RUNX1 c.502G>A, p.Gly168Arg
NM_001754.4:c.502G>A
COSM5945442
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Pathogenic
0 publications
REVEL Score
0.947
Likely Pathogenic
COSMIC Recurrence
2 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.502G>A
Protein Change
G168R
Location
Exon 5
(Exon 5 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 168 in gene RUNX1
Alternate Identifiers
COSM5945442
Variant interpretation based on transcript NM_001754.5
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
Classification
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely Pathogenic by ClinGen Myeloid Malignancy Variant Curation Expert Panel expert panel.
Expert Panel Reviews
Likely Pathogenic
ClinGen Myeloid Malignancy Variant Curation Expert Panel
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
No evidence of other pathogenic variants at position 168 in gene RUNX1
Functional Studies
Summary
The RUNX1 G168R variant has not been functionally characterized.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.947
0.947
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
metasvm: D
metalr: D
primateai: D
Benign:
CADD: 6.10
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2: 'Supporting: Variant must be completely absent from all population databases.' The evidence for this variant shows that it is not present in gnomAD (MAF = 0%). Therefore, this criterion meets the requirements because the variant is completely absent from population databases.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3: 'Supporting For missense variants: REVEL score ≥ 0.88.' The evidence for this variant shows a REVEL score of 0.95, which exceeds the threshold. Therefore, this criterion meets the requirements because multiple in silico tools predict a deleterious effect.
PP5
PP5 (Supporting)
According to standard ACMG guidelines for PP5: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows that it has been reported in ClinVar by one clinical laboratory as Uncertain Significance and by the ClinGen Myeloid Malignancy Variant Curation Expert Panel as Likely Pathogenic. Therefore, this criterion meets the requirements because it is supported by a reputable expert panel.
PM1
PM1 (Supporting)
Strength Modified
According to VCEP guidelines for PM1: 'Supporting: Variant affecting one of the other amino acid residues 89-204 within the RHD.' The evidence for this variant shows that the amino acid change G168R occurs within the RHD (residues 89-204). Although the residue is not one of those specified for a moderate strength assignment (e.g. R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204), it lies within a functionally critical domain. Therefore, this criterion meets the requirements at a supporting level.