Variant classification summary

NM_005896.3:c.395G>T

IDH1 · NP_005887.2:p.(Arg132Leu) · NM_005896.3

GRCh37: chr2:209113112 C>A · GRCh38: chr2:208248388 C>A

Gene: IDH1 Transcript: NM_005896.3

Final call

Pathogenic

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

Variant details

Gene

IDH1

Transcript

NM_005896.3

Protein

NP_005887.2:p.(Arg132Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (strong): Recombinant R132L protein directly tested in purified enzyme assay demonstrated gain-of-function neomorphic activity, catalyzing NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (PMID:19935646). Independently, a glioma sample harboring IDH1 R132L showed markedly elevated (R)-2HG levels on direct tissue analysis (PMID:21326614).

2

PM1 (moderate): The variant affects codon Arg132, the critical active-site residue and a statistically significant mutational hotspot. All cancer-associated IDH1 mutations cluster at this single residue, defining it as a well-characterized functional domain.

3

PM2 (supporting): This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant.

4

PM5 (moderate): Multiple different missense variants at the same residue (R132H, R132C, R132S, R132G) are well-established as pathogenic in glioma and AML (PMID:19246647).

5

PP3 (supporting): REVEL score of 0.835 is in the high-confidence deleterious range, supporting a pathogenic effect.

6

PP5 (supporting): ClinVar reports this variant as Pathogenic (Variation ID 375889; criteria provided, single submitter).

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_005896.3:c.395G>T (p.Arg132Leu) is a missense substitution. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 decision framework (PMC6185798) does not apply to this variant class.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified that the same amino acid change (p.Arg132Leu) has been previously established as pathogenic through a different nucleotide change. The c.395G>T substitution is the only coding change producing p.Arg132Leu from the Arg132 codon (CGT→CTT).
PS2	Not met	No de novo data were identified for this variant. No confirmed de novo observation (with maternity and paternity confirmed) is available in the case evidence.
PS3	Met	R132L recombinant protein was directly tested and demonstrated gain-of-function neomorphic enzymatic activity, catalyzing NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (PMID:19935646). Independently, an IDH1 R132L glioma tumor sample was directly analyzed and showed markedly elevated (R)-2HG levels (>500-fold above wild-type; PMID:21326614). A third study confirmed that R132L mutant enzyme is biochemically targetable by the mutant-specific inhibitor AG-120 (ivosidenib) with IC50 of 13 nM (PMID:29670690). These represent at least two independent publications with variant-specific experimental functional data.	PMID:19935646 PMID:21326614 PMID:29670690
PS4	Not met	No germline case-control data demonstrating statistically significant enrichment of this variant in affected individuals versus controls was identified. The variant is well-documented in somatic cancers (COSMIC n=159), but somatic prevalence does not satisfy germline PS4 criteria. No publication provided variant-specific germline case counts with appropriate controls.
PS5	N/A	Skipped per adjudication directive. PS5 is trivially not applicable for this variant assessment.
PM1	Met	The variant affects codon Arg132, the critical active-site residue of IDH1 and a statistically significant mutational hotspot (cancerhotspots.org). This residue is located in the enzyme's catalytic domain where it forms hydrogen bonds with the α- and β-carboxyl groups of isocitrate. All cancer-associated IDH1 mutations cluster at this single residue, defining it as a well-characterized functional domain where missense variation is established as pathogenic.	PMID:19935646 PMID:19246647 PMID:21326614
PM2	Met	This variant is absent from all population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). The allele frequency of 0.0% is well below the PM2 threshold of <0.1% for a dominant disorder gene with no VCEP/CSPEC override.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Met	Multiple different missense variants at the same residue (Arg132) have been established as pathogenic. Arg132His (R132H), Arg132Cys (R132C), Arg132Ser (R132S), and Arg132Gly (R132G) are well-documented pathogenic substitutions in glioma and AML (PMID:19246647). R132H alone accounts for ~91% of IDH1 mutations in glioma. The presence of multiple pathogenic missense variants at this same codon supports PM5 at moderate strength.	PMID:19246647 PMID:21326614
PM6	Not met	No de novo data were identified for this variant. No confirmed de novo observation (with maternity and paternity confirmed) is available in the case evidence.
PP1	Not met	No co-segregation data were identified for this variant. No family studies demonstrating segregation with disease are available in the evidence.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. For IDH1, the disease mechanism is a highly specific gain-of-function restricted to codon R132 (and rarely R100). The gene does not harbor pathogenic missense variants broadly distributed across its coding sequence; benign missense variation at non-hotspot positions does not clearly satisfy the PP2 criterion. The ultra-restricted mutational spectrum of IDH1 distinguishes it from typical PP2-eligible genes.
PP3	Met	Multiple in silico predictors support a deleterious effect. REVEL score is 0.835 (deleterious; above the 0.75 threshold). BayesDel score is 0.402 (intermediate). SpliceAI predicts no significant splice impact (max delta score 0.10), consistent with the missense mechanism rather than splicing disruption. The REVEL score in the high-confidence deleterious range supports PP3 at supporting level.	revel bayesdel spliceai
PP4	Not met	No phenotype or clinical data for the proband were available in the case evidence. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be assessed without clinical information.
PP5	Met	This variant has been reported in ClinVar as Pathogenic by CeGaT Center for Human Genetics Tuebingen (criteria provided, single submitter; ClinVar Variation ID: 375889). While the submission is from a clinical testing laboratory with criteria provided, the review status is 'single submitter' without expert panel review, limiting the weight to supporting level.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data were available demonstrating observation of this variant in healthy adults. The variant is absent from all population databases, and no control cohort data were provided.
BS3	Not met	Well-established functional studies demonstrate a deleterious gain-of-function effect, not a benign effect. Recombinant R132L protein catalyzes NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (PMID:19935646). Tumor tissue with R132L shows markedly elevated (R)-2HG (PMID:21326614). These findings support pathogenicity, not benign impact.	PMID:19935646 PMID:21326614
BS4	Not met	No segregation data were available. BS4 requires lack of segregation with disease in affected family members, which cannot be assessed without family study data.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. IDH1-associated cancers are driven by gain-of-function missense mutations at codon R132, not by loss-of-function truncating variants. Truncating variants in IDH1 would not be expected to produce the neomorphic 2-HG-producing activity. BP1 is not applicable when the disease mechanism is gain-of-function via missense rather than loss-of-function via truncation.
BP2	Not met	No evidence was available demonstrating that this variant has been observed in trans with a pathogenic variant. No phase data or co-occurrence data were provided.
BP4	Not met	Multiple in silico predictors support a deleterious effect, not a benign effect. REVEL score is 0.835 (deleterious), which contradicts BP4. BP4 requires multiple lines of computational evidence suggesting no impact, which is not the case here.	revel bayesdel
BP5	Not met	No evidence was identified that this variant has been found in a case with an alternate molecular basis for disease. No co-occurring pathogenic variant data were provided.
BP6	Not met	ClinVar reports this variant as Pathogenic, not benign. BP6 requires a reputable source to classify the variant as benign, which is not the case here.	clinvar
BP7	N/A	This is a missense variant (c.395G>T, p.Arg132Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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