GeneBe

GLRA1

protein-coding

glycine receptor alpha 1, the group of Glycine receptors

Gene summary

The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

Previous symbols:
  • STHE

MANE transcript

NM_000171.4

Inheritance

AD, AR

ClinVar variants

P:94U:232B:125

Top phenotype

Hyperekplexia 1

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr5:151,822,513-151,924,851

External References & Databases

Ensembl (ENSG00000145888)NCBI Gene (2741)OMIM (138491)HGNC:4326GenCCUniProt (P23415)AlphaFoldClinVar (GLRA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~102.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperekplexia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007868

Submitter: PanelApp Australia

hyperekplexia 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007868

Submitter: G2P

hereditary hyperekplexiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021022

Submitter: Orphanet

hyperekplexia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007868

Submitter: PanelApp Australia

hyperekplexia 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007868

Submitter: G2P

hyperekplexia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007868

Submitter: Labcorp Genetics (formerly Invitae)

hyperekplexia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007868

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperekplexia 1AD/AR

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Neonates are at risk of sudden death from apnea/aspiration, and surveillance, as well as primary prevention with medical treatments (eg, clonazepam) may be beneficial

Refs: 1334371; 8298642; 7881416; 11104232; 8571969; 16832093; 20301437Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLRA1 variants in ClinVar

9 Conditions Cataloged
Hereditary hyperekplexiaTotal: 457
not providedTotal: 96
Hyperekplexia 1Total: 94
Inborn genetic diseasesTotal: 51
not specifiedTotal: 27
GLRA1-related disorderTotal: 22
GLRA1-related disordersTotal: 2
Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000171.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
106
clinvar
2
clinvar
 109
missense
17
clinvar
33
clinvar
225
clinvar
15
clinvar
2
clinvar
 292
nonsense
10
clinvar
5
clinvar
 15
start loss
4
clinvar
 4
frameshift
10
clinvar
7
clinvar
1
clinvar
 18
splice donor/acceptor (+/-2bp)
2
clinvar
10
clinvar
1
clinvar
 13
Total39552321214451

Highest pathogenic variant AF is 0.0003335524

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000171.4RefSeqNP_000162.29MANE Select
ENST00000274576.9EnsemblENSP00000274576.59MANE Select
NM_001146040.2RefSeqNP_001139512.19Standard
NM_001292000.2RefSeqNP_001278929.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
glra1Danio rerio

Structure: tonic skeletal muscle contraction

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neuroactive ligand-receptor interaction - Homo sapiens (human)
  • Neuronal System
  • Neurotransmitter receptors and postsynaptic signal transmission
  • Transmission across Chemical Synapses

Biological Process

  • action potential
  • startle response
  • regulation of respiratory gaseous exchange by neurological system process
  • ion transport
  • chloride transport

Molecular Function

  • transmembrane signaling receptor activity
  • extracellular ligand-gated ion channel activity
  • chloride channel activity
  • protein binding
  • zinc ion binding

Cellular Component

  • endoplasmic reticulum
  • plasma membrane
  • integral component of plasma membrane
  • external side of plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000455880
Coding exons
9
Length
102330
Individuals with no LoFs
125702
Homozygous LoFs
0
Heterozygous LoFs
46
Defined
125748
p
0.000183
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.421952590.7520.00001513042
Missense (PolyPhen)58108.260.535741234
Synonymous0.01989797.20.9970.00000541869
Loss of Function2.411022.30.4490.00000127241

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000640.000062rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish00.0absent
East Asian0.000920.00092rare
Finnish0.000180.00018rare
European (Non-Finnish)0.0000790.000079rare
South Asian0.000130.00013rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Glycine receptors are ligand-gated chloride channels (PubMed:23994010, PubMed:25730860). Channel opening is triggered by extracellular glycine (PubMed:2155780, PubMed:7920629, PubMed:14551753, PubMed:16144831, PubMed:22715885, PubMed:22973015, PubMed:25973519, PubMed:9009272). Channel opening is also triggered by taurine and beta-alanine (PubMed:16144831, PubMed:9009272). Channel characteristics depend on the subunit composition; heteropentameric channels are activated by lower glycine levels and display faster desensitization (PubMed:14551753). Plays an important role in the down-regulation of neuronal excitability (PubMed:8298642, PubMed:9009272). Contributes to the generation of inhibitory postsynaptic currents (PubMed:25445488). Channel activity is potentiated by ethanol (PubMed:25973519). Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol (By similarity). {ECO:0000250|UniProtKB:Q64018, ECO:0000269|PubMed:14551753, ECO:0000269|PubMed:16144831, ECO:0000269|PubMed:2155780, ECO:0000269|PubMed:22715885, ECO:0000269|PubMed:22973015, ECO:0000269|PubMed:23994010, ECO:0000269|PubMed:25445488, ECO:0000269|PubMed:25730860, ECO:0000269|PubMed:25973519, ECO:0000269|PubMed:7920629, ECO:0000269|PubMed:7925268, ECO:0000269|PubMed:9009272, ECO:0000305|PubMed:8298642}.;
Disease
DISEASE: Hyperekplexia 1 (HKPX1) [MIM:149400]: A neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli. {ECO:0000269|PubMed:10514101, ECO:0000269|PubMed:24108130, ECO:0000269|PubMed:25730860, ECO:0000269|PubMed:7611730, ECO:0000269|PubMed:7881416, ECO:0000269|PubMed:7925268, ECO:0000269|PubMed:7981700, ECO:0000269|PubMed:8298642, ECO:0000269|PubMed:8571969, ECO:0000269|PubMed:8733061, ECO:0000269|PubMed:9009272, ECO:0000269|PubMed:9067762, ECO:0000269|PubMed:9920650, ECO:0000269|Ref.18}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.201

Intolerance Scores

LoFtool
0.0783
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
0.645

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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