Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: RUNX1 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001754.5(RUNX1):c.400G>A (p.Ala134Thr)

CA410202694

3772099 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9a452b57-430e-4fc0-9838-183879bee058
Approved on: 2025-05-02
Published on: 2025-05-02

HGVS expressions

NM_001754.5:c.400G>A
NM_001754.5(RUNX1):c.400G>A (p.Ala134Thr)
NC_000021.9:g.34880665C>T
CM000683.2:g.34880665C>T
NC_000021.8:g.36252962C>T
CM000683.1:g.36252962C>T
NC_000021.7:g.35174832C>T
NG_011402.2:g.1109047G>A
ENST00000675419.1:c.400G>A
ENST00000300305.7:c.400G>A
ENST00000344691.8:c.319G>A
ENST00000358356.9:c.319G>A
ENST00000399237.6:c.364G>A
ENST00000399240.5:c.319G>A
ENST00000437180.5:c.400G>A
ENST00000455571.5:c.361G>A
ENST00000482318.5:c.107G>A
NM_001001890.2:c.319G>A
NM_001122607.1:c.319G>A
NM_001754.4:c.400G>A
NM_001001890.3:c.319G>A
NM_001122607.2:c.319G>A
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Likely Pathogenic

Met criteria codes 4
PP3 PM5 PM1 PM2_Supporting
Not Met criteria codes 20
PS4 PS2 PS3 PS1 PP1 PP2 PP4 PM6 PM3 PM4 PVS1 BS4 BS3 BS1 BP7 BP2 BP3 BP4 BP1 BA1

Evidence Links 0

Expert Panel

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.400G>A (p.Ala134Thr) is a missense variant which affects a hotspot residue within the Runt Homology Domain (RHD): A134 (PM1). This variant is a missense change at the same residue where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468), with RNA data or agreement in splicing predictors (SSF and MES) showing no splicing effects (PM5). It has a REVEL score ≥ 0.88 (0.961) (PP3) and is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). 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, PM5, PP3, PM2_Supporting.
Met criteria codes
PP3
This missense variant has a REVEL score ≥ 0.88 (0.961) (PP3).
PM5
This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5).
PM1
This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
Not Met criteria codes
PS4
Proband data for this variant has not been reported in literature.
PS2
De novo data for this variant has not been reported in literature.
PS3
In vitro or in vivo functional data has not been reported for this variant in the 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.
PP1
Segregation data for this variant has not been reported in literature.
PP2
This rule is not applicable for MM-VCEP.
PP4
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.
PVS1
This variant is not a null variant.
BS4
Segregation data for this variant has not been reported in literature.
BS3
In vitro or in vivo functional data has not been reported for this variant in the literature.
BS1
This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.
BP7
This variant is not a synonymous or intronic variant.
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.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
Curation History
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