VCV000375891.45 - ClinVar

NM_005896.4(IDH1):c.394C>T (p.Arg132Cys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

8 out of 10 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_005896.4(IDH1):c.394C>T (p.Arg132Cys)

Variation ID: 375891 Accession: VCV000375891.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q34 2: 208248389 (GRCh38) [ NCBI UCSC ] 2: 209113113 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 8, 2017	Apr 20, 2025	Sep 8, 2023
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005896.4:c.394C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005887.2:p.Arg132Cys	missense
NM_001282386.1:c.394C>T	NP_001269315.1:p.Arg132Cys	missense
NM_001282387.1:c.394C>T	NP_001269316.1:p.Arg132Cys	missense
NM_005896.3:c.394C>T
NC_000002.12:g.208248389G>A
NC_000002.11:g.209113113G>A
NG_023319.2:g.22686C>T
LRG_610:g.22686C>T
LRG_610t2:c.394C>T	LRG_610p2:p.Arg132Cys
LRG_610t3:c.394C>T	LRG_610p3:p.Arg132Cys

... more HGVS ... less HGVS

Protein change

R132C

Other names

Canonical SPDI

NC_000002.12:208248388:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA16602374 dbSNP: rs121913499 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
IDH1		-	-	GRCh38 GRCh37	463	497

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Acute myeloid leukemia	Pathogenic (3)	criteria provided, single submitter	Mar 12, 2019	RCV000445302.8
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2021	RCV000997650.30
Enchondromatosis Maffucci syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2022	RCV002291276.5
Enchondromatosis	Pathogenic (1)	criteria provided, single submitter	May 9, 2022	RCV002227473.6
Glioma susceptibility 1	Pathogenic (1)	criteria provided, single submitter	-	RCV003323531.5
Maffucci syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 8, 2023	RCV003458426.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 24, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450436.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
Pathogenic (Mar 12, 2019) C Contributing to aggregate classification	criteria provided, single submitter (AMP Guidelines, 2017) Method: clinical testing	Acute myeloid leukemia Affected status: yes Allele origin: somatic	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota Accession: SCV001478446.1 First in ClinVar: Feb 10, 2021 Last updated: Feb 10, 2021
Pathogenic (Mar 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: somatic	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525674.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: 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 … (more) 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). (less) Clinical Features: Osteochondroma (present) , Lower limb asymmetry (present) , Genu valgum (present)
Pathogenic (Aug 11, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ollier disease Maffucci syndrome Affected status: yes Allele origin: somatic	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002583825.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: PS3, PS4, PM2, PP3
Pathogenic (Sep 08, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Maffucci syndrome Affected status: yes Allele origin: somatic	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV004176913.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (May 09, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Enchondromatosis Affected status: yes Allele origin: germline	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002507175.2 First in ClinVar: May 12, 2022 Last updated: Apr 13, 2025	Sex: female
Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (AMP Guidelines, 2017) Method: clinical testing	Glioma susceptibility 1 (Somatic mutation) Affected status: yes Allele origin: somatic	Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University Accession: SCV004028549.2 First in ClinVar: Aug 26, 2023 Last updated: Apr 13, 2025	Comment: 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 … (more) 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). (less) Clinical Features: Hemangioma (present) Zygosity: Single Heterozygote Age: 20-29 years Sex: male
Likely pathogenic (Feb 01, 2017) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001153277.30 First in ClinVar: Feb 03, 2020 Last updated: Apr 20, 2025	Number of individuals with the variant: 1
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: curation	Acute myeloid leukemia Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, University of Rochester Medical Center Accession: SCV002506981.1 First in ClinVar: May 12, 2022 Last updated: May 12, 2022	Publications: PubMed (1) PubMed: 30231226
Pathogenic (Jun 08, 2023) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Acute myeloid leukemia Affected status: yes Allele origin: somatic	Sung Lab, Department of Medicine, Roswell Park Comprehensive Cancer Center Accession: SCV003932621.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023

Comment:

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).

Comment:

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.

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Ivosidenib in IDH1-Mutated Acute Myeloid Leukemia.	DiNardo CD	The New England journal of medicine	2018	PMID: 30231226

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Mar 4, 2025	RCV004668921.2

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Mar 04, 2025)

Contributing to aggregate classification

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094464.2
First In ClinVar: Aug 11, 2024
Last updated: Mar 11, 2025

Publications:: PubMed (3)
PubMed: 19935646‚ 26161668‚ 22885298

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Mutant IDH1 Dysregulates the Differentiation of Mesenchymal Stem Cells in Association with Gene-Specific Histone Modifications to Cartilage- and Bone-Related Genes.	Jin Y	PloS one	2015	PMID: 26161668
Mutant IDH1 is required for IDH1 mutated tumor cell growth.	Jin G	Oncotarget	2012	PMID: 22885298
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.	Dang L	Nature	2009	PMID: 19935646

Text-mined citations for rs121913499 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 20, 2025

ClinVar Genomic variation as it relates to human health

NM_005896.4(IDH1):c.394C>T (p.Arg132Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121913499 ...