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_001754.4(RUNX1):c.352-1G>T

CA248609

14463 (ClinVar)

Gene: RUNX1

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

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 582e74ff-583d-43ab-9de0-41f6d60d889b

HGVS expressions

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

NM_001754.4(RUNX1):c.352-1G>T

NC_000021.9:g.34880714C>A

CM000683.2:g.34880714C>A

NC_000021.8:g.36253011C>A

CM000683.1:g.36253011C>A

NC_000021.7:g.35174881C>A

NG_011402.2:g.1108998G>T

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

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

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

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

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

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

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

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

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

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

Pathogenic

PS4_Supporting PP1_Strong PM2 PVS1

PM6 PM5 PM4 PM1 BA1 BS3 BS1 BS4 BP7 BP4 BP2 PS1 PS3 PP3

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.352-1G>T variant is a canonical splice site variant that is predicted to introduce a frameshift and a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1; PMID: 10508512). This variant was found to co-segregate with disease in multiple affected family members, with more than seven meioses (at least 25 affected individuals) observed in one family/across X families (PP1_Strong; 10508512). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 11830488). 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, PP1_Strong, PM2, PS4_Supporting.

PS4_Supporting

1 (compelling) pedigee identified in the literature.

PP1_Strong

In one pedigree, >25 affected individuals and >7 with leukemia diagnosis .

PM2

The variant is absent from all population databases.

PVS1

Variant at canonical splice site (-1). The transcription predicts to skip exon 5 and generates a frameshift (-1) that predicts to undergo NMD. Cryptic splice acceptor with a frameshift (PMID: 10508512).

PM6