ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.253C>A (p.His85Asn) (rs121912500)

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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 RCV000549373 SCV000965645 likely benign Familial platelet disorder with associated myeloid malignancy 2019-07-26 reviewed by expert panel curation The NM_001754.4:c.253C>A (p.His85Asn) variant has a MAF of 0.00043 (0.043%, 8/18,768 alleles) in the East Asian subpopulation of the gnomAD cohort that is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). This missense variant has a REVEL score >0.75 (0.852) (PP3). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBF-beta binding and sub-cellular localization (BS3; PMID: 23817177, PMID: 10068652). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3, PP3.
Invitae RCV000549373 SCV000638137 uncertain significance Familial platelet disorder with associated myeloid malignancy 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 85 of the RUNX1 protein (p.His85Asn). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs121912500, ExAC 0.04%). This variant has been reported in an individual affected with acute myeloid leukemia (AML), although the germline nature of the variant was not definitively reported (PMID: 10068652). This variant has also been reported in an infant affected with transient myeloproliferative disorder and Down syndrome (PMID: 12200707). ClinVar contains an entry for this variant (Variation ID: 14469). Experimental studies have shown that although this missense change does not impact DNA binding, heterodimerization, subcellular localization, or transcriptional activity of the RUNX1 protein (PMID: 10068652), it disrupts MLL binding, which impairs proper H3K4 histone methylation (PMID: 23817177, 22012064). 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.
OMIM RCV000015555 SCV000035820 pathogenic Transient myeloproliferative disorder of Down syndrome 2002-09-01 no assertion criteria provided literature only
OMIM RCV000015556 SCV000035821 pathogenic Leukemia, acute myeloid, m0 subtype 2002-09-01 no assertion criteria provided literature only

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