VCV000375891.40 - ClinVar

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

Germline

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.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

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.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

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

Variation ID: 375891 Accession: VCV000375891.40

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	Oct 20, 2024	Sep 8, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

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	435	469

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.
Neoplasm of brain	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000418601.4
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000419656.4
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000420988.4
Astrocytoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000421691.4
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000426141.4
Medulloblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428207.4
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000429279.4
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430360.4
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000434107.4
Adenoid cystic carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435816.4
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436904.4
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000437909.4
Brainstem glioma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000438918.4
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000439965.4
Myelodysplastic syndrome	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000441917.4
Acute myeloid leukemia	Pathogenic (4)	criteria provided, single submitter	Mar 12, 2019	RCV000445302.7
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2021	RCV000997650.27
Enchondromatosis	Pathogenic (1)	criteria provided, single submitter	May 9, 2022	RCV002227473.5
Enchondromatosis Maffucci syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 11, 2022	RCV002291276.5
Glioma susceptibility 1	Pathogenic (1)	criteria provided, single submitter	-	RCV003323531.4
Maffucci syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 8, 2023	RCV003458426.1
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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)	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)	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 (May 09, 2022)	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: SCV002507175.1 First in ClinVar: May 12, 2022 Last updated: May 12, 2022	Sex: female
Pathogenic (Mar 01, 2021)	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)	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 (-)	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: SCV004028549.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	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) Age: 20-29 years Sex: male
Pathogenic (Sep 08, 2023)	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)
Likely pathogenic (Feb 01, 2017)	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: SCV001153277.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503819.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (7) PubMed: 22417203‚ 22160010‚ 19657110‚ 26619011‚ 22898539‚ 20946881‚ 22397365 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503818.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503821.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503820.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of brain (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503825.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503822.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503823.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Adenoid cystic carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503824.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503827.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503826.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503828.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Medulloblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503829.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Astrocytoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503831.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503832.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Myelodysplastic syndrome (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503833.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Brainstem glioma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000503830.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T
Pathogenic (-)	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)	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
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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 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).

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.

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
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
The role of mutations in epigenetic regulators in myeloid malignancies.	Shih AH	Nature reviews. Cancer	2012	PMID: 22898539
Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.	Patel JP	The New England journal of medicine	2012	PMID: 22417203
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.	Chotirat S	Journal of hematology & oncology	2012	PMID: 22397365
Impact of genetic features on treatment decisions in AML.	Döhner H	Hematology. American Society of Hematology. Education Program	2011	PMID: 22160010
IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders.	Zou Y	Biochemical and biophysical research communications	2010	PMID: 20946881
Recurring mutations found by sequencing an acute myeloid leukemia genome.	Mardis ER	The New England journal of medicine	2009	PMID: 19657110
http://docm.genome.wustl.edu/variants/ENST00000345146:c.394C>T	-	-	-	-

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	Jul 31, 2024	RCV004668921.1

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

(Jul 31, 2024)

(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: SCV005094464.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

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 Oct 20, 2024

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 ...