The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4(RUNX1):c.328A>G (p.Lys110Glu)

CA248613

14465 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 37efba9c-0430-4e4f-a3ce-fc8c501d717a
Approved on: 2019-07-29
Published on: 2019-08-02

HGVS expressions

NM_001754.4:c.328A>G
NM_001754.4(RUNX1):c.328A>G (p.Lys110Glu)
NC_000021.9:g.34886866T>C
CM000683.2:g.34886866T>C
NC_000021.8:g.36259163T>C
CM000683.1:g.36259163T>C
NC_000021.7:g.35181033T>C
NG_011402.2:g.1102846A>G
ENST00000675419.1:c.328A>G
ENST00000300305.7:c.328A>G
ENST00000344691.8:c.247A>G
ENST00000358356.9:c.247A>G
ENST00000399237.6:c.292A>G
ENST00000399240.5:c.247A>G
ENST00000437180.5:c.328A>G
ENST00000455571.5:c.289A>G
ENST00000482318.5:c.59-6153A>G
NM_001001890.2:c.247A>G
NM_001122607.1:c.247A>G
NM_001001890.3:c.247A>G
NM_001122607.2:c.247A>G
NM_001754.5:c.328A>G
More

Pathogenic

Met criteria codes 6
PS3 PM2 PM1 PP3 PP1_Strong PS4_Supporting
Not Met criteria codes 20
BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PM6 PM3 PM5 PM4 BA1 PP2 PP4 PVS1

Evidence Links 3

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.328A>G (p.Lys110Glu) variant and data from secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization (PS3; PMID: 23848403; 17290219; 11830488). This variant was found to co-segregate with disease in multiple affected family members, with 7 meioses observed in one pedigree (PP1_Strong; PMID: 11830488). 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). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 11830488). 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, PP1_Strong, PM1, PM2, PP3, PS4_Supporting.
Met criteria codes
PS3
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding, CBFβ binding and sub-cellular localization.

PM2
The variant is absent from all population databases.
PM1
Residue that affects DNA binding as a mutational hot spot.
PP3
REVEL: 0.953 > 0.75
PP1_Strong
In 1 pedigree, 7 meioses observed for LEUKEMIA. 12 meioses if also including "bleeding disorder and/or platelet defect".

PS4_Supporting
1 (compelling) pedigee identified in the literature.

Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
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
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
PS2
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
PM3
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
PM4
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
PP2
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.