NM_005896.3:c.394C>T

IDH1 · NP_005887.2:p.(Arg132Cys) · NM_005896.3

GRCh37: chr2:209113113 G>A · GRCh38: chr2:208248389 G>A

Gene: IDH1 Transcript: NM_005896.3

Final call

Pathogenic

PS3 strong PM1 moderate PM2 moderate PM5 moderate PP3 supporting

Variant details

Gene

IDH1

Transcript

NM_005896.3

Protein

NP_005887.2:p.(Arg132Cys)

gnomAD AF

6.199143774261899e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

IDH1 c.394C>T (p.Arg132Cys) is a missense variant at the critical active-site residue R132, the most recurrently mutated amino acid in IDH1 across all cancer types.

Functional studies directly testing R132C demonstrate a neomorphic gain-of-function: the variant enzyme produces the oncometabolite 2-hydroxyglutarate and promotes leukemogenesis in a mouse transplantation model, with median survival shortened from 167 to 83 days (p<0.001).

R132C is effectively targeted by the FDA-approved mutant IDH1 inhibitor ivosidenib (AG-120) with nanomolar potency (IC50 13 nM enzyme, 8 nM cellular), and ivosidenib induces differentiation of primary R132C AML blasts ex vivo.

Multiple different missense changes at the same residue (R132H, R132S, R132G, R132L) are established as pathogenic and share the same gain-of-function mechanism, satisfying PM5.

The variant is essentially absent from population databases (gnomAD v2.1: 0/251,292 alleles; gnomAD v4.1: 1/1,613,126 alleles, AF=0.00006%), meeting PM2 for rarity in controls.

In silico predictors support a deleterious effect (REVEL 0.814) and possible splice alteration (SpliceAI max delta 0.51), contributing supporting evidence (PP3).

The variant has been reported in ClinVar as Pathogenic by multiple clinical laboratories and is recorded in COSMIC with 1,377 somatic observations.

Applying generic ACMG/AMP 2015 combination rules: PS3 (strong) + PM1 (moderate) + PM2 (moderate) + PM5 (moderate) + PP3 (supporting) → Pathogenic (class 5).

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	Missense substitution; does not meet generic PVS1 null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice variants) per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	No different nucleotide change at c.394 producing the same amino acid substitution (p.Arg132Cys) has been identified and established as pathogenic. PS1 requires a known pathogenic variant at the same position producing the identical amino acid change via a different nucleotide substitution.
PS2	Not met	No de novo germline occurrence reported in the available literature. The variant is predominantly observed in somatic contexts (COSMIC n=1377) and as somatic mosaic in Ollier disease/Maffucci syndrome; no confirmed germline de novo report identified.
PS3	Met	Functional studies demonstrate that the IDH1 R132C variant confers a neomorphic gain-of-function activity, producing the oncometabolite 2-hydroxyglutarate (2-HG). PMID:23954893 directly tested R132C in a mouse bone marrow transplantation model, showing accelerated leukemogenesis with shortened survival (median 83 vs 167 days, p<0.001). PMID:19935646 established the mechanism that R132 mutations (including R132H) produce 2-HG. PMID:29670690 confirmed R132C as a target of the FDA-approved inhibitor ivosidenib (AG-120) with nanomolar IC50 (enzyme 13 nM, cellular 8 nM), providing orthogonal pharmacologic validation of the variant's functional significance.	PMID:23954893 PMID:19935646 PMID:29670690 oncokb
PS4	Not met	No case-control prevalence data available in a germline context. The variant has been extensively reported in somatic malignancies (COSMIC n=1377) but these represent somatic rather than germline observations. The ClinVar submissions classified as germline (n=3) lack controlled prevalence comparisons.	clinvar
PS5	Not met	Not a standard ACMG/AMP 2015 criterion. In framework extensions where PS5 represents a well-established functional domain or multiple unrelated patients, this overlaps with PM1 (hotspot domain) and PS3 (functional data), both of which are scored independently. No independent evidence unique to PS5 is available beyond what has been captured under PM1 and PS3.
PM1	Met	Residue R132 lies within the active site of IDH1 (residues 104-136), a well-established critical functional domain. R132 is the single most recurrently mutated amino acid in IDH1 across all cancer types and is flagged as a statistically significant hotspot by cancerhotspots.org. PMID:19935646 demonstrates that mutations at R132 abrogate normal isocitrate-to-αKG conversion and confer neomorphic 2-HG production.	PMID:19935646 oncokb
PM2	Met	Absent from gnomAD v2.1 (0/251,292 alleles, AF=0.00%) and nearly absent from gnomAD v4.1 (1/1,613,126 alleles, AF=0.00006%). Both are well below the 0.1% PM2 threshold for a rare variant absent from population controls.	gnomad_v2 gnomad_v4
PM5	Met	Multiple different missense changes at the same amino acid residue R132 are established as pathogenic: R132H (c.395G>A, the most common IDH1 mutation in gliomas and AML), R132S (c.394C>A), R132G (c.394C>G), and R132L (c.395G>T). All R132 mutations share the same gain-of-function mechanism producing 2-HG (PMID:19935646). The current variant R132C (c.394C>T) occurs at the same critical residue, satisfying PM5.	PMID:19935646 PMID:29670690
PM6	Not met	No confirmed de novo germline observation reported in the available literature. The variant is predominantly observed in somatic/postzygotic contexts.
PP1	Not met	No co-segregation data available. The variant is predominantly somatic with no family studies reported.
PP2	N/A	PP2 applies to genes where missense variants are a common mechanism of disease and the gene has a low rate of benign missense variation. IDH1 disease is driven by specific gain-of-function mutations at critical active-site residues, not by random missense constraint across the gene. PP2 is not appropriate for a gene with a highly restricted mutational spectrum.
PP3	Met	Multiple in silico tools predict a deleterious effect. REVEL score of 0.814 exceeds the 0.5 threshold for a damaging prediction. SpliceAI max delta score of 0.51 suggests possible splice-altering potential. BayesDel score of 0.415 is borderline but the consensus of in silico predictors supports a pathogenic interpretation.	revel spliceai bayesdel
PP4	Not met	No patient-specific phenotype or family history information available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification is Pathogenic, but the aggregate review status is 'criteria provided, single submitter' (1-star). Per ACMG/AMP guidance, PP5 requires at least a 2-star review status (multiple submitters, no conflicts). The user's global PP5 rule specifies 3-star expert panel review is required for supporting-strength application. This variant has 12 submissions but no expert panel review; the review status does not meet the threshold.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1 (0/251,292) and nearly absent from v4.1 (1/1,613,126, AF=0.00006%). Far below the 1% BA1 threshold for a common benign variant.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD v2.1 (0/251,292) and nearly absent from v4.1 (1/1,613,126, AF=0.00006%). Far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence of homozygous occurrence in healthy adults or observation in trans with a pathogenic variant. The single allele observed in gnomAD v4.1 is heterozygous and does not support a benign interpretation.	gnomad_v4
BS3	Not met	All available functional evidence demonstrates a pathogenic gain-of-function effect (2-HG production, leukemogenesis promotion, drug sensitivity). No evidence supports a benign or neutral functional effect. See PS3 for detailed functional data.	PMID:23954893 PMID:19935646 PMID:29670690
BS4	Not met	No evidence of non-segregation with disease in family studies. No family data available in the case materials or literature.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease through a loss-of-function mechanism. IDH1 disease is driven by gain-of-function missense mutations at specific active-site residues, not by loss-of-function. Truncating IDH1 variants are not the primary disease mechanism.	pvs1_gene_context
BP2	Not met	No evidence of observation in trans with a known pathogenic dominant variant. No co-occurrence data available.
BP4	Not met	Multiple in silico predictors support a damaging effect. REVEL score 0.814 (damaging), SpliceAI max delta 0.51 (possible splice impact). In silico evidence does not support a benign classification; it supports pathogenicity (see PP3).	revel spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease. No such data available in the case materials.
BP6	Not met	ClinVar classification is Pathogenic, not benign. The review status is 'criteria provided, single submitter' (1-star), which does not meet the threshold for BP6 even if the classification were benign.	clinvar
BP7	Not met	BP7 applies to synonymous variants not predicted to affect splicing. NM_005896.3:c.394C>T is a missense variant (p.Arg132Cys), not a synonymous change. BP7 does not apply.

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