VCV000156444.24 - ClinVar

NM_005896.4(IDH1):c.395G>A (p.Arg132His)

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.

(25)

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.395G>A (p.Arg132His)

Variation ID: 156444 Accession: VCV000156444.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q34 2: 208248388 (GRCh38) [ NCBI UCSC ] 2: 209113112 (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	Oct 23, 2014	Oct 20, 2024	Aug 2, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005896.4:c.395G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005887.2:p.Arg132His	missense
NM_001282386.1:c.395G>A	NP_001269315.1:p.Arg132His	missense
NM_001282387.1:c.395G>A	NP_001269316.1:p.Arg132His	missense
NM_005896.3:c.395G>A
NC_000002.12:g.208248388C>T
NC_000002.11:g.209113112C>T
NG_023319.2:g.22687G>A
LRG_610:g.22687G>A
LRG_610t2:c.395G>A	LRG_610p2:p.Arg132His
LRG_610t3:c.395G>A	LRG_610p3:p.Arg132His
	O75874:p.Arg132His

... more HGVS ... less HGVS

Protein change

R132H

Other names

Canonical SPDI

NC_000002.12:208248387:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA170874 UniProtKB: O75874#VAR_055455 OMIM: 147700.0001 dbSNP: rs121913500 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.
Glioblastoma multiforme, somatic	Pathogenic (1)	no assertion criteria provided	Aug 21, 2014	RCV000144504.5
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000420454.2
Brainstem glioma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422344.2
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432047.2
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440637.2
Oligodendroglioma	not provided (1)	no classification provided	Mar 10, 2016	RCV000423229.2
Adenoid cystic carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000427239.2
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000419255.2
Myelodysplastic syndrome	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000421389.2
Medulloblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423408.2
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000431117.2
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433068.2
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000439554.2
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000441845.2
Astrocytoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000442517.2
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445280.2
Neoplasm of brain	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428884.2
Acute myeloid leukemia	Pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000429987.2
Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria	Pathogenic (1)	criteria provided, single submitter	Nov 2, 2018	RCV000853347.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV001269510.14
Glioma susceptibility 1	Likely pathogenic (1)	no assertion criteria provided	-	RCV001542733.3
Enchondromatosis	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 9, 2022	RCV002227447.4
Metaphyseal chondromatosis	Pathogenic (1)	criteria provided, single submitter	Aug 2, 2023	RCV003387509.1
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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 (Nov 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	METAPHYSEAL CHONDROMATOSIS WITH D-2-HYDROXYGLUTARIC ACIDURIA Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996209.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This variant has been previously reported as a mosaic change in patients with metaphyseal chondromatosis and elevated D-2-hydroxyglutaric aciduria (PMID: 24049096, 22025298). It is absent … (more) This variant has been previously reported as a mosaic change in patients with metaphyseal chondromatosis and elevated D-2-hydroxyglutaric aciduria (PMID: 24049096, 22025298). It is absent from the gnomAD population databases and thus is presumed to be rare. The c.395G>A, p.Arg132H variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The p.Arg132H variant results in loss of its native enzymatic activity and gain of alternative enzymatic activity (producing D-2-hydroxyglutarate) (PMID 21446021). Structural studies demonstrated that when p.Arg132 is mutated to histidine (R132H), residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG (PMID 19935646). Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism (PMID 18931888). Based on the available evidence, the c.395G>A, p.Arg132H variant is classified as Pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Oct 29, 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: SCV001449548.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Number of individuals with the variant: 1
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: SCV002507195.1 First in ClinVar: May 12, 2022 Last updated: May 12, 2022	Sex: male
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Metaphyseal chondromatosis Increased urinary excretion of (more...) Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV004099007.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: PS4, PM2, PM5, PM6_Strong, PP3
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Enchondromatosis Affected status: yes Allele origin: de novo	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine Accession: SCV002764259.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Mar 01, 2023)	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: SCV004011290.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: IDH1: PS4, PM1, PM2, PP4, PS3:Supporting Number of individuals with the variant: 1
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: SCV000503807.1 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.395G>A
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: SCV000503808.1 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.395G>A
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: SCV000503809.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 26619011‚ 23558169 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.395G>A
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: SCV000503813.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 25157968‚ 19818334‚ 19798509 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.395G>A
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: SCV000503815.1 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.395G>A
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: SCV000503814.1 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.395G>A
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: SCV000503810.1 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.395G>A
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: SCV000503811.1 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.395G>A
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: SCV000503812.1 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.395G>A
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: SCV000503816.1 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.395G>A
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: SCV000503817.1 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.395G>A
Pathogenic (Aug 21, 2014)	no assertion criteria provided Method: literature only	GLIOBLASTOMA MULTIFORME, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000189823.3 First in ClinVar: Oct 14, 2014 Last updated: Oct 29, 2022	Publications: PubMed (4) PubMed: 18772396‚ 21446021‚ 25043048‚ 36201590 Comment on evidence: In 5 of 22 glioblastoma multiforme (GBM) tumors (see 137800), Parsons et al. (2008) detected a change of guanine to adenine at position 395 of … (more) In 5 of 22 glioblastoma multiforme (GBM) tumors (see 137800), Parsons et al. (2008) detected a change of guanine to adenine at position 395 of the IDH1 transcript (G395A), leading to the replacement of arginine with histidine at amino acid residue 132 of the protein (arg132 to his, R132H). Five further GBMs were found to carry the mutation in a subsequent screen. The R132 residue is evolutionarily conserved and is localized to the substrate-binding site, where it forms hydrophilic interactions with the alpha-carboxylate of isocitrate. Bralten et al. (2011) found that overexpression of IDH1-R132H in established glioma cell lines resulted in decreased proliferation and more contact-dependent cell migration compared to wildtype. Intracerebral injection of IDH1-R132H in mice, as compared to injection of wildtype, resulted in increased survival and even absence of tumor in 1 mouse. Reduced cellular proliferation was associated with accumulation of D-2-hydroxyglutarate that is produced by the R132H variant protein. The decreased proliferation was not associated with increased apoptosis, but was associated with decreased AKT1 (164730) activity. The findings indicated that R132H dominantly reduces aggressiveness of established glioma cell lines in vitro and in vivo. Bralten et al. (2011) noted that the findings were apparently contradictory because the presence of an IDH1 mutation was thought to contribute to tumorigenesis; the authors suggested that IDH1 mutations may be involved in tumor initiation and not in tumor progression. IDH1-mutant tumors are typically low-grade and often slow-growing. Schumacher et al. (2014) demonstrated that the R132H variant in the IDH1 gene contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on MHC class II and induce mutation-specific CD4+ T-helper-1 responses. CD4+ T-helper-1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognized IDH1(R132H). Peptide vaccination of humanized mice with IDH1(R132H) p123-142 resulted in an effective MHC class II-restricted mutation-specific antitumor immune response and control of preestablished syngeneic IDH1(R132H)-expressing tumors in a CD4+ T-cell-dependent manner. Yanchus et al. (2022) identified the rs55705857-G allele (613040.0001) as the causative risk variant for susceptibility to IDH-mutant low-grade glioma (LGG) at the 8q24.21 locus (GLM7; 613032). (less)
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: SCV000503806.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (7) PubMed: 19657110‚ 26619011‚ 22898539‚ 22417203‚ 24606448‚ 22397365‚ 22160010 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000345146:c.395G>A
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: SCV000503802.1 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.395G>A
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: SCV000503803.1 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.395G>A
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: SCV000503805.1 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.395G>A
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: SCV000503804.1 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.395G>A
Likely pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Glioma susceptibility 1 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760072.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
not provided (Mar 10, 2016)	no classification provided Method: literature only	Oligodendroglioma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000505707.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 23558169 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000415913:c.395G>A
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Comment:

This variant has been previously reported as a mosaic change in patients with metaphyseal chondromatosis and elevated D-2-hydroxyglutaric aciduria (PMID: 24049096, 22025298). It is absent from the gnomAD population databases and thus is presumed to be rare. The c.395G>A, p.Arg132H variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. The p.Arg132H variant results in loss of its native enzymatic activity and gain of alternative enzymatic activity (producing D-2-hydroxyglutarate) (PMID 21446021). Structural studies demonstrated that when p.Arg132 is mutated to histidine (R132H), residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG (PMID 19935646). Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumors in patients with inborn errors of 2HG metabolism (PMID 18931888). Based on the available evidence, the c.395G>A, p.Arg132H 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
A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.	Yanchus C	Science (New York, N.Y.)	2022	PMID: 36201590
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
A vaccine targeting mutant IDH1 induces antitumour immunity.	Schumacher T	Nature	2014	PMID: 25043048
Molecular evaluation of DNMT3A and IDH1/2 gene mutation: frequency, distribution pattern and associations with additional molecular markers in normal karyotype Indian acute myeloid leukemia patients.	Ahmad F	Asian Pacific journal of cancer prevention : APJCP	2014	PMID: 24606448
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.	Rohle D	Science (New York, N.Y.)	2013	PMID: 23558169
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 R132H decreases proliferation of glioma cell lines in vitro and in vivo.	Bralten LB	Annals of neurology	2011	PMID: 21446021
A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation.	Kato Y	Biochemical and biophysical research communications	2009	PMID: 19818334
Monoclonal antibody specific for IDH1 R132H mutation.	Capper D	Acta neuropathologica	2009	PMID: 19798509
Recurring mutations found by sequencing an acute myeloid leukemia genome.	Mardis ER	The New England journal of medicine	2009	PMID: 19657110
An integrated genomic analysis of human glioblastoma multiforme.	Parsons DW	Science (New York, N.Y.)	2008	PMID: 18772396
http://docm.genome.wustl.edu/variants/ENST00000345146:c.395G>A	-	-	-	-
http://docm.genome.wustl.edu/variants/ENST00000415913:c.395G>A	-	-	-	-
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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	RCV004668802.1

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: SCV005094442.1
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 rs121913500 ...

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.395G>A (p.Arg132His)

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 rs121913500 ...