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Gene | IDH1 |
Variant | R132X |
Impact List | missense |
Protein Effect | unknown |
Gene Variant Descriptions | IDH1 R132X indicates any Idh1 missense mutation that results in the replacement of the arginine (R) at amino acid 132 by a different amino acid. R132 variants are hotspot mutations in Idh1, which often results in conversion of alpha-ketoglutarate to the onco-metabolite 2HG (R(-)-2-hydroxyglutarate) (PMID: 19935646, PMID: 28330869, PMID: 21326614). |
Associated Drug Resistance | |
Category Variants Paths |
IDH1 mutant IDH1 R132X |
Transcript | NM_005896.4 |
gDNA | chr2:g.208248387_208248389 |
cDNA | c.394_396 |
Protein | p.R132 |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_005896.3 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282387.1 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_005896.4 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282386.1 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_005896 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282387.1 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282387 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282386 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
NM_001282386.1 | chr2:g.208248387_208248389 | c.394_396 | p.R132 | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
IDH1 R132X | low grade glioma | predicted - sensitive | Ivosidenib | Phase I | Actionable | In a Phase I trial, low grade glioma patients with an IDH1 mutation (n=66; R132H=57, R132C/G/S=1 each, R132X=5) treated with Tibsovo (ivosidenib) demonstrated an overall response rate of 2.9% (1/35, 1 partial response) and stable disease in 85.7% (30/35) of patients with a non-enhancing glioma versus no responses and stable disease in 45.2% (14/31) of patients with an enhancing glioma, and led to a median progression-free survival of 13.6 months and 1.4 months, respectively (PMID: 32530764; NCT02073994). | 32530764 |
IDH1 R132X | acute myeloid leukemia | sensitive | IDH305 | Phase I | Actionable | In a Phase I trial, IDH305 treatment resulted in objective response in 33% (7/21) of acute myeloid leukemia patients harboring IDH1 R132 mutations, including complete remission in 3 (14%) and partial remission in 4 (19%) patients (Blood 2016 128 (22):1073). | detail... |
IDH1 R132X | oligodendroglioma | sensitive | Vorasidenib | FDA approved | Actionable | In a Phase III trial l (INDIGO) that supported FDA approval, Voranigo (vorasidenib) treatment significantly improved progression-free survival (27.7 vs 11.1 months, HR 0.39, p<0.001) and time to next intervention (HR 0.26, p<0.001) compared to placebo in adult and pediatric patients 12 years and older with WHO grade 2 oligodendroglioma or astrocytoma harboring susceptible IDH1 or IDH2 mutations, including IDH1 R132H/C/G/L/S (PMID: 37272516; NCT04164901). | 37272516 detail... |
IDH1 R132X | astrocytoma, IDH-mutant, grade 2 | sensitive | Vorasidenib | FDA approved | Actionable | In a Phase III trial l (INDIGO) that supported FDA approval, Voranigo (vorasidenib) treatment significantly improved progression-free survival (27.7 vs 11.1 months, HR 0.39, p<0.001) and time to next intervention (HR 0.26, p<0.001) compared to placebo in adult and pediatric patients 12 years and older with WHO grade 2 astrocytoma or oligodendroglioma harboring susceptible IDH1 or IDH2 mutations, including IDH1 R132H/C/G/L/S (PMID: 37272516; NCT04164901). | detail... 37272516 |
IDH1 R132X | brain glioma | predicted - sensitive | Olutasidenib | Phase Ib/II | Actionable | In a Phase Ib/II trial, Rezlidhia (olutasidenib) treatment was well tolerated and did not meet the primary endpoint, with an objective response rate of 8% (2/25, both partial responses) but led to a disease control rate of 48% (12/25) in patients with glioma harboring IDH1 R132H (n=22), R132L (n=2), R132C (n=1), or R132G (n=1) (PMID: 35639513; NCT04380012). | 35639513 |
IDH1 R132X | acute myeloid leukemia | no benefit | BAY1436032 | Phase I | Actionable | In a Phase I trial, treatment with BAY1436032 in acute myeloid leukemia patients harboring an IDH1 R132X mutation demonstrated safety and resulted in an overall response rate of 15% (4/27), including one complete remission, one partial remission, and morphologic leukemia-free state in two patients, stable disease in 67% (18/27), and a median overall survival of 6.6 months, however, due to low response rates for all doses, further clinical development was not supported (PMID: 32733012; NCT03127735). | 32733012 |
IDH1 R132X | acute myeloid leukemia | predicted - sensitive | CG-806 | Preclinical - Patient cell culture | Actionable | In a preclinical study, patient-derived acute myeloid leukemia cells harboring IDH1 R132X mutations demonstrated increased sensitivity to CG-806 compared to wild-type cells in culture (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1323). | detail... |
IDH1 R132X | acute myeloid leukemia | predicted - sensitive | LY3410738 | Phase I | Actionable | In a Phase I trial, LY3410738 demonstrated safety and inhibited D-2-HG in patients with relapsed or refractory IDH-mutant acute myeloid leukemia, resulting in a composite complete remission (CRc) rate of 38% (12/32, 5 CR, 2 CRh, 5 CRi/CRp) in IDH inhibitor-naive patients harbor IDH1 R132 mutations (Cancer Res (2023) 83 (8_Supplement): CT026; NCT04603001). | detail... |