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.378T>G (p.Asp126Glu)

CA410202739

1021717 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9bef8f50-1ee2-4a1b-98ac-f238d944bc24
Approved on: 2023-11-13
Published on: 2023-11-13

HGVS expressions

NM_001754.5:c.378T>G
NM_001754.5(RUNX1):c.378T>G (p.Asp126Glu)
NC_000021.9:g.34880687A>C
CM000683.2:g.34880687A>C
NC_000021.8:g.36252984A>C
CM000683.1:g.36252984A>C
NC_000021.7:g.35174854A>C
NG_011402.2:g.1109025T>G
ENST00000675419.1:c.378T>G
ENST00000300305.7:c.378T>G
ENST00000344691.8:c.297T>G
ENST00000358356.9:c.297T>G
ENST00000399237.6:c.342T>G
ENST00000399240.5:c.297T>G
ENST00000437180.5:c.378T>G
ENST00000455571.5:c.339T>G
ENST00000482318.5:c.85T>G
NM_001001890.2:c.297T>G
NM_001122607.1:c.297T>G
NM_001754.4:c.378T>G
NM_001001890.3:c.297T>G
NM_001122607.2:c.297T>G

Uncertain Significance

Met criteria codes 3
PP3 PM1_Supporting PM2_Supporting
Not Met criteria codes 23
PS2 PS3 PS1 PS4 PP1 PP4 PP2 PM6 PM3 PM5 PM4 BA1 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP4 BP1 BP3 PVS1

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
The c.378T>G (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 126 (p.D126E). This variant resides within a region, amino acids 89-204, of RUNX1 that is defined as a critical functional domain by the ClinGen Myeloid Malignancy VCEP (PMID: 31648317) (PM1_Supporting). The variant is absent from gnomAD v2 and v3 (PM2_Supporting). It also has not been reported in patients with the RUNX1-defined phenotype. The computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.88, evidence that correlates with impact to RUNX1 function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PM1_Supporting, PM2_Supporting, and PP3.
Met criteria codes
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_Supporting
Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204), but within residues 89-204.
PM2_Supporting
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
Not Met criteria codes
PS2
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No relevant data found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches. Mastermind improperly detected PMID: 24220272 (ATM D126E).
PP1
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PP4
Not applicable
PP2
Not applicable
PM6
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM3
Not applicable
PM5
D126/D99 variants are reported in COSMIC and Mastermind, but not at a high enough frequency that they would be likely classified as LP/P.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
BS4
No relevant cases found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No relevant data found in literature search, including LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
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
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
BP3
Not applicable
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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