IDH3G

protein-coding

isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma, the group of Isocitrate dehydrogenases

Gene summary

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. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004135.4

Inheritance

ClinVar variants

P:3U:90

Top phenotype

Retinitis pigmentosa 99

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chrX:153,785,766-153,794,512

External References & Databases

Ensembl (ENSG00000067829)

Transcript & Mutation Effects

hg38 • Region Span ~8.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosaLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0019200

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IDH3G variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 27

not providedTotal: 2

Retinitis pigmentosa 99Total: 2

Spastic quadriplegic cerebral palsyTotal: 1

Rod-cone dystrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004135.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar			11
missense	1 clinvar		47 clinvar			48
nonsense	1 clinvar		2 clinvar			3
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			30 clinvar			30
Total	2	1	90	0	0	93

Highest pathogenic variant AF is 9.1130704e-7

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004135.4	RefSeq	NP_004126.1	13	MANE Select
ENST00000217901.10	Ensembl	ENSP00000217901.5	13	MANE Select
NM_174869.3	RefSeq	NP_777358.1	12	Standard
ENST00000370092.7	Ensembl	ENSP00000359110.3	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Citrate cycle (TCA cycle) - Homo sapiens (human)
Warburg Effect
The oncogenic action of Succinate
The oncogenic action of Fumarate
Pyruvate dehydrogenase deficiency (E3)

Biological Process

carbohydrate metabolic process
tricarboxylic acid cycle
isocitrate metabolic process

Molecular Function

magnesium ion binding
isocitrate dehydrogenase (NAD+) activity
ATP binding
NAD binding

Cellular Component

nucleoplasm
nucleolus
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217901
Coding exons: 13
Length: 8758
Individuals with no LoFs: 125736
Homozygous LoFs: 3
Heterozygous LoFs: 6
Defined: 125745
p: 0.0000358

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.19	107	193	0.555	0.0000174	2575
Missense (PolyPhen)		25	73.186	0.3416		1070
Synonymous	-0.197	90	87.7	1.03	0.00000871	790
Loss of Function	2.29	4	12.9	0.311	8.70e-7	229

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000078	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00015	0.000099	rare
East Asian	0.000080	0.000054	rare
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.000037	0.000026	rare
South Asian	0.000052	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory subunit which plays a role in the allosteric regulation of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers. {ECO:0000269|PubMed:28139779}.;

Recessive Scores

pRec: 0.283

Intolerance Scores

LoFtool: 0.509
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.810

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium