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.334del (p.Leu112fs)

CA512318822

869209 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5d2d9965-bde0-4928-a52c-ecfdb6b61291

HGVS expressions

NM_001754.5:c.334del

NM_001754.5(RUNX1):c.334del (p.Leu112fs)

NC_000021.9:g.34886862del

CM000683.2:g.34886862del

NC_000021.8:g.36259159del

CM000683.1:g.36259159del

NC_000021.7:g.35181029del

NG_011402.2:g.1102852del

ENST00000675419.1:c.334del

ENST00000300305.7:c.334del

ENST00000344691.8:c.253del

ENST00000358356.9:c.253del

ENST00000399237.6:c.298del

ENST00000399240.5:c.253del

ENST00000437180.5:c.334del

ENST00000455571.5:c.295del

ENST00000482318.5:c.59-6147del

NM_001001890.2:c.253del

NM_001122607.1:c.253del

NM_001754.4:c.334del

NM_001001890.3:c.253del

NM_001122607.2:c.253del

Pathogenic

PVS1 PM5_Supporting PS4_Supporting PM2_Supporting

PS2 PS3 PS1 BP5 BP7 BP2 BP3 BP4 BP1 PP4 PP1 PP3 PP2 BA1 PM3 PM1 PM4 PM6 BS2 BS4 BS3 BS1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Myeloid Malignancy VCEP

The NM_001754.4:c.334del (p.Leu112CysfsTer10) variant is a frameshift variant that is predicted to introduce a 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 is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; from internal laboratory data). 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, PM5_supporting.

PVS1

c.334del causes a -1 frameshift and the resulting transcript is predicted to undergo NMD. The variant meets criteria for PVS1.

PM5_Supporting

This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting).

PS4_Supporting

1 proband meeting RUNX1-phenotypic criteria (from internal laboratory data).

PM2_Supporting

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

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.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

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.

PP4

This rule is not applicable for MM-VCEP.

PP1

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

PP3

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

PP2

This rule is not applicable for MM-VCEP.

BA1

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

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.

PM6

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

BS2

This rule is not applicable for MM-VCEP.

BS4

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

BS3

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

BS1

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

Approved on: 2024-03-26

Published on: 2024-03-26

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