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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Variant: NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn)

CA410203418

1518631 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6650db7a-2a3c-48be-9f7f-227ccbe66979

HGVS expressions

NM_001754.5:c.330G>T
NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn)
NC_000021.9:g.34886864C>A
CM000683.2:g.34886864C>A
NC_000021.8:g.36259161C>A
CM000683.1:g.36259161C>A
NC_000021.7:g.35181031C>A
NG_011402.2:g.1102848G>T
ENST00000675419.1:c.330G>T
ENST00000300305.7:c.330G>T
ENST00000344691.8:c.249G>T
ENST00000358356.9:c.249G>T
ENST00000399237.6:c.294G>T
ENST00000399240.5:c.249G>T
ENST00000437180.5:c.330G>T
ENST00000455571.5:c.291G>T
ENST00000482318.5:c.59-6151G>T
NM_001001890.2:c.249G>T
NM_001122607.1:c.249G>T
NM_001754.4:c.330G>T
NM_001001890.3:c.249G>T
NM_001122607.2:c.249G>T

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS3 PP3 PM1
Not Met criteria codes 22
BA1 PVS1 BS3 BS4 BS1 BS2 BP7 BP5 BP2 BP3 BP4 BP1 PS2 PS4 PS1 PP1 PP4 PP2 PM5 PM3 PM4 PM6

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.330G>T (p.Lys110Asn) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). REVEL score is greater than 0.88 (0.884) and SpliceAI is not greater than 0.38 (0.00) (PP3). This variant affects one of the hotspot (K110) residues established by the MM-VCEP for RUNX1 (PM1). The c.328A>G variant is the same amino acid change (p.K110E) as a previously established pathogenic variant (ClinVar ID 14465) curated using MM-VCEP rules for RUNX1 (PS1). 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: PM2_supporting, PP3, PM1, PS1.
Met criteria codes
PM2_Supporting
Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
PS3
The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761).
PP3
REVEL score = 0.884, which is higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PM1
This variant affects one of the hotspot residues (K110) established by the MM-VCEP for RUNX1 (PMID: 31648317; PMID: 10404214; PMID: 10620014; PMID: 11257229; PMID: 26010396).
Not Met criteria codes
BA1
Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
PVS1
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
No case studies found
BS1
Completely absent from gnomAD v2+v3+v4 with a mean coverage of at least 20X.
BS2
Not applicable
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Not applicable
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
Not applicable
BP4
REVEL score = 0.884, which is not less than the v2 threshold of 0.50. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
BP1
Not applicable
PS2
No case studies found
PS4
No case studies found
PS1
The c.330G>C variant also results in p.K110N, and it is classified as likely pathogenic per the MM-VCEP. However, as there is functional data for K110N (not specific to cDNA), this code is not applied.
PP1
No case studies found
PP4
Not applicable
PP2
Not applicable
PM5
K110E has been classified as pathogenic by the MM-VCEP. However, glutamic acid and asparagine have differing properties. In addition, this is a hotspot residue. Although not directly stated in the current version of the rules, PM5 should conservatively not be applied.
PM3
Not applicable
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No case studies found
Approved on: 2023-12-09
Published on: 2023-12-09
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