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Variant: NM_001754.5(RUNX1):c.400G>C (p.Ala134Pro)

CA248623

14468 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: d5e03ae0-3ff2-428d-87e3-ae93412f6bf1

HGVS expressions

NM_001754.5:c.400G>C
NM_001754.5(RUNX1):c.400G>C (p.Ala134Pro)
NC_000021.9:g.34880665C>G
CM000683.2:g.34880665C>G
NC_000021.8:g.36252962C>G
CM000683.1:g.36252962C>G
NC_000021.7:g.35174832C>G
NG_011402.2:g.1109047G>C
ENST00000675419.1:c.400G>C
ENST00000300305.7:c.400G>C
ENST00000344691.8:c.319G>C
ENST00000358356.9:c.319G>C
ENST00000399237.6:c.364G>C
ENST00000399240.5:c.319G>C
ENST00000437180.5:c.400G>C
ENST00000455571.5:c.361G>C
ENST00000482318.5:c.107G>C
NM_001001890.2:c.319G>C
NM_001122607.1:c.319G>C
NM_001754.4:c.400G>C
NM_001001890.3:c.319G>C
NM_001122607.2:c.319G>C

Pathogenic

Met criteria codes 7
PM1 PM2_Supporting PM5_Supporting PS4_Supporting PS3 PP1 PP3
Not Met criteria codes 19
PM6 PM3 PM4 PVS1 BS2 BS4 BS1 BS3 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 BA1 PP4 PP2

Evidence Links 2

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
Transactivation assays demonstrate altered transactivation (<20% of wt) for the missense variant, NM_001754.4:c.400G>C (p.Ala134Pro) and data from secondary assays demonstrate altered CBFβ binding and sub-cellular localization.(PS3; PMID: 23848403). 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). It has a REVEL score >0.75 (0.945) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 12060124). It was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 12060124). This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1484777) 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, PM1, PM2_supporting, PP1, PP3, PS4_Supporting, PM5_Supporting.
Met criteria codes
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).
PM5_Supporting
This variant is a missense change at the same residue (p.A134) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 1484777) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting).
PS4_Supporting
One family with thrombocytopenia and acute myeloid leukemia (PS4_supporting).

PS3
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered CBFβ binding and sub-cellular localization (PMID:23848403) (PS3).

PP1
3 meioses in a family with thrombocytopenia and acute myeloid leukaemia (PP1).

PP3
This missense variant has a REVEL score ≥ 0.88 (0.945) (PP3).
Not Met criteria codes
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.
BS2
This rule is not applicable for MM-VCEP.
BS4
Segregation was not found to be absent in two or more informative meiosis.

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.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
PP4
This rule is not applicable for MM-VCEP.
PP2
This rule is not applicable for MM-VCEP.
Approved on: 2024-03-26
Published on: 2024-03-26
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