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.400G>C (p.Ala134Pro)

CA248623

14468 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: d5e03ae0-3ff2-428d-87e3-ae93412f6bf1

Approved on: 2026-05-27

Published on: 2026-05-27

HGVS expressions

NM_001754.5(RUNX1):c.400G>C (p.Ala134Pro)

NM_001754.5:c.400G>C

NC_000021.9:g.34880665C>G

CM000683.2:g.34880665C>G

NC_000021.8:g.36252962C>G

CM000683.1:g.36252962C>G

NC_000021.7:g.35174832C>G

NG_011402.2:g.1109047G>C

ENST00000675419.1:c.400G>C

ENST00000300305.7:c.400G>C

ENST00000344691.8:c.319G>C

ENST00000358356.9:c.319G>C

ENST00000399237.6:c.364G>C

ENST00000399240.5:c.319G>C

ENST00000437180.5:c.400G>C

ENST00000455571.5:c.361G>C

ENST00000482318.5:c.107G>C

NM_001001890.2:c.319G>C

NM_001122607.1:c.319G>C

NM_001754.4:c.400G>C

NM_001001890.3:c.319G>C

NM_001122607.2:c.319G>C

Pathogenic

PS3 PP1 PP3 PM1_Strong PM2_Supporting PS4_Supporting

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

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.4:c.400G>C (p.Ala134Pro) is a missense variant which affects one of the hotspot residues (A134) within the RHD (PM1_Strong). Transactivation assays demonstrate altered transactivation (<20% of wt) and data from secondary assays demonstrate altered CBFβ binding and sub-cellular localization (PS3; PMID: 23848403). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting) and has a REVEL score of >0.75 (0.95) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 12060124) and was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 12060124). 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, PS3, PM2_Supporting, PP3, PS4_Supporting, PP1.

PS3

Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered CBFβ binding and sub-cellular localization (PMID:23848403) (PS3).

Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered CBFβ binding and sub-cellular localization. PubMed:23848403

PP1

3 meioses in a family with thrombocytopenia and acute myeloid leukaemia (PP1).

3 meioses in a family with thrombocytopenia and acute myeloid leukaemia. PubMed:12060124

PP3

This missense variant has a REVEL score ≥ 0.88 (0.945) (PP3).

PM1_Strong

This variant affects one of the following hotspot residues within the RHD: A134 (PM1).

PM2_Supporting

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

PS4_Supporting

One family with thrombocytopenia and acute myeloid leukemia (PS4_supporting).

One family with thrombocytopenia and acute myeloid leukemia. PubMed:12060124

PS2

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

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

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

This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1484777) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects. However, PM5_supporting cannot be applied since PM1_strong is met.

BA1

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

BS2

This rule is not applicable for MM-VCEP.

PVS1

This variant is not a null variant.

BS4

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

3 meioses in a family with thrombocytopenia and acute myeloid leukaemia. PubMed:12060124

BS1

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

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.

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.

Curation History

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