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]

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Variant: NM_001754.5(RUNX1):c.352-1G>A

CA410202793

436616 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bacb4dd5-65e9-43dd-9c45-b3d9b6a59f6d

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.352-1G>A

NM_001754.5(RUNX1):c.352-1G>A

NC_000021.9:g.34880714C>T

CM000683.2:g.34880714C>T

NC_000021.8:g.36253011C>T

CM000683.1:g.36253011C>T

NC_000021.7:g.35174881C>T

NG_011402.2:g.1108998G>A

ENST00000675419.1:c.352-1G>A

ENST00000300305.7:c.352-1G>A

ENST00000344691.8:c.271-1G>A

ENST00000358356.9:c.271-1G>A

ENST00000399237.6:c.316-1G>A

ENST00000399240.5:c.271-1G>A

ENST00000437180.5:c.352-1G>A

ENST00000455571.5:c.313-1G>A

ENST00000482318.5:c.59-1G>A

NM_001001890.2:c.271-1G>A

NM_001122607.1:c.271-1G>A

NM_001754.4:c.352-1G>A

NM_001001890.3:c.271-1G>A

NM_001122607.2:c.271-1G>A

Pathogenic

PS4_Supporting PM2_Supporting PVS1 PP1

PM6 PM3 PM1 PM4 PM5 BS2 BS4 BS1 BS3 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS3 PS1 BA1 PP4 PP3 PP2

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

The NM_001754.4:c.352-1G>A variant is a canonical splice site variant that is predicted to introduce a frameshift and premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 26175287). This variant was found to co-segregate with disease in multiple affected family members, with three meioses observed in one family (PP1; PMID: 26175287). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PP1.

PS4_Supporting

1 affected proband in a family with FPD/AML.

1 affected proband in a family with FPD/AML (Pedigree 4). PubMed:26175287

PM2_Supporting

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

PVS1

A variant at canonical splice site (-1). The transcription predicts to skip exon 5 and generates a frameshift (-1) that predicts to undergo NMD.

PP1

4 affected individuals (3 meioses) in one family with FPD/AML (Pedigree 4).

4 affected individuals (3 meioses) in one family with FPD/AML (Pedigree 4). PubMed:26175287

PM6

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

PM3

This rule is not applicable for MM-VCEP.

PM1

This variant is not a missense variant.

PM4

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

PM5

This variant is not a missense, or synonymous variant.

BS2

This rule is not applicable for MM-VCEP.

BS4

Segregation was not found to be absent in two or more informative meiosis.

4 affected individuals (3 meioses) in one family with FPD/AML (Pedigree 4). PubMed:26175287

BS1

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

BS3

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

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.

BP3

This rule is not applicable for MM-VCEP.

BP4

This variant does not have applicable in-silico data available.

BP1

This rule is not applicable for MM-VCEP.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is a splicing variant at a canonical splice site.

PS2

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

PS3

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

PS1

This variant is not a missense, or synonymous variant.

BA1

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

PP4

This rule is not applicable for MM-VCEP.

PP3

This variant does not have applicable in-silico data available.

PP2

This rule is not applicable for MM-VCEP.

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