GATA2 c.619dup, p.Asp207GlyfsTer75
NM_001145661.1:c.619dup
Pathogenic
The GATA2 c.619dupG (D207Gfs*75) variant is a truncating frameshift leading to loss of function in a gene where LoF is a known mechanism (PVS1_Very Strong), supported by well-established functional studies (PS3_Strong) and absence from population controls (PM2_Moderate). Computational evidence indicates no splicing impact (BP4_Supporting). These criteria collectively meet a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
GATA2
Transcript
NM_001145661.2
Total Exons
7
Strand
Reverse (−)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001145661.1 | Alternative | 7 exons | Reverse |
Variant Details
HGVS Notation
NM_001145661.1:c.619dup
Protein Change
D207Gfs*75
Location
Exon 4
(Exon 4 of 7)
5'Exon Structure (7 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 207 in gene GATA2
Variant interpretation based on transcript NM_001145661.2
Genome Browser
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HGVS InputNM_001145661:c.619dup
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
No evidence of other pathogenic variants at position 207 in gene GATA2
Functional Summary
The GATA2 D207Gfs*75 variant is a truncating mutation that results in the loss of protein expression. Functional evidence indicates that truncating mutations in GATA2, particularly affecting the ZF1 and ZF2 domains, are associated with hematological malignancies and poor prognosis. In vivo studies using biallelic GATA2 knockout mouse models demonstrate that the loss of GATA2 function is inactivating, leading to increased leukemogenesis. This supports a damaging effect of the variant.
Database Previews
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: NM_001145661.1:c.619dupG is a frameshift (D207Gfs*75) predicted to result in a premature stop codon and loss of normal GATA2 protein, and loss of function is a known mechanism of disease in GATA2. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a LoF‐mediated gene and it is not located in the last exon or predicted to escape nonsense‐mediated decay.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: D207Gfs*75 is a novel frameshift, not a missense change matching any known pathogenic variant. Therefore, this criterion is not applied because there is no matching amino acid change previously reported as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no parental testing or de novo status has been provided. Therefore, this criterion is not applied due to lack of confirmed de novo data.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: truncating GATA2 D207Gfs*75 causes loss of protein expression, and in vivo mouse knockout models confirm LOF leads to leukemogenesis. Therefore, this criterion is applied at Strong strength because multiple well‐established functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case‐control or statistical enrichment data are available. Therefore, this criterion is not applied because prevalence data are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well‐established functional domain without benign variation". The evidence for this variant shows: although D207 lies within zinc‐finger domains, PM1 is reserved for missense variants in hotspots; this variant is a frameshift. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: c.619dupG is not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large control cohorts.
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: GATA2 disorders are dominant and no trans‐phase data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame deletions/insertions or stop‐loss variants". The evidence for this variant shows: c.619dupG causes a frameshift, not an in‐frame insertion or deletion. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: this is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co‐segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data have been provided. 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: SpliceAI scores are low (≤0.03) and do not predict deleterious splicing; no other in silico tools indicate harm. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no detailed phenotype or family history has been 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, but without accessible evidence". The evidence for this variant shows: it is not recorded in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: absent from controls. 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 with full penetrance expected at an early age". The evidence for this variant shows: no healthy homozygotes or carriers have been documented. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: functional studies demonstrate damaging loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation studies are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss of function causes disease". The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant or in trans for a dominant disorder". The evidence for this variant shows: no such cis/trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without known function". The evidence for this variant shows: it is frameshift, not in-frame in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: SpliceAI predicts minimal splicing impact (max score 0.03), and other in silico tools do not predict deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no alternate molecular diagnoses have been reported. 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, but without accessible evidence". The evidence for this variant shows: it is not present in any reputable benign database. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a frameshift, not synonymous. Therefore, this criterion is not applied.