GeneBe

GLUD1

protein-coding

glutamate dehydrogenase 1

Gene summary

This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X. [provided by RefSeq, Jan 2016]

Previous symbols:
  • GLUD

MANE transcript

NM_005271.5

Inheritance

AD

ClinVar variants

P:20U:149B:93

Top phenotype

Hyperinsulinemic hypoglycemia, familial 6; Hyperammonemia-hyperinsulinism

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr10:87,050,202-87,094,843

External References & Databases

Ensembl (ENSG00000148672)NCBI Gene (2746)OMIM (138130)HGNC:4335GenCCUniProt (P00367)AlphaFoldClinVar (GLUD1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~44.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperinsulinism-hyperammonemia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011717

Submitter: PanelApp Australia

hyperinsulinism-hyperammonemia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011717

Submitter: G2P

hyperinsulinism-hyperammonemia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011717

Submitter: Orphanet

hyperinsulinism-hyperammonemia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011717

Submitter: Labcorp Genetics (formerly Invitae)

hyperinsulinism-hyperammonemia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011717

Submitter: ClinGen

GLUD1 was first reported in relation to Autosomal Dominant Hyperinsulinism-Hyperammonemia Syndrome (HI/HA) in 1998 (Stanley et al., PMID: 9571255). At least 30 unique variants, the vast majority of which are missense, have been reported in humans. Notably, this gene has a number of mutational hotspots and de novo variants are responsible for a large percentage of known pathogenic variation. Evidence supporting this gene-disease relationship includes case-level data, limited segregation data, and experimental data. Variants in this gene have been reported in at least 16 probands in three publications (PMIDs: 9571255, 11214910, 26759084), with many more case reports and publications available in the literature. A variant in this gene also segregated with disease in 4 additional members of a single family. The known mechanisms for disease are caused by both neomorphic and hypermorphic variants, either decreasing the sensitivity to GDH's inhibitors or increasing the sensitivity/adding new activators and causing a hyperactive protein (PMIDs: 16574664, 28911206). This gene-disease association is additionally supported by a transgenic mouse model that recapitulates the biochemical abnormalities observed in human probands and functional studies of one particular gain-of-function variant that defines the consistent pathogenic mechanism in this gene. In summary, GLUD1 is definitively associated with autosomal dominant hyperinsulinism-hyperammonemia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Hyperinsulinemic hypoglycemia, familial 6; Hyperammonemia-hyperinsulinismAD

Manifestation: Biochemical; Endocrine

Intervention: Biochemical; Endocrine

Rationale: At initial diagnosis, hypoglycemia can be corrected with IV glucose in order to prevent brain damage; Long-term management includes diazoxide, somatostatin analogs, nifedipine, glucagon, recombinant IGF-I, glucocorticoids, human growth hormone, and dietary intervention (including with leucine restrictions in some recessive forms of disease); If aggressive medical management fails or is not possible, pancreatic resection may be considered

Refs: 9843361; 9571255; 9469993; 10636977; 10871207; 11518822; 11241047; 11297618; 11214910; 19046187; 20857847; 20301549; 22106762; 21932603; 22759688Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLUD1 variants in ClinVar

10 Conditions Cataloged
Hyperinsulinism-hyperammonemia syndromeTotal: 183
Inborn genetic diseasesTotal: 85
not providedTotal: 69
not specifiedTotal: 53
GLUD1-related disorderTotal: 31
GLUD1-related disordersTotal: 6
Monogenic diabetesTotal: 3
Familial hyperinsulinismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005271.5. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
80
clinvar
1
clinvar
 84
missense
8
clinvar
12
clinvar
133
clinvar
12
clinvar
 165
nonsense
2
clinvar
 2
start loss
2
clinvar
 2
frameshift
4
clinvar
 4
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total812149921262

Highest pathogenic variant AF is 6.842323e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005271.5RefSeqNP_005262.113MANE Select
ENST00000277865.5EnsemblENSP00000277865.413MANE Select
NM_001318900.1RefSeqNP_001305829.113Standard
NM_001318901.1RefSeqNP_001305830.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
  • D-Glutamine and D-glutamate metabolism - Homo sapiens (human)
  • Proximal tubule bicarbonate reclamation - Homo sapiens (human)
  • Necroptosis - Homo sapiens (human)
  • Nitrogen metabolism - Homo sapiens (human)

Biological Process

  • glutamate biosynthetic process
  • glutamate catabolic process
  • glutamine metabolic process
  • cellular amino acid biosynthetic process
  • substantia nigra development

Molecular Function

  • glutamate dehydrogenase (NAD+) activity
  • glutamate dehydrogenase [NAD(P)+] activity
  • protein binding
  • ATP binding
  • GTP binding

Cellular Component

  • cytoplasm
  • mitochondrion
  • mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000277865
Coding exons
13
Length
44381
Individuals with no LoFs
125726
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125748
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.061633160.5160.00001623660
Missense (PolyPhen)39101.780.383191204
Synonymous1.35991180.8410.000005871091
Loss of Function2.98823.60.3390.00000101316

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000430.00044rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000720.000070rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Mitochondrial glutamate dehydrogenase that converts L- glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle. May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity). {ECO:0000250}.;
Disease
DISEASE: Familial hyperinsulinemic hypoglycemia 6 (HHF6) [MIM:606762]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. In HHF6 elevated oxidation rate of glutamate to alpha-ketoglutarate stimulates insulin secretion in the pancreatic beta cells, while they impair detoxification of ammonium in the liver. {ECO:0000269|PubMed:10636977, ECO:0000269|PubMed:11214910, ECO:0000269|PubMed:11297618, ECO:0000269|PubMed:9571255}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.709

Intolerance Scores

LoFtool
0.232
RVIS EVS
-0.03
RVIS percentile EVS
51.4

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.878

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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