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.824C>T (p.Pro275Leu)

Curation Version - 1.1
Curation History
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CA10014287

464009 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ed562b68-0918-4a40-899c-7000d16d5da8

Approved on: 2025-03-25

Published on: 2025-03-25

HGVS expressions

NM_001754.5:c.824C>T

NM_001754.5(RUNX1):c.824C>T (p.Pro275Leu)

NC_000021.9:g.34799444G>A

CM000683.2:g.34799444G>A

NC_000021.8:g.36171741G>A

CM000683.1:g.36171741G>A

NC_000021.7:g.35093611G>A

NG_011402.2:g.1190268C>T

ENST00000675419.1:c.824C>T

ENST00000300305.7:c.824C>T

ENST00000344691.8:c.743C>T

ENST00000399240.5:c.551C>T

ENST00000437180.5:c.824C>T

ENST00000482318.5:c.*414C>T

NM_001001890.2:c.743C>T

NM_001754.4:c.824C>T

NM_001001890.3:c.743C>T

Benign

BP4 BA1

PP4 PP1 PP3 PP2 PM6 PM2 PM3 PM1 PM4 PM5 BS2 BS4 BS1 BS3 BP5 BP7 BP2 BP3 BP1 PVS1 PS2 PS4 PS3 PS1

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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

NM_001754.5(RUNX1):c.824C>T (p.Pro275Leu) is a missense variant which has a minor allele frequency (MAF) of 0.00225 (0.2%, 26/11,566 alleles) in the Latino subpopulation of the ExAC cohort, which is ≥ 0.0015 (0.15%) (BA1). This variant also has a REVEL score < 0.15 (0.146) (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4.

BP4

REVEL: 0.146 <0.15 AND agreement in splicing predictors (SSF and MES) predict no splicing effects.

BA1

This variant has an ExAC Allele Frequency of Latino Subpopulation: 0.00225 (26 out of 11566 Alleles) > 0.0015.

PP4

This rule is not applicable for RUNX1.

PP1

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

PP3

This missense variant does not have a REVEL score of ≥ 0.88 (0.146).

PP2

This rule is not applicable for RUNX1.

PM6

De novo data for this variant in patients with the phenotype has not been reported in literature.

PM2

This variant is present in at least one population database.

PM3

This rule is not applicable for RUNX1.

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 OR within residues 89-204.

PM4

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

PM5

There has not yet been a different missense change determined to be pathogenic at this amino acid residue.

BS2

This rule is not applicable for RUNX1.

BS4

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

BS1

This variant has a MAF between 0.00015 (0.015%) and 0.0015 (0.15%) in gnomAD for the Latino population (51/34592, 0.00147) however BA1 has already been applied.

BS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

BP5

This rule is not applicable for RUNX1.

BP7

There is evidence that the nucleotide is highly conserved (PhyloP score = 8.8)

BP2

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

BP3

This rule is not applicable for RUNX1.

BP1

This rule is not applicable for RUNX1.

PVS1

This variant is not a null variant.

PS2

De novo data for this variant in patients with the phenotype has not been reported in literature.

PS4

Though this variant has been reported in an ALL patient, thrombocytopenia was not reported in this patient (J Clin Invest. 2021 Sep 1;131(17):e147898. doi: 10.1172/JCI147898)

PS3

In vitro or in vivo functional data has not been reported for this variant in the literature.

PS1

There has not yet been a missense change determined to be pathogenic at this amino acid residue.

Curation History

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