rs121913499

chr2-208248389-G-Achr2-208248389-G-Cchr2-208248389-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. R132G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IDH1 NM_005896.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 7.10

Genes affected

IDH1 (HGNC:5382): (isocitrate dehydrogenase (NADP(+)) 1) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a binding_site in other chain (size 0) in uniprot entity IDHC_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_005896.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-208248388-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 2-208248389-G-A is Pathogenic according to our data. Variant chr2-208248389-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208248389-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH1	NM_005896.4	c.394C>T	p.Arg132Cys	missense_variant	4/10	ENST00000345146.7
IDH1	NM_001282386.1	c.394C>T	p.Arg132Cys	missense_variant	4/10
IDH1	NM_001282387.1	c.394C>T	p.Arg132Cys	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH1	ENST00000345146.7	c.394C>T	p.Arg132Cys	missense_variant	4/10	1	NM_005896.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151438 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151438 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73904

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acute myeloid leukemia Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 31, 2016	- -
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	- -

not provided Pathogenic:3

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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 24, 2019	- -

Myelodysplastic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Medulloblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Brainstem glioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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. -

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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). -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Astrocytoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

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

- -

Adenoid cystic carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.5	H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		0.26	B;B;B;.
Vest4		0.96
MutPred		0.94		Loss of MoRF binding (P = 0.0402);Loss of MoRF binding (P = 0.0402);Loss of MoRF binding (P = 0.0402);Loss of MoRF binding (P = 0.0402);
MVP		0.96
MPC		0.78
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 34
DS_DL_spliceai		0.32		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913499; hg19: chr2-209113113; COSMIC: COSV61615256; COSMIC: COSV61615256;