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.433A>G (p.Arg145Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16616277

409808 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 83e25d73-6f43-455d-bf50-26f3e9e0f385

Approved on: 2025-01-15

Published on: 2025-01-15

HGVS expressions

NM_001754.5:c.433A>G

NM_001754.5(RUNX1):c.433A>G (p.Arg145Gly)

NC_000021.9:g.34880632T>C

CM000683.2:g.34880632T>C

NC_000021.8:g.36252929T>C

CM000683.1:g.36252929T>C

NC_000021.7:g.35174799T>C

NG_011402.2:g.1109080A>G

ENST00000675419.1:c.433A>G

ENST00000300305.7:c.433A>G

ENST00000344691.8:c.352A>G

ENST00000358356.9:c.352A>G

ENST00000399237.6:c.397A>G

ENST00000399240.5:c.352A>G

ENST00000437180.5:c.433A>G

ENST00000455571.5:c.394A>G

ENST00000482318.5:c.*23A>G

NM_001001890.2:c.352A>G

NM_001122607.1:c.352A>G

NM_001754.4:c.433A>G

NM_001001890.3:c.352A>G

NM_001122607.2:c.352A>G

Uncertain Significance

PS3_Moderate PP3 PM2_Supporting PM1_Supporting

PVS1 PS2 PS4 PS1 BA1 PP1 PP4 PP2 PM5 PM3 PM4 PM6 BS4 BS3 BS1 BS2 BP7 BP5 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 Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.433A>G (p.Arg145Gly) is a missense variant which has a REVEL score ≥ 0.88 (0.925) (PP3). Data from two or more secondary assays (FRET assay and SEUSS) demonstrate altered function, including decreased phosphorylation of RUNX1 and decreased gene expression (PS3_moderate; PMID: 33692461, 32943879). This variant is located within the Runt Homology Domain (RHD; AA 89-204) but does not occur in an established hotspot residue (PM1_supporting). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3_moderate, PP3, PM1_supporting, and PM2_supporting.

PS3_Moderate

Data from two or more secondary assays (FRET assay and SEUSS) demonstrates altered function: decreased phosphorylation of RUNX1 and decreased gene expression (PS3_Moderate; PMID: 33692461, 32943879).

Variant displays varying levels of transactivation, and multiple secondary assays were abnormal compared to WT controls. This paper labeled this variant as "likely non-functional." PubMed:33692461

Scalable functional screening by sequencing displays decreased gene expression in this variant. PubMed:32943879

PP3

This missense variant has a REVEL score ≥ 0.88 (0.925) (PP3).

PM2_Supporting

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

PM1_Supporting

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

PVS1

This variant is not a null variant.

PS2

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

PS4

Proband 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.

BA1

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

PP1

Segregation data for this variant has not been reported in literature.

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

PM5

There has not yet been a different missense change 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.

PM6

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

BS4

Segregation data for this variant has not been reported in literature.

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.

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.

BP7

This variant is not a synonymous or intronic variant.

BP5

This rule is not applicable for MM-VCEP.

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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