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.601dup (p.Arg201fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA913189266

1073884 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 808f09c3-3f62-4523-b5b4-ede068a28f23

Approved on: 2023-12-09

Published on: 2023-12-09

HGVS expressions

NM_001754.5:c.601dup

NM_001754.5(RUNX1):c.601dup (p.Arg201fs)

NC_000021.9:g.34859489dup

CM000683.2:g.34859489dup

NC_000021.8:g.36231786dup

CM000683.1:g.36231786dup

NC_000021.7:g.35153656dup

NG_011402.2:g.1130226dup

ENST00000675419.1:c.601dup

ENST00000300305.7:c.601dup

ENST00000344691.8:c.520dup

ENST00000358356.9:c.520dup

ENST00000399237.6:c.565dup

ENST00000399240.5:c.520dup

ENST00000437180.5:c.601dup

ENST00000467577.1:n.93dup

ENST00000482318.5:c.*191dup

NM_001001890.2:c.520dup

NM_001122607.1:c.520dup

NM_001754.4:c.601dup

NM_001001890.3:c.520dup

NM_001122607.2:c.520dup

Pathogenic

PM5_Supporting PS4_Supporting PM2_Supporting PVS1

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

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.601dup (p.Arg201ProfsTer12) is a frameshift variant. The transcript product is predicted to undergo NMD (PVS1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This variant has been reported in 1 proband with family history meeting RUNX-1 phenotypic criteria (thrombocytopenia) (PMID 26175287) (PS4_supporting). This variant was also reported in Clinvar in 2021 by Invitae but the affected status of the proband is unknown (Variation ID 1073884). There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID: 35764482) (PM5_supporting). In summary, the clinical significance of this variant is pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_supporting, PM2_supporting, PM5_supporting.

PM5_Supporting

There are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) without use of PM5_Supporting (PMID: 35764482). This frameshift variant is downstream c.98.

PS4_Supporting

This variant has been reported in 1 proband with family history meeting RUNX-1 phenotypic criteria (thrombocytopenia) ](PS4_Supporting]; PMID 26175287. This variant was also reported in Clinvar in 2021 by Invitae but the affected status of the proband is unknown (Variation ID 1073884).

PM2_Supporting

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

PVS1

The transcript product of this frameshift variant is predicted to undergo NMD.

BP4

This variant is a loss-of-function variant.

BP3

This variant is a frameshift.

BP1

This rule is not applicable to the MMVCEP.

BP2

No information found in the literature.

BP5

This rule is not applicable to the MMVCEP

BP7

This variant is a loss-of-function variant.

PS1

This variant is a loss-of-function variant.

PS2

There is no proof of testing of other affected family members (PMID 26175287).

PS3

To our knowledge, this synonymous variant was not evaluated in transactivation assays. However, p.(Arg201*) was used in Decker et al functional study as a positive pathogenic control has been shown to be damaging.

PP1

There is no proof of testing of other affected family members (PMID 26175287).

PP2

This variant is a loss-of-function variant.

PP3

This variant is a loss-of-function variant.

PP4

This rule is not applicable to the MMVCEP.

PM1

This variant is not a missense.

PM3

This rule is not applicable for MM-VCEP.

BA1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

PM4

This variant is a frameshift.

PM6

There is no proof of testing of other affected family members (PMID 26175287).

BS2

This rule is not applicable to the MMVCEP.

BS1

This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting).

BS4

There is no proof of testing of other affected family members (PMID 26175287).

BS3

Curation History

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