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:c.349A>T

CA410203348

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7a9d356d-7a73-4ab8-b962-fb71b946fc1f

Approved on: 2024-03-26

Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.349A>T

NC_000021.9:g.34886845T>A

CM000683.2:g.34886845T>A

NC_000021.8:g.36259142T>A

CM000683.1:g.36259142T>A

NC_000021.7:g.35181012T>A

NG_011402.2:g.1102867A>T

ENST00000675419.1:c.349A>T

ENST00000300305.7:c.349A>T

ENST00000344691.8:c.268A>T

ENST00000358356.9:c.268A>T

ENST00000399237.6:c.313A>T

ENST00000399240.5:c.268A>T

ENST00000437180.5:c.349A>T

ENST00000455571.5:c.310A>T

ENST00000482318.5:c.59-6132A>T

NM_001001890.2:c.268A>T

NM_001122607.1:c.268A>T

NM_001754.4:c.349A>T

NM_001001890.3:c.268A>T

NM_001122607.2:c.268A>T

Pathogenic

PS3 PM5_Supporting PM2_Supporting PVS1

PP1 PP3 PP2 PM1 PM3 PM4 PS2 PS4 PS1 PM6 BA1 BP7 BP5 BP2 BP3 BP4 BP1 BS2 BS4 BS3 BS1

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.349A>T (p.Lys117Ter) is a nonsense variant which is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1). There is evidence of very low or abnormal mRNA/protein expression of the c.349A>T (p.Lys117Ter) variant allele as a functional consequence of a null variant or incorrect mRNA/protein products (PS3; PMID: 34166225). 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). 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, PS3, PM2_supporting, PM5_supporting.

PS3

There is evidence of very low or abnormal mRNA/protein expression of the c.349A>T (p.Lys117Ter) variant allele as a functional consequence of a null variant or incorrect mRNA/protein products (PS3; PMID: 34166225).

Transactivation 29.24% of WT. Undergoes NMD. Lower than WT (nonsense meditated decay) in Hela cells. No expression (nonsense meditated decay) in Jurkat cells. PubMed:34166225

PM5_Supporting

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

PM2_Supporting

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

PVS1

This variant is predicted to undergo nonsense mediated decay in a gene in which loss-of-function is an established mechanism (nonsense c.98-c.916 as per VCEP specifications) (PVS1).

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.

PM1

This variant is not a missense variant.

PM3

This rule is not applicable for MM-VCEP.

PM4

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

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.

PS1

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

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.

BP7

This variant is not a synonymous or intronic variant.

BP5

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.

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.

BS2

This rule is not applicable for MM-VCEP.

BS4

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

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.

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