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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.5(RUNX1):c.328A>G (p.Lys110Glu)

CA248613

14465 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 37efba9c-0430-4e4f-a3ce-fc8c501d717a

HGVS expressions

NM_001754.5:c.328A>G

NM_001754.5(RUNX1):c.328A>G (p.Lys110Glu)

NC_000021.9:g.34886866T>C

CM000683.2:g.34886866T>C

NC_000021.8:g.36259163T>C

CM000683.1:g.36259163T>C

NC_000021.7:g.35181033T>C

NG_011402.2:g.1102846A>G

ENST00000675419.1:c.328A>G

ENST00000300305.7:c.328A>G

ENST00000344691.8:c.247A>G

ENST00000358356.9:c.247A>G

ENST00000399237.6:c.292A>G

ENST00000399240.5:c.247A>G

ENST00000437180.5:c.328A>G

ENST00000455571.5:c.289A>G

ENST00000482318.5:c.59-6153A>G

NM_001001890.2:c.247A>G

NM_001122607.1:c.247A>G

NM_001754.4:c.328A>G

NM_001001890.3:c.247A>G

NM_001122607.2:c.247A>G

Pathogenic

PP1_Strong PM5_Supporting PS3 PS4_Supporting PM2_Supporting PP3 PM1

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

Evidence Links 3

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

Transactivation assays demonstrate altered transactivation (<20% of wt) for the NM_001754.4:c.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (PM1). It is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). 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: PS3, PP1_Strong, PM1, PM2_supporting, PP3, PS4_Supporting, PM5_supporting.

PP1_Strong

In 1 pedigree, 7 meioses observed for LEUKEMIA. 12 meioses if also including "bleeding disorder and/or platelet defect".

In 1 pedigree, 7 meioses observed for LEUKEMIA. 12 meioses if also including "bleeding disorder and/or platelet defect". PubMed:11830488

PM5_Supporting

This variant is a missense change at the same residue (p.K110) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1518631, 14465) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting).

PS3

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

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

EMSAs confirmed that K83E mutation affected DNA binding quite severely. PubMed:17290219

Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization. PubMed:11830488

PS4_Supporting

1 (compelling) pedigee identified in the literature.

1 (compelling) pedigee identified in the literature. PubMed:11830488

PM2_Supporting

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

PP3

This missense variant has a REVEL score ≥ 0.88 (0.953) (PP3).

PM1

Residue that affects DNA binding as a mutational hot spot.

PVS1

This variant is not a null variant.

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.

BS4

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

In 1 pedigree, 7 meioses observed for LEUKEMIA. 12 meioses if also including "bleeding disorder and/or platelet defect". PubMed:11830488

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.

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.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

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.

Approved on: 2024-03-26

Published on: 2024-03-26

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