ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.367G>C (p.Asp123His) (rs373498347)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV000795718 SCV000965617 uncertain significance Familial platelet disorder with associated myeloid malignancy 2019-07-29 reviewed by expert panel curation The NM_001754.4:c.367G>C (p.Asp123His) missense variant has a REVEL score >0.75 (0.943) (PP3). This variant affects one of the other residues (AA 105-204; not established as a hot spot by the MM-VCEP) within the RHD PM1_Supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 18723428). 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: PP3, PM1_Supporting, PS4_Supporting.
GeneDx RCV000493659 SCV000582472 uncertain significance not provided 2019-02-27 criteria provided, single submitter clinical testing This variant is denoted RUNX1 c.367G>C at the cDNA level, p.Asp123His (D123H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). Using alternate nomenclature, this variant has been previously published as RUNX1 Asp96His. In one pedigree, this variant was observed in relatives with histories of myelodysplastic syndrome and thrombocytopenia (Owen 2008). RUNX1 Asp123His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Runt domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RUNX1 Asp123His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000795718 SCV000935188 uncertain significance Familial platelet disorder with associated myeloid malignancy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 123 of the RUNX1 protein (p.Asp123His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs373498347, ExAC 0.003%). This variant has been observed in an individual affected with acute myeloid leukemia (PMID: 28933735). In addition, it has been observed to segregate with disease in a family affected with familial platelet disorder with propensity to myeloid malignancy (FPD/AML) (PMID: 18723428). This variant is also known as D96H in the literature. ClinVar contains an entry for this variant (Variation ID: 429813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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