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 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.497G>A (p.Arg166Gln)

CA16616941

417961 (ClinVar)

Gene: RUNX1 (HGNC:861)
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)
Inheritance Mode: Autosomal dominant inheritance
UUID: ba8c0c9c-028c-473b-9259-a8316db5b16d
Approved on: 2026-05-27
Published on: 2026-05-27

HGVS expressions

NM_001754.5:c.497G>A
NM_001754.5(RUNX1):c.497G>A (p.Arg166Gln)
NC_000021.9:g.34880568C>T
CM000683.2:g.34880568C>T
NC_000021.8:g.36252865C>T
CM000683.1:g.36252865C>T
NC_000021.7:g.35174735C>T
NG_011402.2:g.1109144G>A
ENST00000675419.1:c.497G>A
ENST00000300305.7:c.497G>A
ENST00000344691.8:c.416G>A
ENST00000358356.9:c.416G>A
ENST00000399237.6:c.461G>A
ENST00000399240.5:c.416G>A
ENST00000437180.5:c.497G>A
ENST00000482318.5:c.*87G>A
NM_001001890.2:c.416G>A
NM_001122607.1:c.416G>A
NM_001754.4:c.497G>A
NM_001001890.3:c.416G>A
NM_001122607.2:c.416G>A
More

Pathogenic

Met criteria codes 7
PM1_Strong PM6_Supporting PS3 PP1 PP3 PS4_Moderate PM2_Supporting
Not Met criteria codes 19
PVS1 PM3 PM4 PM5 BA1 BS1 BS4 BS3 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS1 PP4 PP2

Evidence Links 6

Expert Panel

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.497G>A (p.Arg166Gln) is a missense variant which affects one of the hotspot residues (R166) within the RHD (PM1_Strong). Transactivation assays demonstrate altered transactivation (<20% of wt) and data from secondary assays demonstrate altered DNA binding, CBFβ binding, and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting) and has a REVEL score of >0.75 (0.96) (PP3). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 10508512, 28960434, 26175287) and was found to co-segregate with disease in multiple affected family members, with three meioses observed across one family (PP1; PMID: 10508512). This variant was reported in two unrelated probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 8960434, 26175287). 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: PM1_Strong, PS3, PM2_Supporting, PP3, PS4_Moderate, PP1, PM6_Supporting.
Met criteria codes
PM1_Strong
This variant affects at least one of the following hotspot residues within the RHD: (R166)(PM1_strong).
PM6_Supporting
There are two probands meeting at least one of the RUNX1- phenotypic criteria with assumed de novo occurrence (without confirmation of maternity and paternity) (PM6_ Supporting; PMID: 28960434, 26175287).
Reported as a de novo change in patient 5 who has onset-at-birth thrombocytopenia with small or normal-sized platelets and without family history. None of the parents carried this variant. PubMed:26175287
Reported as a de novo variant in the patient 182 who has suspected inherited thrombocytopenia through proband-only exome sequencing and parental studies. PubMed:28960434
PS3
Transactivation assays demonstrating altered transactivation (<20% of WT) and data from a secondary assays demonstrating altered DNA binding, CBFβ binding, and sub-cellular localization (PS3; PMID: 11830488, 25840971, 23848403).
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered CBFβ binding and sub-cellular localization. PubMed:11830488
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding and CBFβ binding. PubMed:25840971
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered CBFβ binding and sub-cellular localization. PubMed:23848403
PP1
This variant was found to co-segregate with disease in multiple affected family members, with four meioses observed in one family (PP1; PMID: 10508512).
This variant was found to co-segregate with the FPD/AML (Familial platelet disorder with predisposition to acute myeloid leukemia) trait in four affected family members in pedigree 6. PubMed:10508512
PP3
REVEL: 0.962 >0.75
PS4_Moderate
This variant has been reported in 3 probands meeting at least one of RUNX1 phenotype criteria (PS4_moderate; PMID: 10508512, 28960434, 26175287).
Reported in patient 5 who has onset-at-birth thrombocytopenia with small or normal-sized platelets and without family history. PubMed:26175287
Reported in individual II-2 in pedigree 6 with FPD/AML (Familial platelet disorder with predisposition to acute myeloid leukemia). This individual had preleukemia with trisomy 8. The variant This variant co-segregates with disease in this family (see PP1). PubMed:10508512
Reported in the patient 182 who has suspected inherited thrombocytopenia. PubMed:28960434
PM2_Supporting
The variant is absent from all population databases.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
Not applicable.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No evidence
This variant was found to co-segregate with the FPD/AML (Familial platelet disorder with predisposition to acute myeloid leukemia) trait in four affected family members in pedigree 6. PubMed:10508512
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No evidence
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
Reported as de novo but without confirmation of maternity/paternity.
Reported as a de novo change in patient 5 who has onset-at-birth thrombocytopenia with small or normal-sized platelets and without family history. None of the parents carried this variant. PubMed:26175287
Reported as a de novo variant in the patient 182 who has suspected inherited thrombocytopenia through proband-only exome sequencing and parental studies. PubMed:28960434
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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