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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001754.5(RUNX1):c.861C>G (p.Tyr287Ter)

CA410150112

627152 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0cfee322-cbe5-4fc3-9f1c-644208233b52

HGVS expressions

NM_001754.5:c.861C>G

NM_001754.5(RUNX1):c.861C>G (p.Tyr287Ter)

NC_000021.9:g.34799407G>C

CM000683.2:g.34799407G>C

NC_000021.8:g.36171704G>C

CM000683.1:g.36171704G>C

NC_000021.7:g.35093574G>C

NG_011402.2:g.1190305C>G

ENST00000675419.1:c.861C>G

ENST00000300305.7:c.861C>G

ENST00000344691.8:c.780C>G

ENST00000399240.5:c.588C>G

ENST00000437180.5:c.861C>G

ENST00000482318.5:c.*451C>G

NM_001001890.2:c.780C>G

NM_001754.4:c.861C>G

NM_001001890.3:c.780C>G

Pathogenic

PM2_Supporting PVS1 PP1 PM5_Supporting

PM6 PM1 PM3 PM4 BA1 BS2 BS4 BS3 BS1 BP7 BP5 BP4 BP1 BP2 BP3 PS4 PS2 PS3 PS1 PP3 PP2 PP4

Evidence Links 0

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.861C>G (p.Tyr287Ter) is a nonsense variant which affects all biologically relevant isoforms. This variant is a nonsense variant between c.98 - c.916, ranking at PVS1 according to the RUNX1 decision tree (PVS1). This variant was found to co-segregate with disease in 3 affected family members (PMID: 11830488, Pedigree 3) (PP1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PP1, PM2_supporting, PM5_supporting.

PM2_Supporting

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

PVS1

This variant is a nonsense variant between c.98 - c.916, ranking at PVS1 according to the RUNX1 decision tree.

PP1

This variant was found to co-segregate with disease in 3 affected family members (PMID: 11830488, Pedigree 3)

PM5_Supporting

This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).

PM6

This variant has not been reported in probands in the literature.

PM1

This variant does not affect any of the following amino acid residues, nor is it located within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 NOR is it within residues 89-204

PM3

This rule is not applicable for MM-VCEP

PM4

This in-frame deletion/insertion DOES NOT affect at least one of the other residues (AA 89-204) within the RHD, as it is at location p.Tyr287

BA1

Variant is not present in population databases (gnomAD v2.1 or v3.1.2)

BS2

This rule is not applicable for MM-VCEP

BS4

This variant has not been reported in affected family members.

BS3

This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.

BS1

Variant is not present in population databases (gnomAD v2.1 or v3.1.2)

BP7

This variant is not a silent or intron variant.

BP5

This rule is not applicable for MM-VCEP

BP4

This synonymous/intronic variant has a SpliceAI score ≥ 0.20 (0.01).

BP1

This rule is not applicable for MM-VCEP

BP2

This variant has not been observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

BP3

This rule is not applicable for MM-VCEP

PS4

This variant has not been reported in probands.

PS2

This variant has not been found to co-segregate with the disease in the literature.

PS3

This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.

PS1

This is a stop gain variant, not a missense variant.

PP3

This synonymous/intronic variant does not have a SpliceAI score of ≥ 0.38 (Donor Loss 0.01).

PP2

This rule is not applicable for MM-VCEP

PP4

This rule is not applicable for MM-VCEP

Approved on: 2023-12-09

Published on: 2023-12-09

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