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>T (p.Asp198Val)

CA410207972

627342 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: 05236ec3-500a-4994-b830-31e58ed86bfb

Approved on: 2026-10-05

Published on: 2026-10-05

HGVS expressions

NM_001754.5(RUNX1):c.593A>T (p.Asp198Val)

NM_001754.5:c.593A>T

NC_000021.9:g.34859494T>A

CM000683.2:g.34859494T>A

NC_000021.8:g.36231791T>A

CM000683.1:g.36231791T>A

NC_000021.7:g.35153661T>A

NG_011402.2:g.1130218A>T

ENST00000675419.1:c.593A>T

ENST00000300305.7:c.593A>T

ENST00000344691.8:c.512A>T

ENST00000358356.9:c.512A>T

ENST00000399237.6:c.557A>T

ENST00000399240.5:c.512A>T

ENST00000437180.5:c.593A>T

ENST00000467577.1:n.85A>T

ENST00000482318.5:c.*183A>T

NM_001001890.2:c.512A>T

NM_001122607.1:c.512A>T

NM_001754.4:c.593A>T

NM_001001890.3:c.512A>T

NM_001122607.2:c.512A>T

Likely Pathogenic

PS4_Moderate PP3 PM2_Supporting PM1_Strong

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

Evidence Links 3

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_001754.4:c.593A>T (p.Asp198Val) 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 two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 27479822). 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_Moderate.

PS4_Moderate

2 probands meeting RUNX1-phenotypic criteria (PMID: 27479822; Internal laboratory data).

Somatic mutation from bone marrow cells. PubMed:17485549

Somatic mutation from tumor cells. PubMed:17650443

Family 18-I with thrombocytopenia PubMed:27479822

PP3

REVEL score: 0.959 > 0.88.

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

PM1_Strong

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

PVS1

This variant is not a null variant.

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BP2

This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP3

This rule is not applicable for MM-VCEP.

BP4

This missense variant does not have a REVEL score < 0.50.

BP1

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

BS4

Segregation was not found to be absent in two or more informative meiosis.

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BS1

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

BS2

This rule is not applicable for MM-VCEP.

PP4

This rule is not applicable for MM-VCEP.

PP1

1 meiosis from internal laboratory data.

PP2

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

PS2

De novo data for this variant has not been reported in literature.

PS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

PS1

There has not yet been a missense change resulting in the same change in protein which has been determined to be pathogenic at this amino acid residue.

PM3

This rule is not applicable for MM-VCEP.

PM4

This variant is not an in-frame deletion/insertion.

PM5

This variant is a missense change at the same residue (p. D198) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 561251, 2665098) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects. PM5_supporting cannot be met since PM1_strong is met.

PM6

De novo data for this variant has not been reported in literature.

Curation History

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