GLUD1

glutamate dehydrogenase 1

Basic information

Region (hg38): 10:87050202-87094843

Previous symbols: [ "GLUD" ]

Links

ENSG00000148672 ∙ NCBI:2746 ∙ OMIM:138130 ∙ HGNC:4335 ∙ Uniprot:P00367 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyperinsulinism-hyperammonemia syndrome (Definitive), mode of inheritance: AD
• hyperinsulinism-hyperammonemia syndrome (Strong), mode of inheritance: AR
• hyperinsulinism-hyperammonemia syndrome (Strong), mode of inheritance: AD
• hyperinsulinism-hyperammonemia syndrome (Supportive), mode of inheritance: AD
• hyperinsulinism-hyperammonemia syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperinsulinemic hypoglycemia, familial 6; Hyperammonemia-hyperinsulinism	AD	Biochemical; Endocrine	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	Biochemical; Endocrine	9843361; 9571255; 9469993; 10636977; 10871207; 11518822; 11241047; 11297618; 11214910; 19046187; 20857847; 20301549; 22106762; 21932603; 22759688

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GLUD1 gene.

• Hyperinsulinism-hyperammonemia syndrome (4 variants)
• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GLUD1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	46	3	51
missense	5	6	66	7		84
nonsense			1			1
start loss			1			1
frameshift			1			1
inframe indel			2			2
splice donor/acceptor (+/-2bp)			2			2
splice region			10	5	1	16
non coding			22	19	5	46
Total	5	6	97	72	8

Variants in GLUD1

This is a list of pathogenic ClinVar variants found in the GLUD1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-87050203-G-A		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050206-G-A		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050236-T-C		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 12, 2018)
10-87050250-C-G		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050287-G-A		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050315-C-T		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050332-A-C		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050372-G-A		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 12, 2018)
10-87050469-C-G		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 12, 2018)
10-87050481-G-A		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050499-A-G		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050540-A-G		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050570-G-T		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 12, 2018)
10-87050580-T-TA		Hyperinsulinism, Dominant	Uncertain significance (Jun 14, 2016)
10-87050612-A-G		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 12, 2018)
10-87050753-G-A		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Mar 30, 2018)
10-87050779-C-T		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 13, 2018)
10-87050781-T-C		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87050843-A-G		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 12, 2018)
10-87050883-T-G		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 12, 2018)
10-87050899-T-C		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 12, 2018)
10-87051255-C-T		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 13, 2018)
10-87051282-G-T		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Apr 27, 2017)
10-87051396-A-C		Hyperinsulinism-hyperammonemia syndrome	Likely benign (Jan 13, 2018)
10-87051546-T-C		Hyperinsulinism-hyperammonemia syndrome	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GLUD1	protein_coding	protein_coding	ENST00000277865	13	44381

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00705	0.992	125726	0	22	125748	0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.06	163	316	0.516	0.0000162	3660
Missense in Polyphen		39	101.78	0.38319		1204
Synonymous	1.35	99	118	0.841	0.00000587	1091
Loss of Function	2.98	8	23.6	0.339	0.00000101	316

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000275	0.000275
Ashkenazi Jewish	0.00	0.00
East Asian	0.000435	0.000435
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000722	0.0000703
Middle Eastern	0.000435	0.000435
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Arginine biosynthesis - Homo sapiens (human);Warburg Effect;Argininemia;2-Hydroxyglutric Aciduria (D And L Form);Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Ammonia Recycling;Citrullinemia Type I;Carbamoyl Phosphate Synthetase Deficiency;Argininosuccinic Aciduria;Glucose-Alanine Cycle;Urea Cycle;Glutaminolysis and Cancer;Homocarnosinosis;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;Prolinemia Type II;Prolidase Deficiency (PD);Ornithine Transcarbamylase Deficiency (OTC Deficiency);Arginine and Proline Metabolism;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);Glutamate Metabolism;Amino Acid metabolism;Urea cycle and metabolism of amino groups;Glutamate Glutamine metabolism;Metabolism of amino acids and derivatives;Metabolism;ornithine <i>de novo </i> biosynthesis;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Arginine Proline metabolism;glutamate biosynthesis/degradation;GABA shunt;Transcriptional activation of mitochondrial biogenesis;Mitochondrial biogenesis;Amino acid synthesis and interconversion (transamination);Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.709

Intolerance Scores

• loftool: 0.232
• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.4

Haploinsufficiency Scores

• pHI: 0.454
• hipred: Y
• hipred_score: 0.546
• ghis: 0.539

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.878

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Glud1
• Phenotype: endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: glutamate biosynthetic process;glutamate catabolic process;glutamine metabolic process;cellular amino acid biosynthetic process;substantia nigra development;positive regulation of insulin secretion;oxidation-reduction process;tricarboxylic acid metabolic process
• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix
• Molecular function: glutamate dehydrogenase (NAD+) activity;glutamate dehydrogenase [NAD(P)+] activity;protein binding;ATP binding;GTP binding;identical protein binding;ADP binding;NAD+ binding;leucine binding