Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.5(RUNX1):c.593A>C (p.Asp198Ala)

CA410207974

561251 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: 9e51dbad-5cbe-4a99-8a12-f7daf29fd7ab

Approved on: 2026-10-02

Published on: 2026-10-02

HGVS expressions

NM_001754.5(RUNX1):c.593A>C (p.Asp198Ala)

NM_001754.5:c.593A>C

NC_000021.9:g.34859494T>G

CM000683.2:g.34859494T>G

NC_000021.8:g.36231791T>G

CM000683.1:g.36231791T>G

NC_000021.7:g.35153661T>G

NG_011402.2:g.1130218A>C

ENST00000675419.1:c.593A>C

ENST00000300305.7:c.593A>C

ENST00000344691.8:c.512A>C

ENST00000358356.9:c.512A>C

ENST00000399237.6:c.557A>C

ENST00000399240.5:c.512A>C

ENST00000437180.5:c.593A>C

ENST00000467577.1:n.85A>C

ENST00000482318.5:c.*183A>C

NM_001001890.2:c.512A>C

NM_001122607.1:c.512A>C

NM_001754.4:c.593A>C

NM_001001890.3:c.512A>C

NM_001122607.2:c.512A>C

Likely Pathogenic

PS4_Supporting PP3 PM2_Supporting PM1_Strong

PVS1 BA1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP4 PP1 PP2 PS1 PS2 PS3 PM5 PM3 PM4 PM6

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.593A>C (p.Asp198Ala) is a missense variant which affects one of the hotspot residues (Asp198) within the RHD (amino acids 89-204; PM1_Strong). This variant has a REVEL score ≥ 0.88 (0.96) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting, internal data from PreventionGenetics). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1_Strong, PP3, PM2_Supporting, PS4_Supporting.

PS4_Supporting

Answer from the lab who submitted the variant in Clinvar (PreventionGenetics) : Our patient had AML, a personal and family history of familial thrombocytopenia, easy bruising, and hypocellular marrow at diagnosis. The individual's mother also carried the variant and had thrombocytopenia. Although they were unavailable for testing, the maternal grandmother and great-grandfather also were reported to have easy bruising. The maternal great-grandfather died of leukemia in his 60s.

PP3

This missense variant has a REVEL score ≥ 0.88 (0.962) (PP3). SpliceAI score is null.

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).

PM1_Strong

This variant affects the following hotspot residue within the RHD: D198 (PM1_strong).

PVS1

This is a missense variant.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP5

This rule is not applicable to the MMVCEP.

BP7

This is a missense variant.

BP2

To our knowledge, no publication has reported this variant to date.

BP3

This rule is not applicable to the MMVCEP.

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.

BS4

Clinvar has one entry for this variant but the affected status is unknown. To our knowledge, no publication has reported this variant to date.

BS3

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

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

This rule is not applicable to the MMVCEP.

PP1

PP2

This rule is not applicable to the MMVCEP.

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2

To our knowledge, no publication has reported this variant to date.

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

PM1_strong met.

PM3

This rule is not applicable to the MMVCEP.

PM4

This variant is a missense.

PM6

To our knowledge, no publication has reported this variant to date.

Curation History

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