Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr)

CA410207975

2665098 (ClinVar)

Gene: RUNX1 (HGNC:861)
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)
Inheritance Mode: Autosomal dominant inheritance
UUID: 0bb54213-b944-4359-9c06-3c5e6d93feef
Approved on: 2026-04-29
Published on: 2026-04-29

HGVS expressions

NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr)
NM_001754.5:c.592G>T
NC_000021.9:g.34859495C>A
CM000683.2:g.34859495C>A
NC_000021.8:g.36231792C>A
CM000683.1:g.36231792C>A
NC_000021.7:g.35153662C>A
NG_011402.2:g.1130217G>T
ENST00000675419.1:c.592G>T
ENST00000300305.7:c.592G>T
ENST00000344691.8:c.511G>T
ENST00000358356.9:c.511G>T
ENST00000399237.6:c.556G>T
ENST00000399240.5:c.511G>T
ENST00000437180.5:c.592G>T
ENST00000467577.1:n.84G>T
ENST00000482318.5:c.*182G>T
NM_001001890.2:c.511G>T
NM_001122607.1:c.511G>T
NM_001754.4:c.592G>T
NM_001001890.3:c.511G>T
NM_001122607.2:c.511G>T
More

Pathogenic

Met criteria codes 6
PS4_Supporting PP1 PP3 PM1_Strong PS3_Moderate PM2_Supporting
Not Met criteria codes 20
PP4 PP2 PM3 PM4 PM5 BA1 PM6 BS2 BS3 BS4 BS1 PS2 PS1 BP2 BP3 BP4 BP1 PVS1 BP5 BP7

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.592G>T (p.Asp198Tyr) is a missense variant which affects on of the hotspot residues (D198) in the RHD (PM1_strong) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Yeast assays demonstrated decreased DNA binding, CBFβ binding, and promoter activation (PMID: 17290219, 23848403)(PS3_moderate), and a REVEL score ≥ 0.88 (0.964) supports a deleterious effect (PP3). This variant has been reported in a proband meeting RUNX1 phenotypic criteria and was found to co-segregate with disease in multiple affected family members (PMID: 11675361) (PS4_supporting, PP1). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_strong, PM2_supporting, PS3_moderate, PP3, PS4_supporting, PP1.
Met criteria codes
PS4_Supporting
This variant has been reported in a proband meeting RUNX-1 phenotypic criteria (FPD and/or AML) (PMID 11675361) (PS4_moderate).
PP1
This variant has been reported to co-segregate with disease in 3 affected individuals in a family meeting RUNX-1 phenotypic criteria (FPD and/or AML) (PMID 11675361) (PP1_supporting).
PP3
This missense variant has a REVEL score ≥ 0.88 (0.964) (PP3).
PM1_Strong
This variant affects the following hotspot residue within the RHD: D198 (PM1_strong).
PS3_Moderate
Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs: 17290219, 23848403) (PS3_moderate).
Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs). PubMed:17290219
Yeast assays showed significant decreased DNA binding, CBFbeta binding and promoter activation indicating that this variant impacts protein function (PMIDs). PubMed:23848403
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).
Not Met criteria codes
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
This rule is not applicable to the MMVCEP.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
LP *** 2019 > should be updated with specifications?
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
This rule is not applicable to the MMVCEP.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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