About IDH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
IDH2 c.419G>A, p.(Arg140Gln)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS2Moderate
PS2 · moderate
De novo occurrence of IDH2 c.419G>A (p.Arg140Gln) confirmed by trio analysis with parental status confirmed, per ClinVar submission SCV002768187 (Victorian Clinical Genetics Services). The literature establishes de novo as the primary disease mechanism for D-2-hydroxyglutaric aciduria type II (PMID:21889589).
PS3Strong
PS3 · strong
Multiple independent publications demonstrate unequivocal gain-of-function neomorphic activity of IDH2 R140Q. PMID:21889589 directly assayed the variant in patient-derived lymphoblasts showing 8-fold increased D-2-hydroxyglutarate production (14.4 vs 1.9 nmol/h/mg protein). PMID:23558173 demonstrated selective allosteric inhibition of IDH2/R140Q with AGI-6780 reversing the differentiation block in TF-1 erythroleukemia cells and primary AML blasts, with crystal structure confirmation. PMID:24589777 showed transgenic mice expressing IDH2/R140Q develop cardiomyopathy and neurodegeneration. PMID:20171147 demonstrated neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. The exact variant has been directly tested in multiple independent studies with unequivocal functional effect.
PM1Moderate
PM1 · moderate
The variant alters arginine 140, a residue located in the active site/substrate-binding pocket of IDH2. This is a well-characterized critical functional domain where multiple pathogenic missense changes cluster (R140Q, R140G, R172K, R172M). Cancerhotspots.org identifies this residue as statistically significant. Functional studies confirm that mutations at R140 confer neomorphic gain-of-function activity.
PM2Moderate
PM2 · moderate
The variant is present at extremely low frequency in population databases. gnomAD v2.1 reports 9/282,846 alleles (AF=0.00318%), gnomAD v4.1 reports 71/1,613,752 alleles (AF=0.00440%), with zero homozygotes in both. Highest subpopulation frequency is East Asian at 0.01003% (gnomAD v2.1). All frequencies are well below the 0.1% threshold for PM2 under generic ACMG.
PM5Supporting
PM5 · supporting
A different missense change at the same amino acid residue, IDH2 R140G (c.418C>G, p.Arg140Gly), has been observed in a patient with D-2-hydroxyglutaric aciduria type II (PMID:21889589). Both R140Q and R140G are gain-of-function mutations at codon 140 causing the same disease phenotype. The pathogenic nature of R140G at this residue supports PM5 at supporting level for R140Q.
PP3Supporting
PP3 · supporting
Multiple in silico tools predict a deleterious effect. REVEL score is 0.891 (high confidence damaging). BayesDel score is 0.44497. SpliceAI predicts no splicing impact (max delta=0.00), but the missense prediction is strongly damaging. The variant alters a highly conserved arginine residue in the enzyme active site.
PP5Supporting
PP5 · supporting
This variant is classified as Pathogenic in ClinVar (Variation ID 14716), with 7 clinical laboratories reporting Pathogenic and 5 reporting Likely Pathogenic. Under generic ACMG/AMP, a reputable source classification supports PP5 at supporting level. Review status is 1-star (criteria provided, single submitter), not 3-star expert panel, but multiple independent clinical laboratories concur on pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS2 moderate, PS3 strong, PM1 moderate, PM2 moderate, PM5 supporting, PP3 supporting, PP5 supporting; combination = 1 strong + 3 moderate + 3 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
71 / 1,613,752 alleles
gnomAD v4.1: 71 / 1,613,752 alleles. Recorded AF 4.39968e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18194e-05; MAF= 0.00318%, 9/282846 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100281; MAF= 0.01003%, 2/19944 alleles, homozygotes = 0); grpmax FAF= 2.293e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
12 reported laboratory submissions
7 Pathogenic · 5 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
1037 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57468751, n = 1037 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 7 met · 4 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
IDH2 c.419G>A (p.Arg140Gln) is a pathogenic gain-of-function missense variant that causes D-2-hydroxyglutaric aciduria type II via neomorphic production of D-2-hydroxyglutarate.
Functional studies in patient-derived lymphoblasts demonstrate 8-fold increased D-2-hydroxyglutarate production, and selective pharmacological inhibition with AGI-6780 reverses the disease-associated phenotype.
The variant alters arginine 140 in the IDH2 active site, a critical residue where somatic mutations are also recurrent in acute myeloid leukemia and gliomas.
This variant has been observed as a confirmed de novo event by trio analysis, and de novo occurrence is the established disease mechanism for D-2-hydroxyglutaric aciduria type II.
The variant is extremely rare in population databases (gnomAD AF ~0.004%) and is absent in homozygosity, consistent with a pathogenic role in an autosomal dominant disorder.
In silico predictions strongly support a deleterious effect (REVEL 0.891), consistent with the known gain-of-function mechanism.
This variant is classified as Pathogenic in ClinVar by multiple clinical laboratories and is a well-established cause of D-2-hydroxyglutaric aciduria type II in the literature.
No criteria match.
Met · 7
PS2 ModerateDe novo occurrence of IDH2 c.419G>A (p.Arg140Gln) confirmed by trio analysis with parental status confirmed, per ClinVar submission SCV002768187 (Victorian Clinical Genetics Services). The literature establishes de novo as the primary disease mechanism for D-2-hydroxyglutaric aciduria type II (PMID:21889589). Details ▾Hide ▴
Evidence considered
- ClinVar SCV002768187: de novo confirmed in proband by trio analysis with parental status confirmed
- PMID:21889589: D-2-HGA type II is caused primarily by the heterozygous de novo IDH2 R140Q mutation
Still missing
- Single de novo observation confirmed
- second de novo case would elevate to strong
Sources
PS3 StrongMultiple independent publications demonstrate unequivocal gain-of-function neomorphic activity of IDH2 R140Q. PMID:21889589 directly assayed the variant in patient-derived lymphoblasts showing 8-fold increased D-2-hydroxyglutarate production (14.4 vs 1.9 nmol/h/mg protein). PMID:23558173 demonstrated selective allosteric inhibition of IDH2/R140Q with AGI-6780 reversing the differentiation block in TF-1 erythroleukemia cells and primary AML blasts, with crystal structure confirmation. PMID:24589777 showed transgenic mice expressing IDH2/R140Q develop cardiomyopathy and neurodegeneration. PMID:20171147 demonstrated neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. The exact variant has been directly tested in multiple independent studies with unequivocal functional effect. Details ▾Hide ▴
Evidence considered
- PMID:21889589: IDH2 R140Q enzyme assay in patient lymphoblasts — 8-fold increase in D-2-HG production
- 140-fold increase in intracellular D-2-HG
- PMID:23558173: AGI-6780 selectively inhibits IDH2/R140Q
- reverses differentiation block
- crystal structure of inhibitor-mutant complex
- PMID:24589777: IDH2/R140Q transgenic mice develop cardiomyopathy and neurodegeneration from D-2-HG accumulation
- PMID:20171147: IDH2 mutations including R140Q acquire neomorphic activity producing 2-hydroxyglutarate
- PMID:25398939: Drosophila Idh-R163Q (homologous to human IDH2-R140Q) produces D-2HG and drives phenotypes
Sources
PM1 ModerateThe variant alters arginine 140, a residue located in the active site/substrate-binding pocket of IDH2. This is a well-characterized critical functional domain where multiple pathogenic missense changes cluster (R140Q, R140G, R172K, R172M). Cancerhotspots.org identifies this residue as statistically significant. Functional studies confirm that mutations at R140 confer neomorphic gain-of-function activity. Details ▾Hide ▴
Evidence considered
- Hotspots: residue R140 is in a statistically significant hotspot
- PMID:21889589: R140 is in the enzyme active site
- mutations confer gain-of-function
- ClinVar submissions identify domain/hotspot criteria (PM1)
Sources
PM2 ModerateThe variant is present at extremely low frequency in population databases. gnomAD v2.1 reports 9/282,846 alleles (AF=0.00318%), gnomAD v4.1 reports 71/1,613,752 alleles (AF=0.00440%), with zero homozygotes in both. Highest subpopulation frequency is East Asian at 0.01003% (gnomAD v2.1). All frequencies are well below the 0.1% threshold for PM2 under generic ACMG. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00318% (9/282
- 846 alleles
- 0 homozygotes)
- grpmax FAF=2.293e-05
- gnomAD v4.1: AF=0.00440% (71/1
- 613
- 752 alleles
- grpmax FAF=4.101e-05
Sources
PM5 SupportingA different missense change at the same amino acid residue, IDH2 R140G (c.418C>G, p.Arg140Gly), has been observed in a patient with D-2-hydroxyglutaric aciduria type II (PMID:21889589). Both R140Q and R140G are gain-of-function mutations at codon 140 causing the same disease phenotype. The pathogenic nature of R140G at this residue supports PM5 at supporting level for R140Q. Details ▾Hide ▴
Evidence considered
- PMID:21889589: IDH2 R140G observed in one D-2-HGA type II patient
- same residue
- different missense change with pathogenic effect
Still missing
- R140G not formally classified in ClinVar
- PM5 applied from literature evidence only
Sources
PP3 SupportingMultiple in silico tools predict a deleterious effect. REVEL score is 0.891 (high confidence damaging). BayesDel score is 0.44497. SpliceAI predicts no splicing impact (max delta=0.00), but the missense prediction is strongly damaging. The variant alters a highly conserved arginine residue in the enzyme active site. Details ▾Hide ▴
Evidence considered
- REVEL: 0.891 (damaging)
- BayesDel: 0.44497
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
PP5 SupportingThis variant is classified as Pathogenic in ClinVar (Variation ID 14716), with 7 clinical laboratories reporting Pathogenic and 5 reporting Likely Pathogenic. Under generic ACMG/AMP, a reputable source classification supports PP5 at supporting level. Review status is 1-star (criteria provided, single submitter), not 3-star expert panel, but multiple independent clinical laboratories concur on pathogenicity. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 14716: Pathogenic (7 clinical labs)
- Likely pathogenic (5 clinical labs)
- Review status: criteria provided
- single submitter (1-star)
Sources
Not met · 4 · evaluated, threshold not reached
BA1 The variant allele frequency in gnomAD is approximately 0.004%, far below the 1% threshold for BA1 (stand-alone benign). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00318%
- gnomAD v4.1 AF=0.00440%
- both << 1%
Sources
BS1 The variant allele frequency in gnomAD is approximately 0.004%, below the 0.3% threshold for BS1. Highest subpopulation frequency is 0.01% (East Asian, gnomAD v2.1). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00318%
- gnomAD v4.1 AF=0.00440%
- best subpop EAS=0.01%
- all << 0.3%
Sources
BS3 Well-established functional studies consistently demonstrate a gain-of-function damaging effect — neomorphic production of D-2-hydroxyglutarate from alpha-ketoglutarate (PMID:21889589, PMID:23558173, PMID:20171147). This evidence contradicts BS3 (no damaging effect) and instead supports PS3. Details ▾Hide ▴
Evidence considered
- Functional studies uniformly show gain-of-function damaging effect
- no evidence of benign effect
Sources
BP4 Multiple in silico tools do not support a benign interpretation. REVEL score 0.891 strongly predicts a damaging effect. BayesDel score 0.44497 is also in the damaging range. BP4 requires multiple lines of computational evidence suggesting no impact, which is contradicted by the available predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.891 (damaging
- contradicts BP4)
- BayesDel: 0.44497 (contradicts BP4)
Sources
revelbayesdel
Not assessed · 9 · no assessment recorded
PS4 No formal case-control or statistical enrichment data available to assess variant prevalence in affected versus control populations for PS4 application. Details ▾Hide ▴
Still missing
- Case-control data not available for this variant
PM6 De novo evidence for this variant is captured under PS2. PM6 should not be double-counted with PS2 for the same de novo observation. Details ▾Hide ▴
Evidence considered
- De novo evidence already applied under PS2
PP1 No co-segregation data across families is available for this variant. Details ▾Hide ▴
Still missing
- Segregation data not available
PP2 Insufficient data on benign missense constraint for IDH2 to apply PP2. While missense variants are the established disease mechanism for IDH2, population constraint metrics are needed to assess the rate of benign missense variation. Details ▾Hide ▴
Still missing
- Gene-level missense constraint metrics (e.g.
- gnomAD Z-score
- o/e) not evaluated
PP4 Patient-specific phenotype and family history are not available for assessment. While D-2-hydroxyglutaric aciduria type II is highly specific for IDH2 mutations, the individual patient's phenotype needs to be evaluated. Details ▾Hide ▴
Still missing
- Patient phenotype not available for specificity assessment
BS2 No data available on observation of this variant in healthy adult individuals to evaluate BS2. Details ▾Hide ▴
Still missing
- No data on observation in healthy adults
BS4 No segregation data available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
- Segregation data not available
BP2 No data available on observations of this variant in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
- Observation in trans/cis not available
BP5 No data available on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- Observation in case with alternate molecular basis not available
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002168.3:c.419G>A is a missense variant (p.Arg140Gln). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. apply_generic_pvs1_framework is false per pvs1_variant_assessment. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a predicted null variant.
Sources
PS1 N/ANo different nucleotide change resulting in the same amino acid substitution (p.Arg140Gln) with established pathogenicity has been identified. The only known pathogenic change at this position producing p.Arg140Gln is the variant under assessment itself. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change producing p.Arg140Gln is known.
PM3 N/ANo second pathogenic variant has been reported in trans. IDH2-related D-2-HGA type II is an autosomal dominant (gain-of-function) disorder; biallelic inheritance is not the disease mechanism. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a single-nucleotide substitution, not a deletion or insertion causing a stop codon or frameshift. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AIDH2-related disease (D-2-hydroxyglutaric aciduria type II) is caused by gain-of-function missense mutations (R140Q, R140G), not primarily by truncating variants. BP1 is not applicable for genes where missense variants are the established disease mechanism. Details ▾Hide ▴
Evidence considered
- IDH2 disease mechanism is gain-of-function via missense mutations
- not loss-of-function via truncation
Sources
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame insertion or deletion. Details ▾Hide ▴
No further detail was recorded.
BP6 N/AClinVar classifies this variant as Pathogenic, not Benign. BP6 requires classification as benign by a reputable source. Details ▾Hide ▴
BP7 N/AThis is a missense variant (c.419G>A, p.Arg140Gln), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
PS5 N/ANo evidence that a reputable source has independently classified this variant as pathogenic where the underlying data cannot be shared for independent evaluation. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- IDH2
- Transcript
- NM_002168.3
- Coding (HGVS c.)
- NM_002168.3:c.419G>A
- Protein (HGVS p.)
- NP_002159.2:p.(Arg140Gln)
- GRCh38
- chr15:90088702 C>T
- GRCh37
- chr15:90631934 C>T
- ClinVar
- 14716
- COSMIC
- COSV57468751
Gene diagram
Every interpreted variant in IDH2, mapped onto the exon structure of NM_002168.3. Select a row to find it on the plot.
IDH2NM_002168.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in IDH2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
71 / 1,613,752 alleles
AF 4.4e-05 · 0 homozygotes · FAF 4.1e-05
gnomAD v2.1
9 / 282,846 alleles
AF 3.18e-05 · 0 homozygotes · FAF 2.29e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.4e-05 · 71 / 1,613,752 alleles · 0 hom · FAF 4.1e-05
| European (non-Finnish)61 / 1,179,902 | 5.2e-05 |
| Remaining individuals3 / 62,484 | 4.8e-05 |
| East Asian2 / 44,858 | 4.5e-05 |
| African/African American3 / 74,864 | 4e-05 |
| Ashkenazi Jewish1 / 29,600 | 3.4e-05 |
| European (Finnish)1 / 64,006 | 1.6e-05 |
0 alternate alleles recorded in 4 other groups: Admixed American, Amish, Middle Eastern, South Asian.
gnomAD v2.1
AF 3.2e-05 · 9 / 282,846 alleles · 0 hom · FAF 2.3e-05
| East Asian2 / 19,944 | 0.0001 |
| European (non-Finnish)6 / 129,182 | 4.6e-05 |
| African/African American1 / 24,960 | 4e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.39968e-05; MAF= 0.00440%, 71/1613752 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.16992e-05; MAF= 0.00517%, 61/1179902 alleles, homozygotes = 0); grpmax FAF= 4.101e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18194e-05; MAF= 0.00318%, 9/282846 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100281; MAF= 0.01003%, 2/19944 alleles, homozygotes = 0); grpmax FAF= 2.293e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.891
- BayesDel
- 0.445
How the predictions were used
PP3 SupportingMultiple in silico tools predict a deleterious effect. REVEL score is 0.891 (high confidence damaging). BayesDel score is 0.44497. SpliceAI predicts no splicing impact (max delta=0.00), but the missense prediction is strongly damaging. The variant alters a highly conserved arginine residue in the enzyme active site. Details ▾Hide ▴
Evidence considered
- REVEL: 0.891 (damaging)
- BayesDel: 0.44497
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP4 Multiple in silico tools do not support a benign interpretation. REVEL score 0.891 strongly predicts a damaging effect. BayesDel score 0.44497 is also in the damaging range. BP4 requires multiple lines of computational evidence suggesting no impact, which is contradicted by the available predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.891 (damaging
- contradicts BP4)
- BayesDel: 0.44497 (contradicts BP4)
Sources
revelbayesdel
BP7 N/AThis is a missense variant (c.419G>A, p.Arg140Gln), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.891. BayesDel score = 0.44497.
11 paper records listed. 5 cited in the classification.
Cited in the classification
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PMID 20171147 ↗The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.Ward PS et al. · 2010 Mar 16Demonstrated that leukemia-associated IDH2 mutations at R140 produce a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. IDH2 R140Q was among the mutants characterized, showing gain-of-function 2HG production.→ PS3 Names this variant
Source detail
The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
Location Introduction; Results
Context In vitro enzyme assays with recombinant IDH2 mutants; 2HG quantification by LC-MS/MS
-
PMID 21889589 ↗A lymphoblast model for IDH2 gain-of-function activity in d-2-hydroxyglutaric aciduria type II: novel avenues for biochemical and therapeutic studies.Kranendijk M et al. · 2011 NovDeveloped an enzyme assay for IDH2 R140Q in lymphoblasts from D-2-hydroxyglutaric aciduria type II patients. The exact variant (IDH2 c.419G>A, p.Arg140Gln) was studied in five patient cell lines. Demonstrated 8-fold increase in D-2-HG production and 140-fold increase in intracellular D-2-HG. Confirmed that D-2-HGA type II is caused by heterozygous de novo IDH2 R140Q mutations. Also reported one patient with IDH2 R140G (different amino acid change at same codon).→ PS2 → PS3 → PM1 → PM5 Names this variant
Source detail
Five cell lines were obtained from D-2-HGA type II patients which all carried the heterozygous IDH2 c.[419 G>A], p.[Arg140Gln] (IDH2wt/R140Q) mutation
Location Abstract; Introduction (para 1-2); Materials and Methods (Section 2.1)
Context Patient-derived lymphoblast cell lines; stable-isotope-labeled 2-KG substrate; UPLC-MS/MS detection with chiral separation
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PMID 23558173 ↗Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.Wang F et al. · 2013 May 3Developed AGI-6780, a small molecule that potently and selectively inhibits mutant IDH2/R140Q. Crystal structure of the inhibitor-mutant complex revealed allosteric binding at the dimer interface. Treatment with AGI-6780 reversed the differentiation block in TF-1 erythroleukemia cells expressing IDH2/R140Q and induced differentiation of primary human AML blasts harboring the mutation.→ PS3 Names this variant
Source detail
We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q.
Location Abstract; Results (Figs 1-3); Table 1
Context Recombinant IDH2/R140Q enzyme assay; TF-1 erythroleukemia cells; primary human AML patient samples; X-ray crystallography; flow cytometry for differentiation markers
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PMID 24589777 ↗D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.Akbay EA et al. · 2014 Mar 1Generated transgenic mice with conditional IDH2/R140Q expression. Demonstrated that IDH2/R140Q produces D-2-hydroxyglutarate, which accumulates and causes cardiomyopathy and neurodegeneration in mice. Establishes that R140Q is the mutation responsible for the neomorphic activity in D-2-hydroxyglutaric aciduria type II.→ PS3 Names this variant
Source detail
A missense mutation at codon 140 of IDH2 (R140Q) is responsible for causing the neomorphic activity of reducing alpha-KG to D2-hydroxyglutaric acid (D-2HG)
Location Introduction; Results
Context Transgenic mouse model; conditional IDH2/R140Q expression; D-2HG quantification; cardiac and neurological phenotyping
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PMID 25398939 ↗Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila.Reitman ZJ et al. · 2015 Jan 8Expressed Idh-R163Q, the Drosophila homolog of human IDH2-R140Q, in transgenic flies. Idh-R163Q produced moderately elevated D-2HG (~10-fold) and milder phenotypes compared to the R195H mutant (homologous to IDH1-R132H). Demonstrated that D-2-HG production is essential for mutant phenotypes and that co-expression of D2HGDH rescues them.→ PS3 Names this variant
Source detail
Idh-R163Q, which is homologous to the common leukemia-associated IDH2-R140Q mutant, resulted in moderately elevated D-2HG and milder phenotypes.
Location Abstract; Results; Figure 2
Context Drosophila melanogaster transgenic model; UAS-Gal4 expression system; LC-MS/MS D-2HG quantification; hemocyte and neuronal phenotyping
Other recorded publications
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PMID 21647154 ↗IDH1 and IDH2 mutations in pediatric acute leukemia.Andersson AK et al. · 2011Investigated IDH1 and IDH2 mutations in pediatric acute leukemia. IDH2 R140 mutations were detected in 5 of 227 pediatric AML cases. The variant (R140Q) was confirmed as somatic in the leukemia context.Names this variant
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PMID 23949315 ↗Rapid detection of IDH2 (R140Q and R172K) mutations in acute myeloid leukemia.Ashraf S et al. · 2013Developed an allele-specific PCR assay for detecting IDH2 R140Q and R172K mutations in AML. Among 120 AML patients, 17 harbored IDH2 R140Q. The nucleotide substitution was confirmed as CGG→CAG (c.419G>A) by Sanger sequencing. This is a diagnostic methodology paper confirming the variant in a somatic cancer context.Names this variant
Quoted passage
All mutated patients of IDH2 140 revealed the substitution CGG→CAG
Abstract; Results and discussion; Table 2
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Position statement on the continued importance of targeted approaches in newborn screening programmes alongside whole-genome sequencing. Discusses newborn screening policy and does not mention IDH2 or the variant NM_002168.3:c.419G>A.Does not name this variant
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PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.No paper-specific finding is recorded.
-
PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.No paper-specific finding is recorded.
-
PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
71 / 1,613,752 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
7 Pathogenic · 5 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/14716/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-90631934-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-90088702-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/15-90088702-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002168.3%3Ac.419G…
- OncoKB ↗www.oncokb.org/gene/IDH2/R140Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=131225201
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.39968e-05; MAF= 0.00440%, 71/1613752 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.16992e-05; MAF= 0.00517%, 61/1179902 alleles, homozygotes = 0); grpmax FAF= 4.101e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18194e-05; MAF= 0.00318%, 9/282846 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100281; MAF= 0.01003%, 2/19944 alleles, homozygotes = 0); grpmax FAF= 2.293e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (5 clinical laboratories). (ClinVarID = 14716)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.891. BayesDel score = 0.44497.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57468751, n = 1037 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.