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_001754.4(RUNX1):c.314A>C (p.His105Pro)

CA410203519

561233 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 42a3f999-4991-4180-8cb2-0e8975c5e5bb

HGVS expressions

NM_001754.4:c.314A>C

NM_001754.4(RUNX1):c.314A>C (p.His105Pro)

NC_000021.9:g.34886880T>G

CM000683.2:g.34886880T>G

NC_000021.8:g.36259177T>G

CM000683.1:g.36259177T>G

NC_000021.7:g.35181047T>G

NG_011402.2:g.1102832A>C

NM_001001890.2:c.233A>C

NM_001122607.1:c.233A>C

ENST00000300305.7:c.314A>C

ENST00000344691.8:c.233A>C

ENST00000358356.9:c.233A>C

ENST00000399237.6:c.278A>C

ENST00000399240.5:c.233A>C

ENST00000437180.5:c.314A>C

ENST00000455571.5:c.275A>C

ENST00000482318.5:c.59-6167A>C

Likely Pathogenic

PM2 PM5_Supporting PM1_Supporting PS4_Supporting PP3

PM6 PM4 PVS1 BS3 BS1 BS4 BP4 BP2 BP7 PS1 PS3 BA1 PP1

Evidence Links 0

Expert Panel

Myeloid Malignancy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.314A>C (p.His105Pro) variant affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This missense variant has a REVEL score >0.75 (0.953) (PP3). This variant is a missense change at the same residue (p.His105Pro) where a different missense change has been previously established as a likely pathogenic variant (NM_001754.4:c.315C>A (p.His105Glu)) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; SCV000807773.1). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2, PP3, PM1_supporting, PM5_supporting, PS4_supporting.

PM2

The variant is absent from all population databases.

PM5_Supporting

NM_001754.4:c.315C>A (p.His105Glu) is classified as a Likely Pathogenic variant by ClinGen Myeloid Malignancy Variant Curation Expert Panel.

PM1_Supporting

Residue in RUNT domain (105-204aa).

PS4_Supporting

One family with Thrombocytopenia reported from internal laboratory (SCV000807773.1).

PP3

REVEL: 0.953 >0.75

PM6