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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data


Variant: NM_001754.5(RUNX1):c.593A>G (p.Asp198Gly)

CA410207973

3342374 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 3f28fc37-8920-46d9-b79f-2a5be9bd3642
Approved on: 2025-02-25
Published on: 2025-02-25

HGVS expressions

NM_001754.5:c.593A>G
NM_001754.5(RUNX1):c.593A>G (p.Asp198Gly)
NC_000021.9:g.34859494T>C
CM000683.2:g.34859494T>C
NC_000021.8:g.36231791T>C
CM000683.1:g.36231791T>C
NC_000021.7:g.35153661T>C
NG_011402.2:g.1130218A>G
ENST00000675419.1:c.593A>G
ENST00000300305.7:c.593A>G
ENST00000344691.8:c.512A>G
ENST00000358356.9:c.512A>G
ENST00000399237.6:c.557A>G
ENST00000399240.5:c.512A>G
ENST00000437180.5:c.593A>G
ENST00000467577.1:n.85A>G
ENST00000482318.5:c.*183A>G
NM_001001890.2:c.512A>G
NM_001122607.1:c.512A>G
NM_001754.4:c.593A>G
NM_001001890.3:c.512A>G
NM_001122607.2:c.512A>G
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Likely Pathogenic

Met criteria codes 5
PP3 PS4_Supporting PM1 PM5 PM2_Supporting
Not Met criteria codes 21
BA1 BP7 BP5 PVS1 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP1 PP4 PP2 PM6 PS2 PS3 PS1 PM3 PM4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Myeloid Malignancy VCEP
NM_001754.5(RUNX1):c.593A>G (p.Asp198Gly) is a missense variant that affects a hotspot residue within the Runt Homology Domain: D198 (PM1). This variant is at the same residue (p.Asp198) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 627342) based on MM-VCEP rules for RUNX1 and RNA data (PM5). This variant does not have an available REVEL score, but multiple other predictors (SIFT,PolyPhen2-HDIV, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, MetaLR, FATHMM-MKL) predict a deleterious impact (PP3). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PMID: 28855357, SCV005332537.1) (PS4_ 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, PS4_Supporting.
Met criteria codes
PP3
This variant does not have an available REVEL score, but multiple other predictors (SIFT,PolyPhen2-HDIV, PolyPhen2-HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, MetaLR, FATHMM-MKL) predict a deleterious impact, but this variant does NOT have a SpliceAI score ≥ 0.38 (0.01) (PP3).
PS4_Supporting
This variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 28855357, SCV005332537.1).
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.Asp198) where a different missense change has been previously established as a pathogenic variant (ClinVar ID 627342) based on MM-VCEP rules for RUNX1 and RNA data (PM5).
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
Not Met criteria codes
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
BP7
This variant does not have a phyloP score < 2.0. (Score 7.69457)
BP5
This rule is not applicable for MM-VCEP
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 variant does not have applicable in-silico data available.
BP1
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.
BS2
This rule is not applicable for MM-VCEP
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
PM6
De novo data for this variant has not been reported in literature.
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.
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.
Curation History
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