ClinVar Miner

Submissions for variant NM_001754.4(RUNX1):c.485G>A (p.Arg162Lys) (rs1057519750)

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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 RCV001290705 SCV001478842 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2021-01-12 reviewed by expert panel curation This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant by SCV001203102.1 in a proband (70s) with thrombocytopenia and anemia; however, the germline origins were not confirmed in this case and all other reports of the variant (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). The variant is located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) [PM1]. Although this variant has not been functionally evaluated, computational evidence supports a deleterious effect of this variant [PP3] and another missense variant at the same residue (i.e. p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP [PM5_supporting]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2, PM5_supporting, and PP3.
Invitae RCV001039570 SCV001203102 uncertain significance Familial platelet disorder with associated myeloid malignancy 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 162 of the RUNX1 protein (p.Arg162Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 376021). This variant has been reported to affect RUNX1 protein function (PMID: 25840971). This variant is also known as 404G>A, Arg135Lys in the literature. 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.
Database of Curated Mutations (DoCM) RCV000426735 SCV000504774 likely pathogenic Acute myeloid leukemia 2014-10-02 no assertion criteria provided literature only

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