RUNX1 c.597del, p.Arg201GlufsTer10
NM_001754.4:c.597del
COSMIC ID: COSM9358523
Pathogenic
The RUNX1 c.597del (R201Efs*10) variant introduces a frameshift leading to a premature stop codon in a gene intolerant to loss‐of‐function. PVS1 (Very Strong), PM2 (Supporting), and PM5_supporting (Supporting) criteria together support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PM2
PM5
Genetic Information
Gene & Transcript Details
Gene
RUNX1
Transcript
NM_001754.5
MANE Select
Total Exons
9
Strand
Reverse (−)
Reference Sequence
NC_000021.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 8 exons | Reverse |
| NM_001754.4 | RefSeq Select | 9 exons | Reverse |
Variant Details
HGVS Notation
NM_001754.4:c.597del
Protein Change
R201Efs*10
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 201: R201Q
Alternate Identifiers
COSM9358523
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.597del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 201: R201Q
PM5 criterion applied.
Functional Summary
The RUNX1 R201Efs*10 variant is a truncating mutation in a tumor suppressor gene, likely resulting in loss of function. Functional evidence indicates that such truncating mutations in RUNX1 inhibit its function, predisposing to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows: NM_001754.4:c.597del (R201Efs*10) is a frameshift leading to a premature stop codon in RUNX1, a gene where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a LOF‐sensitive gene.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: R201Efs*10 is a frameshift, not the same amino acid substitution as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Moderate/Supporting) is based on de novo occurrence with parental confirmation. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Not applicable if variant meets PVS1." The evidence for this variant shows: PVS1 has been applied. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 (Supporting) is: "1 proband meeting RUNX1 phenotypic criteria." The evidence for this variant shows: no case-level or proband data reported. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 (Moderate) is: "Variant affecting one of the following amino acid residues within the RHD: ... R201 ..." The evidence for this variant shows: it is a frameshift, not a missense or in-frame indel at position R201. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Variant must be completely absent from all population databases." The evidence for this variant shows: NM_001754.4:c.597del is absent from gnomAD and other control databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: RUNX1 disorders are dominant and no trans configuration data exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 (Moderate) is: "In-frame deletion/insertion impacting key residues." The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM5_supporting is: "PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4)." The evidence for this variant shows: c.597del is a frameshift downstream of c.98. Therefore, this criterion is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 (Moderate) is: "Phenotype consistent with gene but not highly specific; de novo assumed cases." The evidence for this variant shows: no de novo cases reported. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 (Supporting) is: "3 or 4 meioses observed with co-segregation." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting for missense variants with REVEL ≥0.88 or SpliceAI ≥0.38." The evidence for this variant shows: it is a frameshift and SpliceAI score is 0. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype is highly specific for a gene." The evidence for this variant shows: no phenotype or family history details provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency ≥1% in general population." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Minor allele frequency between 0.015% and 0.15%." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Transactivation assays normal (80–115% of wt)." The evidence for this variant shows: functional data indicate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Non-segregation in families." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense in a gene where only LOF causes disease." The evidence for this variant shows: it is a LOF frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant gene." The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region without known function." The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting for missense variants with REVEL <0.50 or SpliceAI ≤0.20." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternative genetic cause." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: none. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting for synonymous/intronic variants with SpliceAI ≤0.20 and low conservation." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.