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]
  • 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.316T>A (p.Trp106Arg)

CA410203508

436617 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8f98e7f4-4645-4121-8da3-bcf507754b5c
Approved on: 2024-09-10
Published on: 2024-09-10

HGVS expressions

NM_001754.4:c.316T>A
NM_001754.4(RUNX1):c.316T>A (p.Trp106Arg)
NC_000021.9:g.34886878A>T
CM000683.2:g.34886878A>T
NC_000021.8:g.36259175A>T
CM000683.1:g.36259175A>T
NC_000021.7:g.35181045A>T
NG_011402.2:g.1102834T>A
ENST00000675419.1:c.316T>A
ENST00000300305.7:c.316T>A
ENST00000344691.8:c.235T>A
ENST00000358356.9:c.235T>A
ENST00000399237.6:c.280T>A
ENST00000399240.5:c.235T>A
ENST00000437180.5:c.316T>A
ENST00000455571.5:c.277T>A
ENST00000482318.5:c.59-6165T>A
NM_001001890.2:c.235T>A
NM_001122607.1:c.235T>A
NM_001001890.3:c.235T>A
NM_001122607.2:c.235T>A
NM_001754.5:c.316T>A
More

Likely Pathogenic

Met criteria codes 4
PS3 PM1_Supporting PP3 PM2_Supporting
Not Met criteria codes 22
PS2 PS4 PS1 BP5 BP7 BP2 BP3 BP4 BP1 PP4 PP1 PP2 BA1 PM6 PM3 PM4 PM5 BS2 BS4 BS1 BS3 PVS1

Evidence Links 1

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
The NM_001754.4:c.316T>A (p.Trp106Arg) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) and data from secondary assay demonstrate altered DNA binding (PS3; PMID: 25840971). This missense variant has a REVEL score >0.75 (0.976) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS3, PM2_supporting, PP3, PM1_supporting.
Met criteria codes
PS3
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assay demonstrate altered DNA binding.
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assay demonstrate altered DNA binding. PubMed:25840971
PM1_Supporting
Residue in RUNT domain (105-204aa).
PP3
REVEL: 0.976 >0.75
PM2_Supporting
The variant is absent from all population databases.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
PMID: 21828118, PMID: 19282830, PMID: 25840971. These three papers are NOT specific for germline RUNX1 variants.
PS1
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
BP2
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
BP4
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
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
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
BA1
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
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
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
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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