The IDH1 NM_005896.4:c.394C>G (NP_005887.2:p.(Arg132Gly)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61615456, n = 278 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Endogenous monoallelic IDH1 R132G cells produced measurable 2HG, and IDH1 knockdown reduced accumulation, supporting altered pathogenic enzyme activity. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.IDH1 encodes a cytoplasmic and peroxisomal enzyme that converts isocitrate to alpha-ketoglutarate and helps produce NADPH, supporting cellular metabolism and antioxidant processes. Altered IDH1 activity is associated with several cancers, including glioma, cholangiocarcinoma, and acute myeloid leukemia. In cancer, abnormal IDH1 activity can produce D-2-hydroxyglutarate, which disrupts cellular enzymes that regulate DNA and histone modification and can promote tumor development.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at moderate strength: endogenous monoallelic IDH1 R132G cells produced measurable 2HG, and IDH1 knockdown reduced accumulation, supporting altered pathogenic enzyme activity.
Met: IDH1 R132 is an active-site residue and statistically significant hotspot, with 0/1,613,198 gnomAD v4.1 alleles observed.
Met at supporting strength: the variant is absent, 0/1,613,198 alleles, below the PM2 supporting threshold of <=0.0001.
Met at moderate strength: missense REVEL score 0.893 exceeds the PP3 threshold of 0.773.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 moderate, PM1 moderate, PP3 moderate, and PM2 supporting satisfy the generic ACMG/AMP fallback rule for three moderate criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 0 / 1,613,198 alleles. Recorded AF 0. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.893. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61615456, n = 278 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 15 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Functional evidence supports PS3 at moderate strength because an endogenous IDH1 R132G cellular model showed IDH1-dependent 2-hydroxyglutarate accumulation, while no benign functional result supports BS3.
No VCEP covers IDH1 in this case; generic ACMG/AMP 2015 rules govern.
PS4 and BP5 remain not assessed because the supplied evidence lacks the exact case-level comparisons required by their definitions.
PP4 remains not assessed because case-level phenotype and family-history specificity are unavailable.
PP5 and BP6 are not met because the exact ClinVar record is a single-submitter somatic record without the required expert-panel Pathogenic/Likely pathogenic or Benign/Likely benign classification.
The variant is missense, so PP3 and BP4 are adjudicated exclusively through REVEL under the supplied generic rule.
REVEL 0.893 meets the calibrated PP3 moderate threshold and does not meet any BP4 threshold.
No criteria match.
PS3 is met at moderate strength. PMID:23264629 directly studied endogenous monoallelic IDH1 R132G in JJ012 chondrosarcoma cells, confirmed the mutation by Sequenom assay, measured cellular 2-hydroxyglutarate by GC-MS, and showed that knockdown of IDH1 impaired 2-hydroxyglutarate accumulation. This is a biologically relevant cellular assay with an endogenous variant context and perturbation controls, supporting an abnormal IDH1 function associated with the R132G allele. PMID:19935646 additionally reports that R132G shares the common ability of R132 substitutions to catalyze NADPH-dependent conversion of alpha-ketoglutarate to 2-hydroxyglutarate, but its detailed experiments did not provide variant-specific R132G measurements. Moderate rather than strong strength is used because the direct R132G evidence is from a single research study and was not shown here to be validated, reproducible, and robust in a clinical diagnostic laboratory setting.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The variant p.Arg132Gly lies at IDH1 residue R132. PMID:19935646 identifies R132 as an IDH1 active-site residue and reports that R132 substitutions share a common altered catalytic activity. PMID:29670690 likewise describes R132 as a key residue within the active site. The Cancer Hotspots result identifies IDH1 R132 as a statistically significant hotspot. The variant is absent from gnomAD v2.1 (0/251,292 alleles) and gnomAD v4.1 (0/1,613,198 alleles), providing the available population evidence against benign variation at this site. These findings satisfy the generic PM1 hotspot/critical-functional-site requirement, although the hotspot extraction is flagged for manual verification.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is met at supporting strength. The variant is absent from the available gnomAD control datasets: 0/251,292 alleles in gnomAD v2.1 exomes and 0/1,613,198 total alleles in gnomAD v4.1, with zero homozygotes in both. The generic ClinGen SVI threshold supplied for PM2 supporting is <= 0.0001, and the observed allele frequency of 0 is below that threshold. No governing VCEP specified a non-cancer or exome-only subset, so the all-comers gnomAD totals were the applicable default; no non-cancer subset was present in the case evidence.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868) ... Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
NM_005896.4:c.394C>G is a missense variant, p.(Arg132Gly), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.893, meeting the supplied ClinGen SVI moderate PP3 threshold of >= 0.773 (Pejaver et al. 2022, PMID:36413997). Therefore PP3 is met at moderate strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
PP5 is not met. The exact variant ClinVar record is classified as somatic Oncogenic/Tier I - Strong with review status criteria provided, single submitter; it has no expert-panel classification and is not an exact-variant Pathogenic or Likely pathogenic expert-panel assertion. The available literature is independently inspectable, so the PP5 condition that evidence is unavailable for independent evaluation is also not satisfied.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The variant has observed allele frequency 0/251,292 in gnomAD v2.1 exomes and 0/1,613,198 total alleles in gnomAD v4.1; no population has an elevated filtering allele frequency, and both observed frequencies are below the generic BA1 threshold of >= 0.05. The reported grpmax FAF is null in both datasets, so no popmax point estimate was used.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868) ... Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met on the available population data. The variant was observed at 0/251,292 alleles in gnomAD v2.1 exomes and 0/1,613,198 alleles in gnomAD v4.1, with no elevated filtering allele frequency; therefore the allele frequency is not greater than expected for the disorder and does not reach the generic >= 0.01 default. A disorder-specific maximum-credible-frequency calculation is unnecessary because the observed frequency is zero; disease prevalence, penetrance, and allelic heterogeneity were not available for an independent calculation.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168) ... Allele frequency is greater than expected for the disorder.
NM_005896.4:c.394C>G is a missense variant, so the governing generic rule selects the REVEL path only; its SpliceAI result cannot substitute for an indeterminate or non-supportive REVEL result. REVEL is 0.893, which is above the supplied BP4 supporting threshold of <= 0.29 (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only.
BP6 is not met. The exact variant ClinVar record has no expert-panel Benign or Likely benign classification; it is a single-submitter somatic Oncogenic/Tier I - Strong record. No exact-variant reputable benign assertion satisfying the required source type is available.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_005887.2:p.(Arg132Gly). PMID:23264629 documents a naturally occurring IDH1 R132G mutation, and PMID:19935646 includes R132G among cancer-associated substitutions, but the supplied evidence does not establish that a previously observed R132G variant was an ACMG/AMP pathogenic variant. The ClinVar record is somatic and classified as Tier I - Strong rather than a germline pathogenic assertion. Therefore the same-amino-acid pathogenic comparator required for PS1 is not established.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No germline proband-parent testing, confirmed maternity and paternity, disease phenotype documentation, or family-history assessment is provided. The available records concern the somatic IDH1 p.Arg132Gly variant in cancer contexts and do not establish a de novo occurrence in a patient with the disease.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing PS4 rule requires a significant prevalence increase in affected individuals compared with controls; the supplied threshold guidance specifies OR or RR >5.0 with a confidence interval that does not include 1.0. The literature packet contains no qualifying case-control study for exact IDH1 c.394C>G (p.Arg132Gly). PMID:29860938 reports grouped R132G/L/S frequencies, not R132G alone, and provides no unaffected or population-control comparison; therefore an exact-variant OR and 95% CI cannot be validly computed. PMID:23264629 reports an R132G cell line, not a case-control cohort. gnomAD v2.1 and v4.1 report 0 alternate alleles, but no exact-variant affected-case count or matched-ancestry case frequency is available. The required comparison is therefore unavailable rather than negative.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed from the available case evidence. No affected-proband observation, second pathogenic variant, parental testing, or phase result establishes that NM_005896.4:c.394C>G is in trans with a pathogenic variant. The case materials also do not establish a recessive IDH1 disorder context or inheritance mode. Therefore, the required allelic relationship is unresolved rather than met or not met.
PM3: For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
PMID:19935646 reports other substitutions at R132, including histidine, serine, cysteine, and leucine, but the supplied paper extraction does not establish any of those alternate missense variants as pathogenic variants under ACMG/AMP. The Cancer Hotspots, COSMIC, OncoKB, and somatic ClinVar evidence concerns cancer occurrence or oncogenicity and cannot by itself establish the required pathogenic comparator. A qualifying different pathogenic missense variant at residue 132 is therefore not established.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No germline patient observation with evidence of assumed de novo status is provided. In particular, the available records do not document an affected proband, parental testing, or the absence of confirmed maternity and paternity needed to distinguish PM6 from PS2.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, genotype results, phenotype assessments, or segregation pattern are documented. Therefore, co-segregation cannot be evaluated, and no stronger PP1 level can be assigned.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The supplied evidence does not provide a gene-level assessment showing that IDH1 has a low rate of benign missense variation, nor does it establish a germline disease context in which missense variants are a common mechanism of disease. The available evidence is primarily somatic oncology evidence and cannot supply both PP2 conditions.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
No patient phenotype, family history, or disease-specific clinical presentation is supplied for this case. The available records describe somatic IDH1 R132G in a chondrosarcoma cell line and grouped IDH1 R132G/L/S in an AML treatment cohort, but do not establish that this patient's phenotype is highly specific for a disease with a single genetic etiology. PP4 cannot be assessed without case-level phenotype and diagnostic context.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. The available gnomAD records show zero variant alleles and zero homozygotes, but population absence cannot establish that this variant was observed in a healthy adult individual. No qualifying healthy-adult heterozygote, homozygote, or hemizygote observation, inheritance model, or evidence that full penetrance is expected at an early age was provided.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No reviewed functional study demonstrates that IDH1 R132G has no damaging effect on protein function or splicing. The available direct R132G study instead reports cellular 2-hydroxyglutarate production and its dependence on IDH1 activity, while the other reviewed studies do not provide a benign functional result for this variant. Therefore BS3 cannot be assessed from the available evidence.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members carrying or lacking the variant are documented, so lack of segregation cannot be demonstrated. The available somatic cancer and cell-line records do not provide a familial phenotype-genotype comparison and cannot support BS4.
Lack of segregation in affected members of a family.
The supplied case materials do not establish that IDH1-related disease is caused primarily by truncating variants. The gene-level loss-of-function context is explicitly unresolved, and the available literature and database records concern somatic IDH1 missense mutations rather than a disease series demonstrating a predominantly truncating mechanism.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed from the available case evidence. No documented pathogenic variant is shown in trans with NM_005896.4:c.394C>G in a fully penetrant dominant disorder, and no documented pathogenic variant is shown in cis with it in any inheritance pattern. The available cancer and database records do not provide the required germline phase or affected-proband evidence.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No case report or clinical record establishes that this variant was found in a patient with an alternate molecular basis for disease. PMID:23264629 concerns a cell line with endogenous R132G, and PMID:29860938 reports grouped R132G/L/S in an AML cohort without documenting an alternate molecular diagnosis for an individual carrying exact R132G. The BP5 evidence requirement is therefore unresolved.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005896.4:c.394C>G in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Gly). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005896.4:c.394C>G in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Gly). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005896.4:c.394C>G in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Gly). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005896.4:c.394C>G in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in IDH1, mapped onto the exon structure of NM_005896.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613198 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74792 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
NM_005896.4:c.394C>G is a missense variant, p.(Arg132Gly), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.893, meeting the supplied ClinGen SVI moderate PP3 threshold of >= 0.773 (Pejaver et al. 2022, PMID:36413997). Therefore PP3 is met at moderate strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only.
NM_005896.4:c.394C>G is a missense variant, so the governing generic rule selects the REVEL path only; its SpliceAI result cannot substitute for an indeterminate or non-supportive REVEL result. REVEL is 0.893, which is above the supplied BP4 supporting threshold of <= 0.29 (Pejaver et al. 2022, PMID:36413997), so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005896.4:c.394C>G in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts possible splice impact for this variant (max delta score = 0.30). REVEL score = 0.893. BayesDel score = 0.412827.
4 paper records listed. 3 cited in the classification.
These data also demonstrate that mutation of R132 to histidine, serine, cysteine, glycine, or leucine share a common ability to catalyze the NADPH-dependent conversion of αKG to 2HG.
Location Discussion, final paragraph
Context Discussion of recombinant IDH1 mutant enzyme studies; detailed assays were reported for R132H, R132C, R132L, and R132S, while R132G was included in the general summary of R132 substitutions.
JJ012 cells have a monoallelic endogenous IDH1 R132G mutation that has previously been reported (26), which we confirmed by Sequenom assay.
Location Experimental Procedures, Cell Culture and Reagents; Results, “Impairing Mitochondrial IDH Flux Increases 2HG Production from Mutant IDH1 in the Cytosol,” including Fig. 4
Context Endogenous monoallelic IDH1 R132G in JJ012 chondrosarcoma cells; siRNA knockdown experiments with cellular 2-hydroxyglutarate quantified by GC-MS.
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite.
Location Abstract
Context Biochemical enzyme inhibition assays and cellular profiling of IDH1-R132 mutant models, including R132H and related R132 mutants.
R132G/L/S Dose-escalation phase 4/33 (12) 5/35 (14) 12/78 (15) Dose-expansion phase 15/92 (16) 24/144 (17) 27/180 (15)
Table 1 (continued), baseline characteristics, “Mutated IDH allele”
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613198 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74792 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 3764951)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.30). REVEL score = 0.893. BayesDel score = 0.412827.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61615456, n = 278 times).
This variant lies in a statistically significant hotspot.