15-90088702-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_002168.4(IDH2):c.419G>A(p.Arg140Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,752 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 (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

IDH2
NM_002168.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

IDH2 (HGNC:5383): (isocitrate dehydrogenase (NADP(+)) 2) 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 mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

IDH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 15-90088702-C-T is Pathogenic according to our data. Variant chr15-90088702-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 11	ENST00000330062.8	NP_002159.2	P48735-1
IDH2	NM_001289910.1 link	c.263G>A	p.Arg88Gln	missense_variant	Exon 4 of 11		NP_001276839.1	P48735-2
IDH2	NM_001290114.2 link	c.29G>A	p.Arg10Gln	missense_variant	Exon 2 of 9		NP_001277043.1	P48735B4DSZ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8 link	c.419G>A	p.Arg140Gln	missense_variant	Exon 4 of 11	1	NM_002168.4	ENSP00000331897.4		P48735-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251462

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000224

Hom.:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 2

Pathogenic:7

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 140 of the IDH2 protein (p.Arg140Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with D-2-hydroxyglutaric aciduria (PMID: 20847235). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDH2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects IDH2 function (PMID: 25398939). For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory de novo and mosaic in a 2-year-old male with motor delays, absent speech, hypertonia, epilepsy, short statures, failure to thrive, vision loss, MRI suggestive of Leigh disease -

Aug 02, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the IDH2 gene demonstrated a sequence change, c.419G>A, in exon 4 that results in an amino acid change, p.Arg140Gln. This variant has been described in the EXAC database with a low population frequency of 0.01% (dbSNP rs121913502). The p.Arg140Gln change affects a highly conserved amino acid residue located in a domain of the IDH2 protein that is known to be functional. This pathogenic sequence change has previously been described in at least 14 patients with IDH2-related D2-hydroxyglutaric aciduira type II, including in the confirmed de novo state in some families (Kranendijk et al., 2010). In one family with the p.Arg140Gln pathogenic sequence change, the patient's mother was identified as having somatic mosaicism for the variant (Kranendijk et al., 2010). In vitro enzyme assays in lymphoblasts demonstrate that this variant has increased reaction rates compare to controls, and results in a gain of function (Kranendijk et. al., 2011) -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with D-2-hydroxyglutaric aciduria 2 (MIM#613657). Mutant IDH2 was unable to carry out the decarboxylation of isocitrate to a-ketoglutarate (a-KG), but instead gained the neomorphic activity to reduce a-KG to R(-)-2-hydroxyglutarete (2-HG) (PMID: 21647154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is also located in the substrate binding region (Decipher, UniProt). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least ten individuals with D-2-hydroxyglutaric aciduria 2 (ClinVar, PMID: 20847235). However, it should also be noted that the same variant has been reported in somatic tissues across various malignancies (PMIDs: 24589777, 21647154, 23949315). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Patient lymphoblast cell lines heterozygous for the p.(Arg140Gln) variant demonstrated increased conversion of 2-ketoglutarate to D-2-hydroxyglutarate compared with cells from healthy individuals (PMID: 21889589). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). However, it should be noted that mosaicism has been reported for this variant (PMID: 24049096). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (ClinVar ID: VCV000014716.9, PMID:20847235, PS1). It is observed at an low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000318). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.891, 3Cnet: 0.833, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Pathogenic:1

Dec 30, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.419G>A (p.R140Q) alteration is located in exon 4 (coding exon 4) of the IDH2 gene. This alteration results from a G to A substitution at nucleotide position 419, causing the arginine (R) at amino acid position 140 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (9/282846) total alleles studied. The highest observed frequency was 0.010% (2/19944) of East Asian alleles. This alteration has been detected in multiple individuals with D-2-hydroxyglutaric aciduria type 2, including multiple cases of reported de novo occurrence. Additionally, somatic mosaicism for this alteration has been reported in an affected individual as well as an unaffected individual (Kranendijk, 2010; Nota, 2013). Another alteration at the same codon, c.418C>G (p.R140G), has been detected in an individual with D-2-hydroxyglutaric aciduria type 2 (Kranendijk, 2010). This amino acid position is highly conserved in available vertebrate species. An enzyme assay demonstrated that the mean reaction rate in D-2-HGA type II lymphoblasts with this alteration was 8-fold higher than that of controls and D2-HGA type I cells, with a corresponding 140-fold increase in intracellular D-2-hydroxyglutarate (D-2-HG) level (Kranendijk, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Apr 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An enzyme assay which determines IDH2 activity in lymphoblast extracts confirmed that R140Q results in gain of function in D-2 hydroxyglutaric aciduria type 2 (Kranendijk et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20171147, 34641967, 21889589, 20847235, 24049096, 23558173) -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.2

H;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.99

MVP

0.91

MPC

1.6

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over