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Variant: NM_001754.5(RUNX1):c.611G>A (p.Arg204Gln)

CA410207938

561253 (ClinVar)

Gene: RUNX1
Condition: hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ad45320e-ac57-472f-b6c0-f7a6ebda5841
Approved on: 2024-03-26
Published on: 2024-03-26

HGVS expressions

NM_001754.5:c.611G>A
NM_001754.5(RUNX1):c.611G>A (p.Arg204Gln)
NC_000021.9:g.34859476C>T
CM000683.2:g.34859476C>T
NC_000021.8:g.36231773C>T
CM000683.1:g.36231773C>T
NC_000021.7:g.35153643C>T
NG_011402.2:g.1130236G>A
ENST00000675419.1:c.611G>A
ENST00000300305.7:c.611G>A
ENST00000344691.8:c.530G>A
ENST00000358356.9:c.530G>A
ENST00000399237.6:c.575G>A
ENST00000399240.5:c.530G>A
ENST00000437180.5:c.611G>A
ENST00000467577.1:n.103G>A
ENST00000482318.5:c.*201G>A
NM_001001890.2:c.530G>A
NM_001122607.1:c.530G>A
NM_001754.4:c.611G>A
NM_001001890.3:c.530G>A
NM_001122607.2:c.530G>A
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Pathogenic

Met criteria codes 6
PP3 PM1 PS4_Moderate PM5_Supporting PP1_Strong PM2_Supporting
Not Met criteria codes 20
PS2 PS3 PS1 PP4 PP2 PM3 PM4 PM6 PVS1 BA1 BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1

Evidence Links 5

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
The NM_001754.4:c.611G>A (p.Arg204Gln) variant affects one of the 13 hotspot residues established by the MM-VCEP for RUNX1 (PM1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). This missense variant has a REVEL score >0.75 (0.958) (PP3). This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria (PS4_ moderate; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families (PP1_strong; PMID: 19357396, PMID: 27112265, PMID: 26316320, PMID: 27479822). This variant is a missense change at the same residue (p.R204) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 2177591) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PM1, PM2, PS4_moderate, PP3, PM5_supporting.
Met criteria codes
PP3
This missense variant has a REVEL score ≥ 0.88 (0.958) (PP3).
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).
PS4_Moderate
This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria.
F19.I and F19.II in the same pedigree with thrombocytopenia. PubMed:27479822
The same family as PMID: 19357396 PubMed:26316320
Pedigree D with FPD/AML PubMed:27112265
Pedigree 2 with FPD/AML PubMed:19357396
PM5_Supporting
This variant is a missense change at the same residue (p.R204) where a different missense change has been previously established as a likely pathogenic variant (ClinVar ID 2177591) based on MM-VCEP rules for RUNX1 and RNA data or agreement in splicing predictors (SSF and MES) show no splicing effects (PM5_Supporting).
PP1_Strong
This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families.
F19.I and F19.II in the same pedigree with thrombocytopenia, 1 meiosis. PubMed:27479822
The same family as PMID: 19357396 PubMed:26316320
3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation. PubMed:27112265
4 affected individuals in Pedigree 2 with FPD/AML, 4 meioses in segregation. PubMed:19357396
PM2_Supporting
This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting).
Not Met criteria codes
PS2
De novo data for this variant has not been reported in literature.
PS3
This variant has not been featured in in vitro or in vivo functional studies showing a damaging effect on the gene or gene product.
Transactivation-Luciferase reporter assay in Hela cells 31.91% compared to WT. PubMed:34166225
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.
PP4
This rule is not applicable for MM-VCEP.
PP2
This rule is not applicable for MM-VCEP.
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.
PVS1
This variant is not a null variant.
BA1
This variant does not have a MAF ≥ 0.0015 (0.15%) in any general continental population dataset.
BS4
Segregation was not found to be absent in two or more informative meiosis.
F19.I and F19.II in the same pedigree with thrombocytopenia, 1 meiosis. PubMed:27479822
The same family as PMID: 19357396 PubMed:26316320
3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation. PubMed:27112265
4 affected individuals in Pedigree 2 with FPD/AML, 4 meioses in segregation. PubMed:19357396
BS3
This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.
Transactivation-Luciferase reporter assay in Hela cells 31.91% compared to WT. PubMed:34166225
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.
BP5
This rule is not applicable for MM-VCEP.
BP7
This variant is not a synonymous or intronic 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.
Curation History
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