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(RUNX1):c.179C>T (p.Ala60Val)

CA10014576

463986 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: aa5c9149-1528-4fb7-84bd-9ee7b5f8857c

HGVS expressions

NM_001754.4:c.179C>T
NM_001754.4(RUNX1):c.179C>T (p.Ala60Val)
NC_000021.9:g.34887015G>A
CM000683.2:g.34887015G>A
NC_000021.8:g.36259312G>A
CM000683.1:g.36259312G>A
NC_000021.7:g.35181182G>A
NG_011402.2:g.1102697C>T
NM_001001890.2:c.98C>T
NM_001122607.1:c.98C>T
NM_001001890.3:c.98C>T
NM_001122607.2:c.98C>T
NM_001754.5:c.179C>T
ENST00000300305.7:c.179C>T
ENST00000344691.8:c.98C>T
ENST00000358356.9:c.98C>T
ENST00000399237.6:c.143C>T
ENST00000399240.5:c.98C>T
ENST00000437180.5:c.179C>T
ENST00000455571.5:c.140C>T
ENST00000482318.5:c.59-6302C>T

Benign

Met criteria codes 2
BS3 BS1
Not Met criteria codes 16
BA1 PVS1 BS4 BP7 BP4 BP2 PS3 PS1 PS4 PP3 PP1 PM5 PM4 PM1 PM2 PM6

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
The NM_001754.4:c.179C>T variant that results in the Ala60Val missense change has an MAF of 0.0002950 (0.02%, 10/33902 alleles) in the Latino subpopulation of the gnomAD v2.1.1 cohort, which is between 0.00015 (0.015%) and 0.0015 (0.15%) (BS1). Transactivation assays demonstrate normal transactivation (80-115% of wt) and data from a secondary EMSA demonstrate normal DNA binding (BS3; PMID: 23817177). The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1, BS3.
Met criteria codes
BS3
From PMID: 23817177: luciferase reported assay showed normal transactivation (Figure 4) and EMSA showed normal DNA binding (Figure 2).
Luciferase reported assay showed normal transactivation (Figure 4) and EMSA showed normal DNA binding (Figure 2). However, the variant showed defective binding to MLL, potentially affecting epigenetic regulation. PubMed:23817177
BS1
The variant is reported at a frequency of 0.0002950 (10/33902 Latino alleles) in gnomAD v2.1.1 and at a frequency of 0.00007323 (1/13656 Latino alleles) in gnomAD v3. The frequency reported in gnomAD v2.1.1 meets criteria for BS1; threshold: >0.00015
Not Met criteria codes
BA1
meets BS1
PVS1
N/A
BS4
No data currently available
BP7
N/A
BP4
The REVEL score is 0.284 and does not meet the threshold of <0.15
BP2
N/A
PS3
Meets BS3
PS1
No data currently available
PS4
The variant has not been reported in the germ line of patients with familial platelet disorder with predisposition to hematologic malignancies in the literature, to the best of our knowledge.
PP3
The REVEL score is 0.284 and does not meet the threshold of >0.75
PP1
No data currently available
PM5
No data currently available
PM4
N/A
PM1
N/A
PM2
meets BS1
PM6
No data currently available
Approved on: 2021-01-11
Published on: 2021-01-11
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