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:c.503G>A

CA410202475

3367214 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: 228d5007-e165-453d-94df-d85cf6abe224

Approved on: 2026-10-05

Published on: 2026-10-05

HGVS expressions

NM_001754.5:c.503G>A

NC_000021.9:g.34880562C>T

CM000683.2:g.34880562C>T

NC_000021.8:g.36252859C>T

CM000683.1:g.36252859C>T

NC_000021.7:g.35174729C>T

NG_011402.2:g.1109150G>A

ENST00000675419.1:c.503G>A

ENST00000300305.7:c.503G>A

ENST00000344691.8:c.422G>A

ENST00000358356.9:c.422G>A

ENST00000399237.6:c.467G>A

ENST00000399240.5:c.422G>A

ENST00000437180.5:c.503G>A

ENST00000482318.5:c.*93G>A

NM_001001890.2:c.422G>A

NM_001122607.1:c.422G>A

NM_001754.4:c.503G>A

NM_001001890.3:c.422G>A

NM_001122607.2:c.422G>A

Likely Pathogenic

PM2_Supporting PP1 PP3 PS4_Moderate PM1_Supporting

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

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.503G>A (p.Gly168Glu) is a missense variant which affects one of the amino acid residues (Gly168) within the RHD (amino acids 89-204; PM1_Supporting). This variant has a REVEL score ≥ 0.88 (0.98) (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: 39375928) and was found to co-segregate with disease in three observed meioses in one family (PP1; PMID:39375928). 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.

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PP1

This variant has been observed in 3 meioses across 1 family (PMID:39375928) (PP1).

PP3

This missense variant has a REVEL score ≥0.50 (0.947) and the SpliceAI score is not ≥0.38 (0.05 Donor Loss 18bp) (PP3)

PS4_Moderate

This variant has been reported in 2 probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ Moderate; PMID: 39375928, internal lab data).

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_supporting).

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PP4

This rule is not applicable for MM-VCEP

PP2

This rule is not applicable for MM-VCEP

PVS1

not a null variant

PM6

No case studies found

PM5

Cannot be applied due to the application of PM1

PM3

This rule is not applicable for MM-VCEP

PM4

Not a frameshift variant

BS4

No case studies found

BS3

No functional studies found

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

BS2

This rule is not applicable for MM-VCEP

PS2

No case studies found

PS3

No functional studies found

PS1

Same location 168 seen different amino acid changes and termination as LP however not the same to be PS1 applicable

BP7

Not synonymous or intronic variant

BP5

This rule is not applicable for MM-VCEP

BP2

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

BP3

This rule is not applicable for MM-VCEP

BP4

This missense variant has a REVEL score ≥0.50(0.947) and SpliceAI score is not ≥0.38 (0.05 Donor Loss 18bp) (PP3)

BP1

This rule is not applicable for MM-VCEP

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.