1 cohort (21-36164623-T-C (GRCh37)) and MAF of 0.0003559 (0.03559%, 14/39338, 39338 alleles) in the African/African American population of gnomAD v3.1.2 cohort (21-34792326-T-C (GRCh38)) is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). It was reported in two or three probands (2) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 34166225). This missense has a REVEL score ≤0.50 (0.140) and SpliceAI score is ≤0.20 (0.00) (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BP4 and PS4_moderate.
Invitae RCV000456619 SCV000550163 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-09-08 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 418 of the RUNX1 protein (p.Met418Val). This variant is present in population databases (rs578042376, gnomAD 0.02%). 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: 409820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 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.
GeneDx RCV003332177 SCV004040251 uncertain significance not provided 2023-03-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the apparent germline of children with T-cell acute lymphoblastic leukemia (Li et al., 2021); This variant is associated with the following publications: (PMID: 34166225)
Baylor Genetics RCV003470458 SCV004209877 likely benign Acute myeloid leukemia 2022-08-31 criteria provided, single submitter clinical testing

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