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.320G>A (p.Arg107His)

CA410203483

812740 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e59501e0-bbc7-4d71-81e9-5efe9055a407

HGVS expressions

NM_001754.5:c.320G>A

NM_001754.5(RUNX1):c.320G>A (p.Arg107His)

NC_000021.9:g.34886874C>T

CM000683.2:g.34886874C>T

NC_000021.8:g.36259171C>T

CM000683.1:g.36259171C>T

NC_000021.7:g.35181041C>T

NG_011402.2:g.1102838G>A

ENST00000675419.1:c.320G>A

ENST00000300305.7:c.320G>A

ENST00000344691.8:c.239G>A

ENST00000358356.9:c.239G>A

ENST00000399237.6:c.284G>A

ENST00000399240.5:c.239G>A

ENST00000437180.5:c.320G>A

ENST00000455571.5:c.281G>A

ENST00000482318.5:c.59-6161G>A

NM_001001890.2:c.239G>A

NM_001122607.1:c.239G>A

NM_001754.4:c.320G>A

NM_001001890.3:c.239G>A

NM_001122607.2:c.239G>A

Likely Pathogenic

PP1 PP3 PM2_Supporting PM1 PS4_Supporting

PVS1 BS2 BS3 BS4 BS1 BP2 BP3 BP4 BP1 BP7 BP5 PS2 PS3 PS1 BA1 PP4 PP2 PM5 PM3 PM4 PM6

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.320G>A (p.Arg107His) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (R107) (PM1). This missense variant has a REVEL score >0.88 (0.953) (PP3). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27112265). In summary, this variant meets the criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2_supporting, PP1, PP3, PS4_supporting.

PP1

Proband was detected with Thrombocytopenia at age 26. Thrombocytopenia was detected in 3-year-old daughter. AML detected in brother and father deceased from AML

PP3

This missense variant has a REVEL score >0.88 (0.953) and SpliceAI score 0.00

PM2_Supporting

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

PM1

This variant affects one of the hotspot residues established by the MM-VCEP for RUNX1 (R107)

PS4_Supporting

This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 27112265.)

PVS1

Not a null variant, does not meet PVS1

BS2

This rule is not applicable for MM-VCEP

BS3

No functional testing evidence found

BS4

Proband was detected with Thrombocytopenia at age 26. Thrombocytopenia was detected in 3-year-old daughter. AML detected in brother and father deceased from AML

BS1

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

BP2

No homozygotes found in gnomAD -- absent in population databases

BP3

This rule is not applicable for MM-VCEP

BP4

This missense variant does not have a REVEL score ≤0.50 (0.953) and SpliceAI score 0.00.

BP1

This rule is not applicable for MM-VCEP

BP7

Evolutionary conservation prediction algorithms predict the site as being conserved (PhyloP score 7.32524 > 2.0 or the variant is the reference nucleotide in one primate and/or three mammal species)

BP5

This rule is not applicable for MM-VCEP

PS2

Variant is not De Novo

PS3

No functional testing evidence found

PS1

R107 is a critical hotspot established by the ClinGen MM-VCEP. In addition, found in COSMIC as pathogenic in 3 different variants

BA1

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

PP4

This rule is not applicable for MM-VCEP

PP2

This rule is not applicable for MM-VCEP

PM5

R107 is a critical hotspot established by the ClinGen MM-VCEP. In addition, found in COSMIC as pathogenic in 3 different variants

PM3

This rule is not applicable for MM-VCEP

PM4

Not an in-frame deletion/ insertion

PM6

Variant is not De Novo

Approved on: 2022-07-07

Published on: 2022-07-07

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