15-90088607-T-C

Variant names:

• chr15-90088607-T-C
• rs1057519906
• NM_002168.4:c.514A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_002168.4(IDH2):​c.514A>G​(p.Arg172Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R172S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: IDH2 NM_002168.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.56
• Publications: 169 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• d-2-hydroxyglutaric aciduria 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• D-2-hydroxyglutaric aciduria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-90088605-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2691259.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 15-90088607-T-C is Pathogenic according to our data. Variant chr15-90088607-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH2	NM_002168.4	c.514A>G	p.Arg172Gly	missense_variant	Exon 4 of 11	ENST00000330062.8	NP_002159.2
IDH2	NM_001289910.1	c.358A>G	p.Arg120Gly	missense_variant	Exon 4 of 11		NP_001276839.1
IDH2	NM_001290114.2	c.124A>G	p.Arg42Gly	missense_variant	Exon 2 of 9		NP_001277043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH2	ENST00000330062.8	c.514A>G	p.Arg172Gly	missense_variant	Exon 4 of 11	1	NM_002168.4	ENSP00000331897.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maffucci syndrome Pathogenic:1

Jul 09, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An IDH2 c.514A>G (p.Arg172Gly) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in at least one individual with solitary cartilaginous tumor (Pansuriya TC et al., PMID: 22057234). It is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. This variant has been reported in the ClinVar database as a likely pathogenic somatic variant in at least 5 individuals with different cancers (ClinVar ID: 376439; Chang, MT et al., PMID: 26619011), and it has been reported in numerous types of cancer in the cancer database COSMIC (Genomic mutation ID: COSV57468989). The IDH2 c.514A>G (p.Arg172Gly) variant resides within the small domain of IDH2 that is defined as a critical functional domain (Waitkus MS et al., PMID: 26188014; Testa U et al., PMID: 32859092; Xu Y et al., PMID: 28852116). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to IDH2 function. In support of this prediction, functional studies using cell lines show that this variant disrupts the resulting enzyme's ability to catalyze conversion of isocitrate to alpha-ketoglutarate and results in a gain of function to IDH2 as indicated by production of 2HG (2-hydroxyglutarate), and leads to activation of HIF-1-alpha signaling and nuclear accumulation of beta-catenin in cell culture (Fu Yet al., PMID: 22309944; Jin G et al., PMID: 21326614). Other variants in the same codon, (p.Arg172Ser, p.Arg172Thr, p.Arg172Met) have been reported in individuals with Ollier disease and Maffucci syndrome (Pansuriya TC et al., PMID: 22057234; Revencu N et al., PMID: 38778413). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation (Leon-Quintero FZ et al., PMID: 39434542), the IDH2 c.514A>G (p.Arg172Gly) variant is classified as likely pathogenic. -

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	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Benign	0.067
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		1.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.90		Loss of stability (P = 0.0343);.;
MVP		0.85
MPC		1.6
ClinPred		1.0	D
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.99

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

Other links and lift over

dbSNP: rs1057519906; hg19: chr15-90631839; COSMIC: COSV57468989;