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:c.315C>A

CA410203511

666274 (ClinVar)

Gene: RUNX1 (HGNC:861)
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)
Inheritance Mode: Autosomal dominant inheritance
UUID: f6a20713-2a4b-4e08-91db-86f46749c256
Approved on: 2024-09-10
Published on: 2024-09-10

HGVS expressions

NM_001754.4:c.315C>A
NC_000021.9:g.34886879G>T
CM000683.2:g.34886879G>T
NC_000021.8:g.36259176G>T
CM000683.1:g.36259176G>T
NC_000021.7:g.35181046G>T
NG_011402.2:g.1102833C>A
ENST00000675419.1:c.315C>A
ENST00000300305.7:c.315C>A
ENST00000344691.8:c.234C>A
ENST00000358356.9:c.234C>A
ENST00000399237.6:c.279C>A
ENST00000399240.5:c.234C>A
ENST00000437180.5:c.315C>A
ENST00000455571.5:c.276C>A
ENST00000482318.5:c.59-6166C>A
NM_001001890.2:c.234C>A
NM_001122607.1:c.234C>A
NM_001001890.3:c.234C>A
NM_001122607.2:c.234C>A
NM_001754.5:c.315C>A
More

Likely Pathogenic

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

Evidence Links 2

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.315C>A (p.His105Gln) variant affects one of the residues (AA 105-204) within the RHD which is not an established hotspot residue (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 assays demonstrate altered DNA binding and functional consequences in mouse model. (PS3; PMID: 22318203; PMID: 25840971). This missense variant has a REVEL score >0.75 (0.901) (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
PM1_Supporting
Residue in RUNT domain (105-204aa).
PS3
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding and functional consequences in mouse model.
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assays demonstrate altered DNA binding and functional consequences in mouse model. H105Q disturbed myeloid differentiation and induced a blast crisis or accelerated phase–like phenotype in mice. PubMed:22318203
Transactivation assays demonstrate altered transactivation (<20% of WT). Secondary assay demonstrate altered DNA binding. PubMed:25840971
PP3
REVEL: 0.901 >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
All patients reported in literature with this variant were not confirmed as germline variants (PMID 22318203, PMID 29722345, PMID 25840971, PMID 24030381, PMID 19282830).
PS1
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
PVS1
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
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
PM6
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
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
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
Curation History
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