GAD1

glutamate decarboxylase 1

Basic information

Region (hg38): 2:170813212-170861151

Previous symbols: [ "GAD" ]

Links

ENSG00000128683 ∙ NCBI:2571 ∙ OMIM:605363 ∙ HGNC:4092 ∙ Uniprot:Q99259 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spastic quadriplegic cerebral palsy (Supportive), mode of inheritance: AR
• neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (Limited), mode of inheritance: AR
• developmental and epileptic encephalopathy 89 (Strong), mode of inheritance: AR
• early infantile epileptic encephalopathy (Definitive), mode of inheritance: AR
• neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (Limited), mode of inheritance: AR
• cerebral palsy, spastic quadriplegic, 1 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathy 89	AR	General	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	Neurologic	9084927; 15571623; 32282878

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GAD1 gene.

• Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (170 variants)
• not provided (45 variants)
• Inborn genetic diseases (19 variants)
• Developmental and epileptic encephalopathy 89 (4 variants)
• not specified (2 variants)
• Cerebral palsy spastic quadriplegic (2 variants)
• Hereditary spastic paraplegia (1 variants)
• Refractory epilepsy (1 variants)
• Pyridoxine-dependent epilepsy (1 variants)
• Infantile spasms (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GAD1 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	39	2	43
missense		1	58	5	1	65
nonsense	1	1				2
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1			2
splice region			7	5		12
non coding			29	25	28	82
Total	1	3	90	69	31

Highest pathogenic variant AF is 0.00000657

Variants in GAD1

This is a list of pathogenic ClinVar variants found in the GAD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-170816715-T-G		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170816717-G-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170816820-C-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Apr 28, 2017)
2-170816824-T-C		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170816836-C-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170816857-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170816868-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Benign (Jan 13, 2018)
2-170816886-T-C		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170816936-G-C		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170816942-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Likely benign (Jan 12, 2018)
2-170816951-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170816951-G-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170816954-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Benign (Jan 12, 2018)
2-170816965-G-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Benign (Mar 06, 2018)
2-170817021-G-C		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 12, 2018)
2-170818186-T-C			Benign (Nov 11, 2018)
2-170818539-C-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170818551-C-CCT		Cerebral palsy spastic quadriplegic	Uncertain significance (Jun 14, 2016)
2-170818553-A-C		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Likely benign (May 01, 2022)
2-170818563-A-G		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170818608-C-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jan 13, 2018)
2-170818609-A-G		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Likely benign (Dec 07, 2022)
2-170818625-T-A		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Jul 16, 2018)
2-170818626-C-G		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Nov 30, 2004)
2-170818629-C-T		Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	Uncertain significance (Feb 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GAD1	protein_coding	protein_coding	ENST00000358196	16	47939

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0462	0.954	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.32	217	337	0.645	0.0000194	3932
Missense in Polyphen		69	154.08	0.44782		1813
Synonymous	0.291	122	126	0.967	0.00000782	1116
Loss of Function	3.89	9	33.1	0.272	0.00000161	390

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000904	0.0000904
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000532	0.0000527
Middle Eastern	0.000164	0.000163
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the production of GABA.
• Pathway: Alanine, aspartate and glutamate metabolism - Homo sapiens (human);Type I diabetes mellitus - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Butanoate metabolism - Homo sapiens (human);beta-Alanine metabolism - Homo sapiens (human);Taurine and hypotaurine metabolism - Homo sapiens (human);Carnosinuria, carnosinemia;Ureidopropionase deficiency;GABA-Transaminase Deficiency;2-Hydroxyglutric Aciduria (D And L Form);Beta-Alanine Metabolism;Hypoacetylaspartia;Aspartate Metabolism;Homocarnosinosis;Hyperinsulinism-Hyperammonemia Syndrome;Succinic semialdehyde dehydrogenase deficiency;Taurine and Hypotaurine Metabolism;4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency;Glutamate Metabolism;Canavan Disease;Alanine and aspartate metabolism;MECP2 and Associated Rett Syndrome;One carbon metabolism and related pathways;Biogenic Amine Synthesis;Alanine Aspartate Asparagine metabolism;Glutamate Glutamine metabolism;Methionine Cysteine metabolism;Neuronal System;glutamate dependent acid resistance;Arginine Proline metabolism;GABA shunt;GABA synthesis;GABA synthesis, release, reuptake and degradation;Neurotransmitter release cycle;Transmission across Chemical Synapses (Consensus)

Recessive Scores

• pRec: 0.787

Intolerance Scores

• loftool: 0.483
• rvis_EVS: -0.51
• rvis_percentile_EVS: 21.56

Haploinsufficiency Scores

• pHI: 0.968
• hipred: Y
• hipred_score: 0.771
• ghis: 0.558

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.980

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gad1
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; growth/size/body region phenotype; taste/olfaction phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; skeleton phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: glutamate catabolic process;glutamate decarboxylation to succinate;chemical synaptic transmission;gamma-aminobutyric acid biosynthetic process;protein-pyridoxal-5-phosphate linkage;social behavior;locomotory exploration behavior;response to drug
• Cellular component: plasma membrane;cell cortex;vesicle membrane;axon terminus;presynaptic active zone;inhibitory synapse;clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane
• Molecular function: glutamate decarboxylase activity;protein binding;glutamate binding;pyridoxal phosphate binding;protein heterodimerization activity;protein N-terminus binding