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.328A>C (p.Lys110Gln)

CA410203432

3367215 (ClinVar)

Gene: RUNX1 (HGNC:861)

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

Inheritance Mode: Autosomal dominant inheritance

UUID: 330a8e63-9235-4c9a-afc2-d05f0bf9cc33

Approved on: 2026-04-29

Published on: 2026-04-29

HGVS expressions

NM_001754.5:c.328A>C

NM_001754.5(RUNX1):c.328A>C (p.Lys110Gln)

NC_000021.9:g.34886866T>G

CM000683.2:g.34886866T>G

NC_000021.8:g.36259163T>G

CM000683.1:g.36259163T>G

NC_000021.7:g.35181033T>G

NG_011402.2:g.1102846A>C

ENST00000675419.1:c.328A>C

ENST00000300305.7:c.328A>C

ENST00000344691.8:c.247A>C

ENST00000358356.9:c.247A>C

ENST00000399237.6:c.292A>C

ENST00000399240.5:c.247A>C

ENST00000437180.5:c.328A>C

ENST00000455571.5:c.289A>C

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

NM_001001890.2:c.247A>C

NM_001122607.1:c.247A>C

NM_001754.4:c.328A>C

NM_001001890.3:c.247A>C

NM_001122607.2:c.247A>C

Likely Pathogenic

PP3 PM1_Strong BP2 PM2_Supporting PS4_Supporting

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

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.328A>C (p.Lys110Gln) is a missense variant which affects one of the hotspot residues (K110) in the RHD (PM1_strong). This variant has a REVEL score ≥ 0.88 (0.957) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It has been observed in a homozygous state (BP2) in a proband meeting at least one of the RUNX1 phenotypic criteria (AML) (PS4_supporting; PMID: 28855357). 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_strong, PP3, PM2_supporting, BP2, and PS4_supporting.

PP3

This missense variant has a REVEL score >0.88 (0.957) (PP3).

PM1_Strong

This variant affects one of the hotspot residues established by the MM-VCEP in the RHD: K110 (PM1_strong).

BP2

This variant is detected in a homozygous state in an individual (BP2; PMID: 28855357).

PM2_Supporting

This variant is completely absent from all population databases (gnomAD v2.1.1, v3.1.2, and v4.0.0) with at least 20x coverage for RUNX1 (PM2_supporting).

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 28855357).

PS2

This rule cannot be applied since, to our knowledge, we have no information about segregation reported in any study.

PS3

To our knowledge, no in vitro or in vivo functional studies are available for this variant.

PS1

This rule cannot be applied because, to our knowledge, this missense variant does not result in the same amino acid change as a previously identified pathogenic variant, regardless of nucleotide change.

PP1

This rule cannot be applied since, to our knowledge, we have no information about cosegregation in the reported study.

PP4

The MMVCEP does not evaluate this rule.

PP2

The MMVCEP does not evaluate this rule.

PM6

This rule cannot be applied since, to our knowledge, we have no information about segregation reported in any study.

PM5

This variant is a missense change at the same residue (p.Lys110Gln), where two or more (3) different missense changes have been previously established as likely pathogenic (ClinVar ID: 1518631 and ClinGen: CA410203418, and ClinVar ID: 561234 and ClinGen: CA410203419) and pathogenic variants (ClinVar ID: 14465 and ClinGen: CA248613) based on MM-VCEP rules for RUNX1 and RNA data. Additionally, agreement in splicing predictors (SSF and MES) shows no splicing effects (PM5_Strong). However, this rule is not applicable in combination with PM1.

PM3

The MMVCEP does not evaluate this rule.

PM4

This rule cannot be applied since this is a missense variant.

BA1

This rule cannot be applied since the variant is completely absent from all population databases.

BS2

The MMVCEP does not evaluate this rule.

PVS1

This rule cannot be applied since this is a missense variant.

BS4

This rule cannot be applied since, to our knowledge, we have no information about segregation in the reported study.

BS3

To our knowledge, no in vitro or in vivo functional studies are available for this variant.

BS1

This rule cannot be applied since the variant is completely absent from all population databases.

BP7

This rule cannot be applied since this is a missense variant.

BP5

The MMVCEP does not evaluate this rule.

BP4

This rule cannot be applied since this missense variant does not have a REVEL score <0.50 (0.957).

BP3

The MMVCEP does not evaluate this rule.

Curation History

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