Variant classification summary

NM_002168.3:c.419G>A

IDH2 · NP_002159.2:p.(Arg140Gln) · NM_002168.3

GRCh37: chr15:90631934 C>T · GRCh38: chr15:90088702 C>T

Gene: IDH2 Transcript: NM_002168.3

Final call

Pathogenic

PS2 moderate PS3 strong PM1 moderate PM2 moderate PM5 supporting PP3 supporting PP5 supporting

Variant details

Gene

IDH2

Transcript

NM_002168.3

Protein

NP_002159.2:p.(Arg140Gln)

gnomAD AF

4.3996847099182524e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

6

In silico predictions strongly support a deleterious effect (REVEL 0.891), consistent with the known gain-of-function mechanism.

7

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework
PS1	N/A	No 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.
PS2	Met	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).	clinvar PMID:21889589
PS3	Met	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.	PMID:21889589 PMID:23558173 PMID:24589777 PMID:20171147 PMID:25398939
PS4	Not assessed	No formal case-control or statistical enrichment data available to assess variant prevalence in affected versus control populations for PS4 application.
PS5	N/A	No evidence that a reputable source has independently classified this variant as pathogenic where the underlying data cannot be shared for independent evaluation.
PM1	Met	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.	PMID:21889589 PMID:20171147 clinvar
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Met	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.	PMID:21889589
PM6	Not assessed	De novo evidence for this variant is captured under PS2. PM6 should not be double-counted with PS2 for the same de novo observation.
PP1	Not assessed	No co-segregation data across families is available for this variant.
PP2	Not assessed	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.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Met	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.	clinvar
BA1	Not met	The variant allele frequency in gnomAD is approximately 0.004%, far below the 1% threshold for BA1 (stand-alone benign).	gnomad_v2 gnomad_v4
BS1	Not met	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).	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available on observation of this variant in healthy adult individuals to evaluate BS2.
BS3	Not met	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.	PMID:21889589 PMID:23558173 PMID:20171147
BS4	Not assessed	No segregation data available to evaluate lack of segregation with disease.
BP1	N/A	IDH2-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.	PMID:21889589
BP2	Not assessed	No data available on observations of this variant in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4	Not met	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.	revel bayesdel
BP5	Not assessed	No data available on observation of this variant in a case with an alternate molecular basis for disease.
BP6	N/A	ClinVar classifies this variant as Pathogenic, not Benign. BP6 requires classification as benign by a reputable source.	clinvar
BP7	N/A	This is a missense variant (c.419G>A, p.Arg140Gln), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splice impact.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame insertion or deletion.
PM3	N/A	No 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.
PM4	N/A	Variant is a single-nucleotide substitution, not a deletion or insertion causing a stop codon or frameshift.

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