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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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001754.4(RUNX1):c.305T>A (p.Leu102Gln)

CA410203565

561232 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9b50b3c6-852c-4808-92af-a5477c274e0d
Approved on: 2024-08-12
Published on: 2024-08-12

HGVS expressions

NM_001754.4:c.305T>A
NM_001754.4(RUNX1):c.305T>A (p.Leu102Gln)
NC_000021.9:g.34886889A>T
CM000683.2:g.34886889A>T
NC_000021.8:g.36259186A>T
CM000683.1:g.36259186A>T
NC_000021.7:g.35181056A>T
NG_011402.2:g.1102823T>A
ENST00000675419.1:c.305T>A
ENST00000300305.7:c.305T>A
ENST00000344691.8:c.224T>A
ENST00000358356.9:c.224T>A
ENST00000399237.6:c.269T>A
ENST00000399240.5:c.224T>A
ENST00000437180.5:c.305T>A
ENST00000455571.5:c.266T>A
ENST00000482318.5:c.59-6176T>A
NM_001001890.2:c.224T>A
NM_001122607.1:c.224T>A
NM_001001890.3:c.224T>A
NM_001122607.2:c.224T>A
NM_001754.5:c.305T>A

Uncertain Significance

Met criteria codes 4
PP3 PS4_Supporting PM1_Supporting PM2_Supporting
Not Met criteria codes 22
PP1 PP4 PP2 PM5 PM4 PM3 PS1 PS2 PS3 PM6 BA1 PVS1 BP7 BP5 BP3 BP2 BP4 BP1 BS2 BS4 BS3 BS1

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.4(RUNX1):c.305T>A (p.Leu102Gln) is a missense variant which is located within the Runt Homology Domain (AA 89-204), but does not occur in an established hotspot residue (PM1_supporting). This variant is absent from gnomAD v2 and v3 (PM2_supporting). It has also been reported in a family where the proband met RUNX1-phenotypic criteria (PS4_supporting), and the variant segregated with thrombocytopenia in 2 affected family members (ClinVar: SCV000807772.1); however, PP1_supporting cannot be applied due to insufficient meioses for segregation. The computational predictor, REVEL, gives a score of 0.925, 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: PS4_supporting, PM1_supporting, PM2_supporting, and PP3.
Met criteria codes
PP3
REVEL score = 0.925, which is higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20).
PS4_Supporting
This variant has been reported in a proband with AML, platelet storage disorder, and thrombocytopenia with bleeding (SCV000807772.1).
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
PP1
This variant was found to co-segregate with disease in 2 affected family members of a proband (SCV000807772.1).
PP4
Not applicable
PP2
Not applicable
PM5
L102/L75 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
PM3
Not applicable
PS1
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS2
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PS3
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
PM6
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BA1
Completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3).
PVS1
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
BP5
Not applicable
BP3
Not applicable
BP2
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BP4
REVEL score = 0.925, 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
BS2
Not applicable
BS4
No literature was found in LOVD, HGMD, ClinVar, COSMIC, Mastermind, and Google/Google Scholar searches.
BS3
No literature was found in 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).
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