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_001754.4(RUNX1):c.1190A>G (p.Gln397Arg)

CA10014193

532673 (ClinVar)

Gene: RUNX1

Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c12e966a-f7a4-468b-9c26-af1bd643dee1

Approved on: 2022-07-07

Published on: 2022-07-07

HGVS expressions

NM_001754.4:c.1190A>G

NM_001754.4(RUNX1):c.1190A>G (p.Gln397Arg)

NC_000021.9:g.34792388T>C

CM000683.2:g.34792388T>C

NC_000021.8:g.36164685T>C

CM000683.1:g.36164685T>C

NC_000021.7:g.35086555T>C

NG_011402.2:g.1197324A>G

ENST00000675419.1:c.1190A>G

ENST00000300305.7:c.1190A>G

ENST00000344691.8:c.1109A>G

ENST00000399240.5:c.917A>G

ENST00000437180.5:c.1190A>G

ENST00000482318.5:c.*780A>G

NM_001001890.2:c.1109A>G

NM_001001890.3:c.1109A>G

NM_001754.5:c.1190A>G

NM_001754.5(RUNX1):c.1190A>G (p.Gln397Arg)

Benign

BA1 BP4

PVS1 BP5 BP7 BP2 BP3 BP1 BS3 BS4 BS1 BS2 PP1 PP4 PP3 PP2 PM5 PM1 PM3 PM4 PS3 PS1 PS2 PS4 PM6 PM2

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

This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID: 19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID: 30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4.

BA1

gnomAD v2: ALL:0.026% (53/202938 alleles) - EAS:0.36% (53/14624 alleles, no homozygotes) gnomAD v3: ALL:0.026% (11/142690) - EAS:0.36% (11/3118 alleles, no homozygotes)

BP4

This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (no score changes in algorithms).

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP5

Not applicable.

BP7

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP2

No unaffected homozygotes reported in gnomAD v2/v3 or otherwise. Phasing unclear for case reports.

BP3

Not applicable.

BP1

Not applicable.

BS3

Q370R in K562 cells showed normal transactivation by dual luciferase assay (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations).

BS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

gnomAD v2: ALL:0.026% (53/202938 alleles) - EAS:0.36% (53/14624 alleles, no homozygotes) gnomAD v3: ALL:0.026% (11/142690 alleles) - EAS:0.36% (11/3118 alleles, no homozygotes)

BS2

Not applicable.

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

Not applicable.

PP3

This missense variant does not have a REVEL score >0.75 (0.238) nor does it result in significant score change at the canonical splice site or elsewhere (as measured by SpliceAI, MES, and SSF-like).

PP2

Not applicable.

PM5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

This variant is not located at a critical residue (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R204, R210) or region (aa 89-204).

PM3

Not applicable.

PM4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

The variant has been reported in 2 patients with de novo AML (likely germline based on identification at complete remission) (PMID: 19808697) and reported in homozygosity in a patient with a personal and family history of thrombocytopenia (PMID: 30103613). The variant has also been reported in other cases of MDS, AML, and T-ALL, but germline origin was not confirmed in these cases (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). However, PS4 code cannot apply because this variant meet BA1.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

gnomAD v2: ALL:0.026% (53/202938 alleles) - EAS:0.36% (53/14624 alleles, no homozygotes) gnomAD v3: ALL:0.026% (11/142690 alleles) - EAS:0.36% (11/3118 alleles, no homozygotes)

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