Evidence Repository - Clinical Genome Resources

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.496C>T (p.Arg166Ter)

Curation History

1459069 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8a2da505-9427-4852-82be-47e489d4a0f4

Approved on: 2022-04-25

Published on: 2022-07-05

HGVS expressions

NM_001754.5:c.496C>T

NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter)

Pathogenic

PM2_Supporting PVS1 PS4_Supporting

PS2 PS3 PS1 PP1 PP4 PP3 PP2 PM1 PM5 PM3 PM4 PM6 BA1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP7 BP5

Evidence Links 1

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter) is a nonsense variant that is predicted to undergo NMD (PVS1, SNV Tree). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295). 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, PS4_supporting.

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

PVS1

NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter) is a nonsense variant that is predicted to undergo NMD (PVS1, SNV Tree)

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27210295)

PS2

This variant has not been seen in de novo

PS3

: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meet PVS1

R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay PubMed:33692461

PS1

Not a missense variant

PP1

This variant seems to co-segregate with disease in multiple affected family members, with three or four (X) meioses observed in one family/across X families (PP1; PMID: 27210295) however cannot be confirmed.

PP4

This rule is not applicable for MM-VCEP

PP3

Not a missense, synonymous, or intronic variant

PP2

This rule is not applicable for MM-VCEP

PM1

Not a missense variant

PM5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

This rule is not applicable for MM-VCEP

PM4

Not an in-frame deletion/insertion

PM6

This variant has not been seen in de novo

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

BS2

This rule is not applicable for MM-VCEP

BS3

: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1

BS4

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting).

BP2

Not seem in homozygotes in gnomAD v2.1.1 and v3.1.2

BP3

This rule is not applicable for MM-VCEP

BP4

Not a missense, synonymous, or intronic variant

BP1

This rule is not applicable for MM-VCEP

BP7

Not a synonymous or intronic variant

BP5

This rule is not applicable for MM-VCEP

Curation History

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