Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA410206653

1684407 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ce743931-6733-4846-be91-285d39bd2c39

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.802C>T

NM_001754.5(RUNX1):c.802C>T (p.Gln268Ter)

NC_000021.9:g.34834413G>A

CM000683.2:g.34834413G>A

NC_000021.8:g.36206710G>A

CM000683.1:g.36206710G>A

NC_000021.7:g.35128580G>A

NG_011402.2:g.1155299C>T

ENST00000675419.1:c.802C>T

ENST00000300305.7:c.802C>T

ENST00000344691.8:c.721C>T

ENST00000358356.9:c.721C>T

ENST00000399237.6:c.766C>T

ENST00000399240.5:c.532+25061C>T

ENST00000437180.5:c.802C>T

ENST00000469087.1:n.338C>T

ENST00000482318.5:c.*392C>T

NM_001001890.2:c.721C>T

NM_001122607.1:c.721C>T

NM_001754.4:c.802C>T

NM_001001890.3:c.721C>T

NM_001122607.2:c.721C>T

Pathogenic

PVS1 PM5_Supporting PS2_Supporting PM2_Supporting PS4_Supporting

BS1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS3 BA1 PP1 PP2 PP3 PP4 PM6 PM1 PM3 PM4

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

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_001754.5(RUNX1):c.802C>T (p.Gln268Ter) is a nonsense variant that is predicted to cause a premature stop codon in biologically-relevant exon 7/9 which is present in all biologically transcripts. The variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1).This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This nonsense variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 36736831). The same case was proven to be de novo (PS2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PM5_supporting, PS2_supporting, PS4_supporting.

PVS1

Nonsense: c.98-c.916 as per VCEP specifications

PM5_Supporting

Nonsense variant that is downstream of c.98 (in transcript NM_001754.4).

PS2_Supporting

One proven de novo case, therefore, a total of 0.5 points = PS2_Supporting. PMID: 36736831.

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2).

PS4_Supporting

1 proband meeting 2 criteria of the RUNX1-phenotypic criteria: mild to moderate thrombocytopenia with normal platelet size and volume in the absence of other causative factors such as autoimmune AND diagnosis of a hematologic malignancy (MDS). PMID: 28983057 + 36736831 (same proband for both publications).

BS1

PM2 met

BS4

nil data

BS3

Not applicable.

BS2

Not applicable.

BP5

Not applicable.

BP7

Not applicable (nonsense variant).

BP4

Not applicable (nonsense variant).

BP3

Not applicable.

BP1

Not applicable.

BP2

nil data

PS1

Not applicable.

PS3

One study (PMID 36736831) on platelet phenotype and platelet transcriptomics supports the pathogenicity of the RUNX1 variant p.(Gln268Ter), by confirming aberrant expression of genes recognized as RUNX1 targets. In particular, platelets from the patient in the study had markedly reduced fibrinogen binding and reduced secretion of δ-granules vs controls after stimulation with collagen-related peptide. Platelet aggregation induced by low doses of CRP and collagen was highly impaired. In addition, analysis of the platelet transcriptome, compared to 5 controls, showed altered expression in 73.3% of the 15 well-recognized RUNX1 target genes. However, the criterion is not applicable since this variant meets PVS1 (RUNX1 specification).

BA1

PM2 met

PP1

nil data

PP2

Not applicable.

PP3

Not applicable (nonsense variant).

PP4

Not applicable.

PM6

PS2_Supporting met.

PM1

This variant does not reside within a region of RUNX1 that is defined as a mutational hotspot or critical functional domain by the ClinGen MM-VCEP.

PM3

Not applicable.

PM4

Not applicable (nonsense variant).

Curation History

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