GAD1

protein-coding

glutamate decarboxylase 1

Gene summary

This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid. A pathogenic role for this enzyme has been identified in the human pancreas since it has been identified as an autoantigen and an autoreactive T cell target in insulin-dependent diabetes. This gene may also play a role in the stiff man syndrome. Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures. Alternative splicing of this gene results in two products, the predominant 67-kD form and a less-frequent 25-kD form. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_000817.3

Inheritance

ClinVar variants

P:16U:105B:74

Top phenotype

Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathy 89

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr2:170,813,213-170,861,151

External References & Databases

Ensembl (ENSG00000128683)

Transcript & Mutation Effects

hg38 • Region Span ~47.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy 89LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030856

Submitter: G2P

spastic quadriplegic cerebral palsySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016215

Submitter: Orphanet

developmental and epileptic encephalopathy 89STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030856

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy 89STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030856

Submitter: PanelApp Australia

early infantile epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016021

Submitter: ClinGen

GAD1 was first reported in relation to an autosomal recessive developmental delay in 2004 (Lynex CN, et al., 2004, PMID: 15571623), in association with spastic cerebral palsy, however subsequent reports have reported epileptic encephalopathy as the predominant presentation with spasticity present in approximately half of the patients. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 15 unique variants (missense, nonsense, frameshift, in-frame deletion, and splicing) have been reported in humans. Variants in this gene have been reported in at least 14 probands in 5 publications (PMIDs: 28454995, 31144778, 32282878, 15571623, 32705143). Variants in this gene segregated with disease in additional family members. This gene-disease association is supported by its function in glutamate decarboxylase activity (PMID: 1549570), its expression in the brain (PMID: 9177246), and zebrafish model (PMID: 30200754) as well as three mouse models (PMIDs: 9177246, 9326630, 20333300) that partially recapitulate disease. In summary, GAD1 is definitively associated with autosomal recessive epileptic encephalopathy.

cerebral palsy, spastic quadriplegic, 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011329

Submitter: Ambry Genetics

neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033613

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathy 89AR

Manifestation: 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: 9084927; 15571623; 32282878

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GAD1 variants in ClinVar

10 Conditions Cataloged

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesTotal: 172

Inborn genetic diseasesTotal: 62

not providedTotal: 36

Developmental and epileptic encephalopathy 89Total: 18

GAD1-related disorderTotal: 9

not specifiedTotal: 5

Pyridoxine-dependent epilepsyTotal: 1

Hereditary spastic paraplegiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000817.3. 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			5 clinvar	64 clinvar	1 clinvar	70
missense	1 clinvar	2 clinvar	98 clinvar	8 clinvar	1 clinvar	110
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	1 clinvar			5
Total	8	8	105	72	2	195

Highest pathogenic variant AF is 0.000017785635

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000817.3	RefSeq	NP_000808.2	16	MANE Select
ENST00000358196.8	Ensembl	ENSP00000350928.3	16	MANE Select
NM_013445.4	RefSeq	NP_038473.2	6	Standard
ENST00000344257.10	Ensembl	ENSP00000341167.5	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

glutamate catabolic process
glutamate decarboxylation to succinate
chemical synaptic transmission
gamma-aminobutyric acid biosynthetic process
protein-pyridoxal-5-phosphate linkage

Molecular Function

glutamate decarboxylase activity
protein binding
glutamate binding
pyridoxal phosphate binding
protein heterodimerization activity

Cellular Component

plasma membrane
cell cortex
vesicle membrane
axon terminus
presynaptic active zone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358196
Coding exons: 16
Length: 47939
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.32	217	337	0.645	0.0000194	3932
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the production of GABA.;

Recessive Scores

pRec: 0.787

Intolerance Scores

LoFtool: 0.483
RVIS EVS: -0.51
RVIS percentile EVS: 21.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.980

Gene Damage Prediction

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