GPT2

protein-coding

glutamic--pyruvic transaminase 2

Gene summary

This gene encodes a mitochondrial alanine transaminase, a pyridoxal enzyme that catalyzes the reversible transamination between alanine and 2-oxoglutarate to generate pyruvate and glutamate. Alanine transaminases play roles in gluconeogenesis and amino acid metabolism in many tissues including skeletal muscle, kidney, and liver. Activating transcription factor 4 upregulates this gene under metabolic stress conditions in hepatocyte cell lines. A loss of function mutation in this gene has been associated with developmental encephalopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

MANE transcript

NM_133443.4

Inheritance

ClinVar variants

P:24U:76B:35

Top phenotype

Neurodevelopmental disorder with spastic paraplegia and/or microcephaly

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr16:46,884,362-46,931,289

External References & Databases

Ensembl (ENSG00000166123)

Transcript & Mutation Effects

hg38 • Region Span ~46.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glutamate pyruvate transaminase 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014567

Submitter: Labcorp Genetics (formerly Invitae)

glutamate pyruvate transaminase 2 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014567

Submitter: ClinGen

GPT2 was first reported in relation to autosomal recessive glutamate pyruvate transaminase 2 deficiency in 2014 (Iglesias et al., PMID: 24901346). This neurologic syndrome is characterized by delayed psychomotor development, moderately to severely impaired intellectual development, and poor or absent speech. More severely affected individuals show poor overall growth with progressive microcephaly, axial hypotonia, oromotor dysfunction with drooling, joint contractures, and spastic paraplegia resulting in walking difficulties. Eight variants (missense, frameshift, nonsense, and splice variants) that have been reported in 7 probands (and 22 family members) in 4 publications (PMIDs: 31471722, 29882329, 25758935, and 27601654) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by its biochemical function catalyzing a reversible transamination reaction between L-alanine and 2-oxoglutarate to produce glutamate and pyruvate (PMID: 11863375), required for amino acid metabolism and neurotransmitter production. As well as its expression at increasing levels in brain during early postnatal development (PMID: 27601654) and a mouse model with decreases in postnatal brain growth and reduced alanine levels, akin to the human phenotype (PMID: 27601654). In summary, GPT2 is definitively associated with autosomal recessive glutamate pyruvate transaminase 2 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

glutamate pyruvate transaminase 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014567

Submitter: PanelApp Australia

glutamate pyruvate transaminase 2 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014567

Submitter: Orphanet

glutamate pyruvate transaminase 2 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014567

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with spastic paraplegia and/or microcephalyAR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25758935

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPT2 variants in ClinVar

15 Conditions Cataloged

Inborn genetic diseasesTotal: 58

not providedTotal: 52

Glutamate pyruvate transaminase 2 deficiencyTotal: 38

not specifiedTotal: 12

GPT2-related disorderTotal: 6

Intellectual disabilityTotal: 3

GPT2-related neurodevelopmental disorderTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_133443.4. 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			2 clinvar	22 clinvar	7 clinvar	31
missense	3 clinvar	5 clinvar	70 clinvar	5 clinvar	1 clinvar	84
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss						0
frameshift	2 clinvar	7 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)		2 clinvar	2 clinvar			4
Total	8	16	76	27	8	135

Highest pathogenic variant AF is 0.000018037383

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_133443.4	RefSeq	NP_597700.1	11	MANE Select
ENST00000340124.9	Ensembl	ENSP00000345282.4	11	MANE Select
NM_001142466.3	RefSeq	NP_001135938.1	10	Standard
ENST00000440783.2	Ensembl	ENSP00000413804.2	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Arginine biosynthesis - Homo sapiens (human)
Glucose-Alanine Cycle
Amino Acid metabolism
Alanine Aspartate Asparagine metabolism

Biological Process

2-oxoglutarate metabolic process
cellular amino acid biosynthetic process
L-alanine metabolic process
L-alanine catabolic process

Molecular Function

L-alanine:2-oxoglutarate aminotransferase activity
pyridoxal phosphate binding

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340124
Coding exons: 11
Length: 46920
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 125747
p: 0.000127

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.88	216	309	0.700	0.0000180	3401
Missense (PolyPhen)		69	126.67	0.54472		1339
Synonymous	0.573	122	130	0.936	0.00000834	1043
Loss of Function	2.69	10	24.3	0.412	0.00000120	279

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00021	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00029	0.00028	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00043	0.00042	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate. {ECO:0000269|PubMed:11863375}.;

Recessive Scores

pRec: 0.757

Intolerance Scores

LoFtool: 0.243
RVIS EVS: -0.43
RVIS percentile EVS: 25.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.777

Gene Damage Prediction

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