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.596G>A (p.Gly199Glu)

CA410207966

869210 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: de750d9a-56cc-4163-b7de-f2837e11ad9b

Approved on: 2026-10-15

Published on: 2026-10-15

HGVS expressions

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

NM_001754.5:c.596G>A

NC_000021.9:g.34859491C>T

CM000683.2:g.34859491C>T

NC_000021.8:g.36231788C>T

CM000683.1:g.36231788C>T

NC_000021.7:g.35153658C>T

NG_011402.2:g.1130221G>A

ENST00000675419.1:c.596G>A

ENST00000300305.7:c.596G>A

ENST00000344691.8:c.515G>A

ENST00000358356.9:c.515G>A

ENST00000399237.6:c.560G>A

ENST00000399240.5:c.515G>A

ENST00000437180.5:c.596G>A

ENST00000467577.1:n.88G>A

ENST00000482318.5:c.*186G>A

NM_001001890.2:c.515G>A

NM_001122607.1:c.515G>A

NM_001754.4:c.596G>A

NM_001001890.3:c.515G>A

NM_001122607.2:c.515G>A

Likely Pathogenic

PM1_Supporting PP1 PP3 PS4_Moderate PM2_Supporting

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

Evidence Links 2

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.596G>A (p.Gly199Glu) is a missense variant which affects one of the amino acid residues (Gly199) within the RHD (amino acids 89-204; PM1_Supporting). 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: 26884589, 25159113, 24732596) and was found to co-segregate with disease in three observed meioses across two families (PP1; PMID: 26884589, 25159113, 24732596). 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: PM1_Supporting, PP3, PM2_Supporting, PS4_Moderate, PP1.

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

PP1

2 segregations observed in the family described in PMIDs: 26884589, 25159113, 24732596. 1 segregation seen in an additional family (from internal laboratory data). Together, 3 segregation across 2 families meet criteria fro PP1.

2 family members with thrombocytopenia in addition to the proband (2 segregations) in pedigree 57. In addition, Yoshimi et al, 2014, PMID: 25159113, report detection of another missense variant, p.Asp234Gly, in CDC25C in one of the affected individuals from this family. This Family 57 is likely the same as Pedigree 1 in Sakurai, 2014 - PMID: 24732596. All three reports are on Japanese families with FPD/AML. PubMed:26884589

PP3

This missense variant has a REVEL score ≥ 0.88 (0.956) (PP3).

PS4_Moderate

One proband from PMIDs: 26884589, 25159113, 24732596 and one proband from internal laboratory data meet criteria for PS4_Moderate.

One proband 51yo (from family 57) with thrombocytopenia and no other bleeding symptoms, diagnosed with FPD/AML. PubMed:26884589

PM2_Supporting

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

PVS1

This variant is not a null variant.

PM6

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

PM3

This rule is not applicable for MM-VCEP.

PM4

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

PM5

There has not yet been a different missense change determined to be pathogenic at this amino acid residue.

BA1

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

BS4

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

BS3

This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.

Patient-derived T-cells infected by Sendai viruses to generate iPSCs with the Gly199Glu mutation. Hematopoietic differentiation was induced and analyzed for emergence of hematopoietic progenitors, which was found to be impaired (40-60% of WT for CD34+ and 20-40% for CD45+), but early erythroid-MgK progenitors were not affected. CD34+ cells subjected to colony-forming assays showed significantly reduced GM/E/mix CFCs. PubMed:24732596

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.

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

This rule is not applicable for MM-VCEP.

PS2

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

PS1

There has not yet been a missense change determined to be pathogenic at this amino acid residue.

PS3

Data from PMID: 24732596 shows reduced colony forming potential of CD34+ hematopoietic progenitors of patient-derived iPSCs. However, this evidence does not meet criteria for PS3_Moderate: ≥ 2 secondary assays demonstrating altered function.

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

Curation History

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