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.401C>T (p.Ala134Val)

CA410202690

1484777 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5c7a8e1e-ee26-4a2d-b939-711c5c6df9d6

HGVS expressions

NM_001754.5:c.401C>T

NM_001754.5(RUNX1):c.401C>T (p.Ala134Val)

NC_000021.9:g.34880664G>A

CM000683.2:g.34880664G>A

NC_000021.8:g.36252961G>A

CM000683.1:g.36252961G>A

NC_000021.7:g.35174831G>A

NG_011402.2:g.1109048C>T

ENST00000675419.1:c.401C>T

ENST00000300305.7:c.401C>T

ENST00000344691.8:c.320C>T

ENST00000358356.9:c.320C>T

ENST00000399237.6:c.365C>T

ENST00000399240.5:c.320C>T

ENST00000437180.5:c.401C>T

ENST00000455571.5:c.362C>T

ENST00000482318.5:c.108C>T

NM_001001890.2:c.320C>T

NM_001122607.1:c.320C>T

NM_001754.4:c.401C>T

NM_001001890.3:c.320C>T

NM_001122607.2:c.320C>T

Likely Pathogenic

PM1 PM5 PM2_Supporting PP3

PS2 PS4 PS3 PS1 PM3 PM4 PM6 BA1 PVS1 BP2 BP3 BP4 BP1 BP7 BP5 BS2 BS4 BS3 BS1 PP1 PP4 PP2

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

NM_001754.5(RUNX1):c.401C>T (p.Ala134Val) is a missense variant which affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). This variant is a missense change at the same residue (p.Ala134) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468) based on MM-VCEP rules for RUNX1, and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5). This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM5, PP3, PM2_supporting.

PM1

This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).

PM5

This variant is a missense change at the same residue (p.Ala134) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 14468) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5).

PM2_Supporting

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

PP3

This missense variant has a REVEL score ≥ 0.88 (0.949) (PP3).

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.

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 resulting in the same change in protein which has been determined to be pathogenic at this amino acid residue.

PM3

This rule is not applicable for MM-VCEP.

PM4

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

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.

PVS1

This variant is not a null 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 missense variant does not have a REVEL score < 0.50.

BP1

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BP5

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

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.

PP1

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

PP4

This rule is not applicable for MM-VCEP.

PP2

This rule is not applicable for MM-VCEP.

Approved on: 2024-06-24

Published on: 2024-06-24

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