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.316T>C (p.Trp106Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA410203507

1045299 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 990cbcb7-9949-4d3d-a86e-3e9670d16809

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001754.5:c.316T>C

NM_001754.5(RUNX1):c.316T>C (p.Trp106Arg)

NC_000021.9:g.34886878A>G

CM000683.2:g.34886878A>G

NC_000021.8:g.36259175A>G

CM000683.1:g.36259175A>G

NC_000021.7:g.35181045A>G

NG_011402.2:g.1102834T>C

ENST00000675419.1:c.316T>C

ENST00000300305.7:c.316T>C

ENST00000344691.8:c.235T>C

ENST00000358356.9:c.235T>C

ENST00000399237.6:c.280T>C

ENST00000399240.5:c.235T>C

ENST00000437180.5:c.316T>C

ENST00000455571.5:c.277T>C

ENST00000482318.5:c.59-6165T>C

NM_001001890.2:c.235T>C

NM_001122607.1:c.235T>C

NM_001754.4:c.316T>C

NM_001001890.3:c.235T>C

NM_001122607.2:c.235T>C

Likely Pathogenic

PS1_Moderate PS3_Moderate PP3 PM2_Supporting PM1_Supporting

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

Evidence Links 1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.316T>C (p.Trp106Arg) is found within the runt homology domain (RHD) in a residue which is not an established hotspot (PM1_supporting). The c.316T>C variant is the same amino acid change (p.Trp106Arg) as a previously established likely pathogenic variant (ClinVar ID 436617) curated using MM-VCEP rules for RUNX1 (PS1_Moderate). This missense variant has a REVEL score ≥ 0.88 (0.976) (PP3) and transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q)(PS3_moderate, PMID: 25840971). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PS1_moderate, PS3_moderate, PP3, PM1_supporting, PM2_supporting.

PS1_Moderate

The c.316T>C variant is the same amino acid change (p.Trp106Arg) as a previously established likely pathogenic variant (ClinVar ID 436617) curated using MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PS1_Moderate).

PS3_Moderate

Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q)(PS3_moderate, PMID: 25840971).

DNA binding present (+), CBFB dimerization present (+), sAML transformation present (+), and C-FMS activation was found to be abnormally low. PubMed:25840971

PP3

This missense variant has a REVEL score ≥ 0.88 (0.976) (PP3).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

BP7

This variant is not a synonymous or intronic variant.

BP5

This rule is not applicable for MM-VCEP.

BP3

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.

BP4

This missense variant does not have a REVEL score < 0.50.

BP1

This rule is not applicable for MM-VCEP.

PS2

De novo data for this variant has not been reported in literature.

PS4

Proband data for this variant has not been reported in literature.

PP4

This rule is not applicable for MM-VCEP.

PP1

Segregation data for this variant has not been reported in literature.

PP2

This rule is not applicable for MM-VCEP.

PM4

This variant is not an in-frame deletion/insertion.

PM5

PS1 was applied.

PM3

This rule is not applicable for MM-VCEP.

PVS1

This variant is not a null variant.

PM6

De novo data for this variant has not been reported in literature.

BA1

This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.

BS2

This rule is not applicable for MM-VCEP.

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

This variant does not have a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental dataset.

BS4

Segregation data for this variant has not been reported in literature.

Curation History

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