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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln)

CA248610

14464 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 52b9ca56-4641-4652-8c86-bee9650bacf2
Approved on: 2019-07-30
Published on: 2019-08-02

HGVS expressions

NM_001754.4:c.602G>A
NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln)
NC_000021.9:g.34859485C>T
CM000683.2:g.34859485C>T
NC_000021.8:g.36231782C>T
CM000683.1:g.36231782C>T
NC_000021.7:g.35153652C>T
NG_011402.2:g.1130227G>A
NM_001001890.2:c.521G>A
NM_001122607.1:c.521G>A
ENST00000300305.7:c.602G>A
ENST00000344691.8:c.521G>A
ENST00000358356.9:c.521G>A
ENST00000399237.6:c.566G>A
ENST00000399240.5:c.521G>A
ENST00000437180.5:c.602G>A
ENST00000467577.1:n.94G>A
ENST00000482318.5:c.*192G>A

Pathogenic

Met criteria codes 6
PS3 PS4 PP3 PP1 PM2 PM1
Not Met criteria codes 12
BP7 PVS1 BP4 BP2 PS1 PM6 PM4 PM5 BA1 BS3 BS4 BS1

Evidence Links 9

Expert Panel

Criteria Specification Information

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.602G>A (p.Arg201Gln) variant and data from a secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 17290219, 11830488, 23817177, 22318203, 25840971, 23848403). This variant has been reported in four probands meeting at least one of the RUNX1-phenotypic criteria (PS4; PMID: 27112265, 28748566, 10508512). 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). The variant has a REVEL score >0.75 (0.94) (PP3). It was found to co-segregate with disease in multiple affected family members, with four meioses observed in across 3 families (PP1; PMID: 27112265, 28748566, 10508512). 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, PS4, PM1, PM2, PP1, PP3.
Met criteria codes
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 assay demonstrate altered sub-cellular localization. PubMed:23817177
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization. PubMed:11830488
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding and sub-cellular localization. PubMed:22318203
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization. PubMed:23848403
The number of CFU-C in R174Q/+ AGM regions was reduced slightly more than in DelE4/+ fetuses, suggesting that the R174Q mutation creates a weakly dominant-negative Runx1 allele. R174Q/+ mice had a smaller percentage of CD4 + cells and a lower CD4 + : CD8 + ratio than DelE4/ + animals. PubMed:17290219
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assay demonstrate altered DNA binding. PubMed:25840971
PS4
4 probands counted across publications.
1 proband with thrombocytopenia and leukemia PubMed:10508512
1 proband (Patient 64) with lifelong history of severe thrombocytopenia and bleeding tendency. She developed myelodysplasia when aged 65 years and 1 proband with chronic thrombocytopenia. PubMed:28748566
1 proband with secondary AML to MDS. PubMed:27112265
PP3
REVEL: 0.94 >0.75
PP1
4 segregations counted additively across publications
2 segregations - 3 individuals with chronic thrombocytopenia, no MDS PubMed:28748566
1 segregation - 2 affected individuals with thrombocytopenia and leukemia PubMed:10508512
Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped. PubMed:27112265
PM2
The variant is absent from all population databases.
PM1
Residue that affects DNA binding and is a somatic hot spot as a mutational hot spot.
Not Met criteria codes
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
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
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
2 segregations - 3 individuals with chronic thrombocytopenia, no MDS PubMed:28748566
1 segregation - 2 affected individuals with thrombocytopenia and leukemia PubMed:10508512
Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped. PubMed:27112265
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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