The IDH1 NM_005896.4:c.394C>A (NP_005887.2:p.(Arg132Ser)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61615649, n = 217 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Recombinant IDH1 R132S showed gain-of-function NADPH-dependent alpha-ketoglutarate reduction to 2-hydroxyglutarate in a variant-specific enzyme assay. 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 supporting: recombinant IDH1 R132S showed gain-of-function NADPH-dependent alpha-ketoglutarate reduction to 2-hydroxyglutarate in a variant-specific enzyme assay.
Met: Arg132 is an IDH1 active-site hotspot, and the variant lies in a statistically significant hotspot with gnomAD allele count 0.
Met at supporting strength: gnomAD v4.1 observed 0/1,613,196 alleles (AF 0), below the PM2 threshold of 0.0001.
Met at moderate strength: missense REVEL score 0.904 exceeds the PP3 moderate threshold of 0.773.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 and PM2 supporting plus PM1 and PP3 moderate satisfy the generic ACMG/AMP rule for 2 moderate and 2 supporting criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 0 / 1,613,196 alleles. Recorded AF 0. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.904. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61615649, n = 217 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 · 8 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Only the requested codon/residue/domain criteria were assessed.
PM1 is met from the Arg132 active-site hotspot evidence and absence of the variant in gnomAD; PS1 is not met, PM5 is not assessed because a validated pathogenic comparator is lacking, and PP2/BP1 are not assessed because their required gene-level mechanisms are not established in the supplied evidence.
None of PS2, PM6, PP1, or BS4 can be assessed because the available evidence contains no germline proband-parent testing, pedigree, informative meioses, familial segregation, or affected-relative non-segregation data.
The exact IDH1 p.Arg132Ser variant has direct variant-specific biochemical evidence of altered, disease-relevant enzyme activity supporting PS3 at supporting strength; the same result does not support BS3.
No VCEP covers IDH1 in this case; generic ACMG/AMP 2015 definitions govern.
The available literature establishes occurrence of IDH1 p.Arg132Ser in affected cohorts but does not provide the matched controls needed for PS4.
ClinVar's exact-variant Pathogenic assertion is a single-submitter clinical-laboratory result, not an expert-panel classification, so it does not trigger PP5 or BP6.
The variant is missense, so PP3 and BP4 use the mutually exclusive REVEL path and do not use SpliceAI.
REVEL 0.904 supports PP3 at moderate strength and does not support BP4.
No criteria match.
PS3 is met at supporting strength. Dang et al. directly tested the exact IDH1 p.Arg132Ser variant (NM_005896.4:c.394C>A) using recombinant, site-directed-mutagenesis-derived protein expressed and purified from E. coli. In enzymatic assays, R132S produced a gain of function for NADPH-dependent reduction of alpha-ketoglutarate to 2-hydroxyglutarate, the disease-relevant altered biochemical activity. This is direct variant-specific functional evidence with an appropriate wild-type comparison and biologically relevant enzyme readout. The evidence is not calibrated above supporting because the bundle documents one research assay study rather than reproducible validation in a clinical diagnostic laboratory setting or multiple independently replicated assays.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
IDH1 p.Arg132Ser lies at Arg132, a recurrent IDH1 mutational hotspot and active-site residue. The Cancer Hotspots result states that the variant lies in a statistically significant hotspot, and PMID:19935646 describes cancer-associated IDH1 mutations occurring at a single amino-acid residue of the active site. The variant is absent from gnomAD v2.1 and gnomAD v4.1; no benign population observation was identified for this variant. No VCEP domain table applies because IDH1 has no governing VCEP in this case.
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 gnomAD v2.1 and is observed 0 times among 1,613,196 all-comers gnomAD v4.1 alleles, with 0 homozygotes; the resulting AF of 0 is at or below the supplied generic PM2 supporting threshold of 0.0001. No governing VCEP specifies a non-cancer or exome-only source, so the default all-comers datasets apply.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020)
The variant is a missense substitution, so the governing generic rule selects the REVEL path only. REVEL is 0.904, meeting the supplied PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for this missense PP3 assessment, and BayesDel is not available for generic ACMG strength calibration.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is IDH1 p.Arg132Ser from NM_005896.4:c.394C>A. The reviewed literature reports this exact amino-acid substitution, but no source establishes a pathogenic p.Arg132Ser variant caused by a different nucleotide change. Reports of the same nucleotide change or the same amino-acid substitution do not independently satisfy PS1, and no alternate-nucleotide pathogenic comparator was identified.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
ClinVar contains an exact-variant Pathogenic submission from one clinical laboratory with criteria provided, single submitter status, and no expert-panel submission. This is not a ClinVar expert-panel classification. The reviewed literature provides case and functional observations but does not constitute a reputable recent source reporting this exact variant as pathogenic with evidence unavailable for independent evaluation under PP5.
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 is absent from gnomAD v2.1 and has an all-comers gnomAD v4.1 allele count of 0/1,613,196 (AF 0; homozygotes 0), far below the generic stand-alone threshold of 0.05. gnomAD v4.1 reports grpmax FAF as null, so a filtering FAF cannot be independently confirmed; there is nevertheless no observed population frequency supporting BA1. The variant is a missense SNV, so the ACMG/AMP indel calling caveat does not apply.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The variant is absent from gnomAD v2.1 and has an all-comers gnomAD v4.1 allele count of 0/1,613,196 (AF 0; homozygotes 0), below the generic default threshold of 0.01. The required filtering metric, grpmax FAF, is null in the supplied gnomAD v4.1 record, but no observed frequency exceeds the disorder-appropriate threshold. Because the observed frequency is zero, a maximum-credible-frequency calculation is not needed to reject BS1; no elevated ancestry-specific frequency or founder signal is present.
Allele frequency is greater than expected for disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not met. No healthy adult individual carrying NM_005896.4:c.394C>A (IDH1 p.Arg132Ser) is reported in the supplied evidence. gnomAD shows 0 observed alleles and 0 homozygotes, which cannot establish the required observation in a healthy adult; no disease-specific full-penetrance early-onset context is available to support this criterion.
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.
BS3 is not met. The directly relevant variant-specific functional study reports that IDH1 p.Arg132Ser produces a gain of function in NADPH-dependent reduction of alpha-ketoglutarate to 2-hydroxyglutarate, rather than showing no damaging effect on protein function or splicing. No variant-specific benign functional result, normal activity result, or normal splicing result was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, so BP4 must be evaluated through the REVEL path only. REVEL is 0.904, which is above the supplied BP4 supporting threshold of <= 0.29; therefore BP4 is not met. The SpliceAI max delta of 0.609 is not applicable to the missense BP4 path, and BayesDel has no generic ACMG-strength calibration.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The exact-variant ClinVar record is Pathogenic from a single clinical laboratory and has no expert-panel submission. No exact-variant ClinVar expert-panel classification of Benign or Likely benign is present, and no qualifying reputable benign report was identified.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PS2 cannot be assessed because the available evidence does not document a germline proband with confirmed maternity and paternity, parental variant testing, or absence of family history. The available variant-specific literature concerns IDH1 p.Arg132Ser in somatic cancer cohorts and does not establish a de novo germline occurrence.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The PS4-screened literature was verified. PMID:21912393 reports IDH1 p.R132S in 3 of 301 patients with chronic-phase primary myelofibrosis, and PMID:21760534 reports R132S in 2 of 94 successfully sequenced diffuse-glioma cases. These are affected-case cohorts without unaffected or population control counts for the same disease and ancestry. gnomAD v4.1 reports 0/1,613,196 alleles, but the case cohorts are not shown to be ancestry-matched and no valid case-control comparison is provided. Therefore an odds ratio and 95% confidence interval suitable for the PS4 threshold cannot be computed from the available evidence; the evidence does not establish the required significant increase compared with controls.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: 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 evidence. The case documents IDH1 p.Arg132Ser in somatic cancer observations, but does not establish a recessive disorder, an affected proband with a relevant germline phenotype, a second pathogenic variant, or parental/offspring testing demonstrating that the variants are in trans. The cited cancer literature reports co-occurring somatic mutations in some tumors, but this does not establish germline allelic phase.
For recessive disorders, detected in trans with a pathogenic variant
The evidence documents other IDH1 substitutions at Arg132, including R132H, R132C, R132L and R132G, and reports recurrent R132 substitutions in cancer. However, the available cited records do not establish a specific different missense Arg132 variant as pathogenic under the generic ACMG/AMP germline rule; the target's single-submitter ClinVar classification cannot be used as a pathogenic comparator. Therefore PM5 cannot be adjudicated without a validated pathogenic comparator record for a different Arg132 missense change.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PM6 cannot be assessed because no presumed de novo germline occurrence is documented. There is no proband-level parental testing, no statement that maternity and paternity were unconfirmed, and no germline family or phenotype report for this variant.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because no affected family members, informative meioses, variant-positive relatives, or phenotype concordance data are provided. The available reports of IDH1 p.Arg132Ser are somatic cancer cohort observations and do not constitute familial cosegregation evidence.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The available evidence describes recurrent IDH1 missense substitutions and an active-site hotspot, but it does not provide the gene-level benign missense rate or a sufficiently established disease mechanism meeting both PP2 requirements. The absence of this individual variant from gnomAD cannot substitute for a gene-level benign missense assessment.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available evidence identifies IDH1 p.Arg132Ser in somatic myelofibrosis and glioma cohorts, but it does not provide the patient's phenotype, family history, or a phenotype highly specific for a single genetic etiology. The multiple cancer contexts reported for IDH1 R132S do not substitute for a specific clinical phenotype assessment.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS4 cannot be assessed because no affected family members with documented absence of the variant are reported. The case contains no pedigree, relative genotypes, phenotype evaluations, or non-segregation observations, so lack of segregation cannot be distinguished from missing family data.
Lack of segregation in affected members of a family.
The available evidence does not establish that IDH1-related disease is caused primarily by truncating variants. Reports of recurrent somatic IDH1 missense substitutions and gain-of-function biochemical findings do not satisfy the gene-level BP1 requirement, and no qualifying truncating-versus-missense disease spectrum is documented in the supplied sources.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed from the available evidence. No fully penetrant dominant IDH1 disorder is established for this case, and no pathogenic variant in trans or pathogenic variant in cis with IDH1 p.Arg132Ser has been documented by parental testing, offspring testing, tumor phasing, or another validated phasing method.
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.
PMID:21912393 reports IDH1 R132S in a 301-patient myelofibrosis cohort and describes IDH mutations occurring with JAK2V617F, but the supplied extraction does not establish that each R132S observation had JAK2V617F or that JAK2V617F was an alternate molecular basis for the disease in the relevant case. No case-level alternate molecular-basis evidence sufficient for BP5 is available.
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>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Ser). 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>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Ser). 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>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Ser). 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>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Ser). 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%, 0/1613196 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74792 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, so the governing generic rule selects the REVEL path only. REVEL is 0.904, meeting the supplied PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for this missense PP3 assessment, and BayesDel is not available for generic ACMG strength calibration.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so BP4 must be evaluated through the REVEL path only. REVEL is 0.904, which is above the supplied BP4 supporting threshold of <= 0.29; therefore BP4 is not met. The SpliceAI max delta of 0.609 is not applicable to the missense BP4 path, and BayesDel has no generic ACMG-strength calibration.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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>A in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Ser). 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 = 0.61). REVEL score = 0.904. BayesDel score = 0.419369.
8 paper records listed. 1 cited in the classification.
Similar to R132H mutant protein, R132C, R132L, and R132S mutations all result in a gain-of-function for NADPH-dependent reduction of αKG (Supplementary Figure 4).
Location Results, section "Mutant IDH1 directly converts αKG to 2HG"; Discussion
Context Recombinant human IDH1 R132S protein was generated by site-directed mutagenesis, expressed and purified from E. coli, and assessed in enzymatic assays.
In 7 (7.4%) of the 94 cases, we detected non-R132H mutations ofIDH1 as follows: 3 with IDH1-R132C mutation (1 diffuse astrocytoma, 1 oligodendroglioma, 1 anaplastic astrocytoma), 2 with IDH1-R132S mutation (1 anaplastic astrocytoma, 1 secondary glioblastoma), and 2 with IDH1-R132G mutations (1 diffuse astrocytoma, 1 anaplastic astrocytoma).
Results, Genetic Analysis; Discussion
The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C).
Results, paragraph 2
IDH1 R132C/S/L/G/V 5%–8% ... IDH1 R132C/S/L/G/P 15%–30% ... IDH1 R132G/H/L/S 30%–50%
Table 1, "Frequency of IDH1 and IDH2 mutant alleles in human cancers"
R132H is the most common IDH1 substitution in gliomas, followed by R132C, R132S, R132L, and R132G.
Introduction, first paragraph; Results, sections "IDH1 R132 mutants bind IDH1-WT" and "IDH mutants produce 2HG"
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%, 0/1613196 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74792 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 375893)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.61). REVEL score = 0.904. BayesDel score = 0.419369.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61615649, n = 217 times).
This variant lies in a statistically significant hotspot.