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.227G>C (p.Arg76Pro)

CA410203853

2422003 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 83eb9d71-5be9-482f-b0c4-d1096b085a3c

HGVS expressions

NM_001754.5:c.227G>C

NM_001754.5(RUNX1):c.227G>C (p.Arg76Pro)

NC_000021.9:g.34886967C>G

CM000683.2:g.34886967C>G

NC_000021.8:g.36259264C>G

CM000683.1:g.36259264C>G

NC_000021.7:g.35181134C>G

NG_011402.2:g.1102745G>C

ENST00000675419.1:c.227G>C

ENST00000300305.7:c.227G>C

ENST00000344691.8:c.146G>C

ENST00000358356.9:c.146G>C

ENST00000399237.6:c.191G>C

ENST00000399240.5:c.146G>C

ENST00000437180.5:c.227G>C

ENST00000455571.5:c.188G>C

ENST00000482318.5:c.59-6254G>C

NM_001001890.2:c.146G>C

NM_001122607.1:c.146G>C

NM_001754.4:c.227G>C

NM_001001890.3:c.146G>C

NM_001122607.2:c.146G>C

Uncertain Significance

PP3 PM2_Supporting

PVS1 BS2 BS4 BS3 BS1 BP3 BP2 BP4 BP1 BP7 BP5 PS1 PS2 PS4 PS3 BA1 PP4 PP1 PP2 PM5 PM4 PM3 PM1 PM6

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.227G>C (p.Arg76Pro) is a missense variant. This variant is completely absent from all population databases with 30x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). The REVEL score is ≥ 0.88 (0.906) (PP3). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM2_supporting, PP3.

PP3

This missense variant has a REVEL score ≥ 0.88 (0.906) (PP3). SpliceAI score is < 0.38 (0).

PM2_Supporting

This variant is completely absent from all population databases with 30x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

PVS1

This is a missense variant.

BS2

To our knowledge, no publication has reported this variant to date.

BS4

To our knowledge, no publication has reported this variant to date.

BS3

To our knowledge, this variant was not evaluated in transactivation assays.

BS1

This variant is completely absent from all population databases with 30x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

BP3

This rule is not applicable to the MMVCEP.

BP2

To our knowledge, no publication has reported this variant to date.

BP4

This missense variant has a REVEL score ≥ 0.88 (0.906) (PP3). SpliceAI score is < 0.38 (0).

BP1

This rule is not applicable to the MMVCEP.

BP7

This is a missense variant.

BP5

This rule is not applicable to the MMVCEP.

PS1

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

PS2

To our knowledge, no publication has reported this variant to date.

PS4

Clinvar has one entry for this variant but the affected status is unknown. To our knowledge, no publication has reported this variant to date.

PS3

To our knowledge, functional assays have not been reported for this variant.

BA1

This variant is completely absent from all population databases with 30x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

PP4

This rule is not applicable to the MMVCEP.

PP1

To our knowledge, no publication has reported this variant to date.

PP2

This rule is not applicable to the MMVCEP.

PM5

Another missense variant [c.226C>T, p.Arg76Cys] in the same codon but the affected status is unknown (ClinVar Variation ID 576717). However, this other variant has not (yet) met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen MMVCEP.

PM4

This is a missense variant.

PM3

This rule is not applicable to the MMVCEP.”

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 MMVCEP.

PM6

To our knowledge, no publication has reported this variant to date.

Approved on: 2023-11-13

Published on: 2023-11-13

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