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.586A>G (p.Thr196Ala)

CA410207987

988811 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: d5ad94ce-5501-4361-a280-2142d4eed57a

Approved on: 2026-10-05

Published on: 2026-10-05

HGVS expressions

NM_001754.5(RUNX1):c.586A>G (p.Thr196Ala)

NM_001754.5:c.586A>G

NC_000021.9:g.34859501T>C

CM000683.2:g.34859501T>C

NC_000021.8:g.36231798T>C

CM000683.1:g.36231798T>C

NC_000021.7:g.35153668T>C

NG_011402.2:g.1130211A>G

ENST00000675419.1:c.586A>G

ENST00000300305.7:c.586A>G

ENST00000344691.8:c.505A>G

ENST00000358356.9:c.505A>G

ENST00000399237.6:c.550A>G

ENST00000399240.5:c.505A>G

ENST00000437180.5:c.586A>G

ENST00000467577.1:n.78A>G

ENST00000482318.5:c.*176A>G

NM_001001890.2:c.505A>G

NM_001122607.1:c.505A>G

NM_001754.4:c.586A>G

NM_001001890.3:c.505A>G

NM_001122607.2:c.505A>G

Likely Pathogenic

PP3 PM1_Strong PM2_Supporting PS4_Moderate

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

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_001754.4:c.586A>G (p.Thr196Ala) is a missense variant which affects one of the hotspot residues (Thr196) 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; PMIDs: 27479822, 31698193). 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.

PP3

This missense variant has a REVEL score >0.88(0.957) and does not have any splicing effects (SpliceAI Score : 0.00)

PM1_Strong

This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1

PM2_Supporting

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

PS4_Moderate

This variant has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27479822, SCV001450794.1, PMID: 31698193).

PP1

This variant was not found to co-segregate with disease in multiple affected family members.

PP2

This rule is not applicable for MM-VCEP

PP4

This rule is not applicable for MM-VCEP

PM4

Not applicable as this is a Missense variant

PM5

This variant is a missense change at the same residue (p.Thr196) where a different missense change has been previously reported as a pathogenic variant (PMID: 34233450, p.(Thr196Ile), p.(Thr196Arg)) based on MM-VCEP rules for RUNX1and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects. PM5 cannot be applied at this stage as these variants still need to be recognized as pathogenic by MM-VCEP.

PM3

This rule is not applicable for MM-VCEP

BA1

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

PM6

This variant has not been reported in probands in the literature.

BS2

This variant is completely absent in gnomAD

BS3

No functional data found

BS4

This variant has not been reported in affected family members.

BS1

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

PS2

This variant has not been reported in probands in the literature.

PS3

No functional data found

PS1

The same amino acid change has not been reported as pathogenic at this residue.

BP3

This rule is not applicable for MM-VCEP

BP4

This missense variant has a REVEL score >0.88(0.957) and does not have any splicing effects (SpliceAI Score : 0.00)

BP1

This rule is not applicable for MM-VCEP

BP2

Variant is absent in gnomAD and no homozygotes present with pathogenic variant inheritance pattern

PVS1

This is a missense variant and PVS1 is only applied for null variants therefore this rule would not apply

BP7

Not a synonymous variant therefore cannot be applied

BP5

This rule is not applicable for MM-VCEP

Curation History

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