Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)

CA248628

14471 (ClinVar)

Gene: RUNX1 (HGNC:861)

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Inheritance Mode: Autosomal dominant inheritance

UUID: 1023c045-33cc-4c4b-9297-ea4832be8def

Approved on: 2024-06-24

Published on: 2024-06-24

HGVS expressions

NM_001754.5:c.467C>A

NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)

NC_000021.9:g.34880598G>T

CM000683.2:g.34880598G>T

NC_000021.8:g.36252895G>T

CM000683.1:g.36252895G>T

NC_000021.7:g.35174765G>T

NG_011402.2:g.1109114C>A

ENST00000675419.1:c.467C>A

ENST00000300305.7:c.467C>A

ENST00000344691.8:c.386C>A

ENST00000358356.9:c.386C>A

ENST00000399237.6:c.431C>A

ENST00000399240.5:c.386C>A

ENST00000437180.5:c.467C>A

ENST00000482318.5:c.*57C>A

NM_001001890.2:c.386C>A

NM_001122607.1:c.386C>A

NM_001754.4:c.467C>A

NM_001001890.3:c.386C>A

NM_001122607.2:c.386C>A

Likely Pathogenic

PM1_Supporting PM2_Supporting PP3 PP1_Strong PS4_Supporting

BS2 PVS1 BS1 BS4 BS3 BP4 BP3 BP1 BP2 BP5 BP7 BA1 PS1 PS2 PS3 PP2 PP4 PM6 PM3 PM5 PM4

Evidence Links 2

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.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). 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: PP1_Strong, PM2_supporting, PP3, PM1_Supporting, PS4_Supporting.

PM1_Supporting

This variant affects one of the other residues (AA 89-204) within the RHD (PM1_Supporting).

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 (0.906) (PP3).

PP1_Strong

8 affected individuals in one pedigree with 7 meioses.

8 affected individuals in one pedigree (Pedigree 1) with 7 meioses. PubMed:19357396

The same family (Pedigree B) reported in PMID: 19357396. PubMed:27112265

PS4_Supporting

1 affected proband in a family with FPD/AML (PMID: 19357396, PMID: 27112265).

1 affected proband in a family with FPD/AML (Pedigree 1). PubMed:19357396

The same family (Pedigree B) reported in PMID: 19357396. PubMed:27112265

BS2

This rule is not applicable for MM-VCEP.

PVS1

This variant is not a null variant.

BS1

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

BS4

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

8 affected individuals in one pedigree (Pedigree 1) with 7 meioses. PubMed:19357396

The same family (Pedigree B) reported in PMID: 19357396. PubMed:27112265

BS3

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

BP4

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

BP3

This rule is not applicable for MM-VCEP.

BP1

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.

BP5

This rule is not applicable for MM-VCEP.

BP7

This variant is not a synonymous or intronic variant.

BA1

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

PS1

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

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.

PP2

This rule is not applicable for MM-VCEP.

PP4

This rule is not applicable for MM-VCEP.

PM6

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

PM3

This rule is not applicable for MM-VCEP.

PM5

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

PM4

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

Curation History

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