ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.596G>A (p.Gly199Glu)

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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 RCV001078217 SCV001244326 likely pathogenic Familial platelet disorder with associated myeloid malignancy 2020-01-14 reviewed by expert panel curation The NM_001754.4:c.596G>A (p.Gly199Glu) variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 26884589, 25159113, 24732596; internal laboratory data). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It affects one of the non-hot-spot residues (AA 105-204) within the RHD (PM1_Supporting). The variant was found to co-segregate with disease in multiple affected family members, with three meioses observed across 2 families (PP1; PMID: 26884589, 25159113, 24732596; internal laboratory data). This missense variant has a REVEL score >0.75 (0.956) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PS4_Moderate, PP1, PP3, PM1_Supporting.
Invitae RCV001078217 SCV001544669 uncertain significance Familial platelet disorder with associated myeloid malignancy 2020-06-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 199 of the RUNX1 protein (p.Gly199Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with thrombocytopenia (PMID: 25159113). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 869210). This variant has been reported to affect RUNX1 protein function (PMID: 24732596). 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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