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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  • See Evidence submitted by expert panel for details.

Variant: NM_001754.4:c.315C>A

CA410203511

666274 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f6a20713-2a4b-4e08-91db-86f46749c256

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
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
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

Likely Pathogenic

Met criteria codes 4
PS3 PM1_Supporting PP3 PM2
Not Met criteria codes 14
PVS1 BS3 BS1 BS4 BP4 BP2 BP7 PS1 PS4 BA1 PP1 PM5 PM4 PM6

Evidence Links 2

Expert Panel

Criteria Specification Information

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 (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). 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). All patients reported in literature with this variant were not confirmed as germline variants (PMID 22318203, PMID 29722345, PMID 25840971, PMID 24030381, PMID 19282830). 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, PP3, PM1_supporting.
Met criteria codes
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
PM1_Supporting
Residue in RUNT domain (105-204aa).
PP3
REVEL: 0.901 >0.75
PM2
The variant is absent from all population databases.
Not Met criteria codes
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
BS1
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
BP4
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
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
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).
BA1
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
PM5
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-01-12
Published on: 2021-01-12
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