Submissions for variant NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn)

dbSNP: rs1569084082

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448447	SCV004176250	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score is greater than 0.88 (0.884) and SpliceAI is not greater than 0.38 (0.00) (PP3). This variant affects one of the hotspot (K110) residues established by the MM-VCEP for RUNX1 (PM1). The c.328A>G variant is the same amino acid change (p.K110E) as a previously established pathogenic variant (ClinVar ID 14465) curated using MM-VCEP rules for RUNX1 (PS1). 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_supporting, PP3, PM1, PS1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002024005	SCV002310348	pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-08-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 110 of the RUNX1 protein (p.Lys110Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with leukemia (PMID: 10068652). This variant is also known as K83N. ClinVar contains an entry for this variant (Variation ID: 1518631). 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 expected to disrupt RUNX1 protein function. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 10068652, 19448675, 21725049, 29055018). This variant disrupts the p.Lys110 amino acid residue in RUNX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1958483, 11830488). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.