2-208248389-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_005896.4(IDH1):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Pathogenic.
Frequency
Consequence
NM_005896.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IDH1 | NM_005896.4 | c.394C>T | p.Arg132Cys | missense_variant | Exon 4 of 10 | ENST00000345146.7 | NP_005887.2 | |
IDH1 | NM_001282386.1 | c.394C>T | p.Arg132Cys | missense_variant | Exon 4 of 10 | NP_001269315.1 | ||
IDH1 | NM_001282387.1 | c.394C>T | p.Arg132Cys | missense_variant | Exon 4 of 10 | NP_001269316.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151438Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461688Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727162
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151438Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73904
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Mar 01, 2021 | This variant results in the substitution of arginine with cysteine at position 132 within the IDH1 protein. This variant is absent from large population cohorts (Genome Aggregation Database v2.1), and has been previously reported pathogenic in numerous individuals (PMID: 23485734, PMID: 30677207, PMID: 22057236, PMID: 22057234). In addition, functional studies demonstrate that the p.R132C mutation leads to neomorphic gain of function of the IDH1 protein (PMID: 19935646). - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 24, 2019 | - - |
Acute myeloid leukemia Pathogenic:3
Pathogenic, no assertion criteria provided | curation | Molecular Diagnostics Laboratory, University of Rochester Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Mar 12, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center | Jun 08, 2023 | - - |
Enchondromatosis;C0024454:Maffucci syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 11, 2022 | PS3, PS4, PM2, PP3 - |
Maffucci syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Sep 08, 2023 | The IDH1 c.394C>T (p.Arg132Cys) variant was identified at an allelic fraction consistent with somatic origin. It has been detected in several individuals affected with Maffucci syndrome and Ollier disease caused by somatic IDH1 c.394C>T (p.Arg132Cys) pathogenic variants (Pansuriya TC et al., PMID: 22057234; Nejo T et al., PMID: 30579273; Saiji E et al., PMID: 31240473; Amary MF et al. PMID: 22057236). This variant has been reported in the ClinVar database as pathogenic by eight submitters and as likely pathogenic by a single submitter (ClinVar ID: 375891) in both a germline and a somatic state. It also has been reported in 1150 cases in the cancer database (COSMIC ID: COSV61615256). IDH1 c.394C>T (p.Arg132Cys) is only observed on 1/151438 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within a region, amino acids 104-136, of IDH1 that is defined as a critical functional domain (Reitman ZJ et al., PMID: 20513808). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to IDH1 function. Functional studies using cell lines show that this variant disrupts the resulting enzyme's ability to catalyze conversion of isocitrate to alpha-ketoglutarate (Dang L et al., PMID: 19935646). Other variants in this codon have been reported in individuals with Maffucci syndrome and Ollier disease and are considered pathogenic (Pansuriya TC et al., PMID: 22057234, ClinVar ID: 156444). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the IDH1 c.394C>T (p.Arg132Cys) variant is classified as pathogenic. - |
Glioma susceptibility 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University | - | The c.394C>T p.(Arg132Cys) variant in IDH1 gene was identified in the proband’s hemangioma at low read depth by whole genome sequencing. This variant was categorized in the Tier I variants by AMP Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer (Marilyn M. Li, 2017). - |
Enchondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | May 09, 2022 | - - |
Neoplasm Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at