Hyperekplexia 2

Summary

Hyperekplexia 2 (MONDO:0013828) is a disease caused by GLRB (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GLRB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 408

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperekplexia 2
Mondo ID	MONDO:0013828
OMIM	614619
DOID	DOID:0060697
UMLS	C3553291
MedGen	766205
GARD	0015826
Is cancer (heuristic)	no

Also known as: GLRB hereditary hyperekplexia · hereditary hyperekplexia caused by mutation in GLRB · HKPX2 · hyperekplexia 2 · hyperekplexia type 2

Data availability: 408 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › hyperekplexia › hereditary hyperekplexia › hyperekplexia 2

Related subtypes (4): hyperekplexia 1, developmental and epileptic encephalopathy, 8, hyperekplexia 3, hyperekplexia 4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

408 retrieved; paginated sample, class counts are floors:

175 uncertain significance, 160 likely benign, 34 benign, 17 pathogenic, 10 conflicting classifications of pathogenicity, 7 benign/likely benign, 4 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064420	NM_000824.5(GLRB):c.1114C>T (p.Gln372Ter)	GLRB	Pathogenic	criteria provided, single submitter
1076905	NM_000824.5(GLRB):c.634C>T (p.Arg212Ter)	GLRB	Pathogenic	criteria provided, single submitter
1459343	NM_000824.5(GLRB):c.371del (p.Gly124fs)	GLRB	Pathogenic	criteria provided, single submitter
16058	NM_000824.5(GLRB):c.752G>A (p.Gly251Asp)	GLRB	Pathogenic	no assertion criteria provided
16059	NM_000824.5(GLRB):c.610+5G>A	GLRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2095370	NM_000824.5(GLRB):c.618C>G (p.Tyr206Ter)	GLRB	Pathogenic	criteria provided, single submitter
2710247	NM_000824.5(GLRB):c.704del (p.Lys235fs)	GLRB	Pathogenic	criteria provided, single submitter
2754032	NM_000824.5(GLRB):c.84del (p.Lys31fs)	GLRB	Pathogenic	criteria provided, single submitter
2772628	NM_000824.5(GLRB):c.449del (p.Ser150fs)	GLRB	Pathogenic	criteria provided, single submitter
3638329	NM_000824.5(GLRB):c.756C>G (p.Tyr252Ter)	GLRB	Pathogenic	criteria provided, single submitter
3688899	NM_000824.5(GLRB):c.762del (p.Cys255fs)	GLRB	Pathogenic	criteria provided, single submitter
4747421	NM_000824.5(GLRB):c.298-1G>A	GLRB	Pathogenic	criteria provided, multiple submitters, no conflicts
540368	NM_000824.5(GLRB):c.1221dup (p.Val408fs)	GLRB	Pathogenic	criteria provided, single submitter
574411	NM_000824.5(GLRB):c.448dup (p.Ser150fs)	GLRB	Pathogenic	criteria provided, single submitter
574419	NM_000824.5(GLRB):c.123-2A>G	GLRB	Pathogenic	criteria provided, single submitter
582806	NM_000824.5(GLRB):c.472del (p.Gln158fs)	GLRB	Pathogenic	criteria provided, single submitter
653331	NM_000824.5(GLRB):c.24del (p.Phe9_Leu10insTer)	GLRB	Pathogenic	criteria provided, single submitter
802099	NM_000824.5(GLRB):c.122+1G>A	GLRB	Pathogenic	criteria provided, single submitter
1067051	NM_000824.5(GLRB):c.297+1G>T	GLRB	Likely pathogenic	criteria provided, single submitter
3246671	NC_000004.11:g.(?158091564)(158091880_?)del	GLRB	Likely pathogenic	criteria provided, single submitter
4728274	NM_000824.5(GLRB):c.122+1G>C	GLRB	Likely pathogenic	criteria provided, single submitter
663950	NC_000004.12:g.(?157170412)(157170748_?)del	GLRB	Likely pathogenic	criteria provided, single submitter
1121991	NM_000824.5(GLRB):c.205C>T (p.Pro69Ser)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1159907	NM_000824.5(GLRB):c.736T>C (p.Tyr246His)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1543487	NM_000824.5(GLRB):c.1458G>C (p.Leu486Phe)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1588001	NM_000824.5(GLRB):c.838A>G (p.Ile280Val)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2252581	NM_000824.5(GLRB):c.1414C>T (p.Arg472Ter)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347921	NM_000824.5(GLRB):c.822C>T (p.Tyr274=)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347925	NM_000824.5(GLRB):c.952G>A (p.Ala318Thr)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
651260	NM_000824.5(GLRB):c.185G>A (p.Arg62Lys)	GLRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GLRB	Definitive	Autosomal recessive	hyperekplexia 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLRB	Orphanet:3197	Hereditary hyperekplexia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLRB	HGNC:4329	ENSG00000109738	P48167	Glycine receptor subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLRB	Glycine receptor subunit beta	Subunit of heteromeric glycine-gated chloride channels.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLRB	Other/Unknown	no		Neurotrans-gated_channel_TM, Neur_channel, Neur_chan_lig-bd

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 10	1
frontal pole	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLRB	236	ubiquitous	marker	frontal pole, Brodmann (1909) area 10, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLRB	1,382

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLRB	P48167	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.010	GLRB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic transmission, glycinergic	1	4213.0×	0.002	GLRB
gamma-aminobutyric acid receptor clustering	1	3370.4×	0.002	GLRB
righting reflex	1	1872.4×	0.002	GLRB
startle response	1	1123.5×	0.003	GLRB
acrosome reaction	1	887.0×	0.003	GLRB
adult walking behavior	1	495.6×	0.004	GLRB
chloride transmembrane transport	1	237.3×	0.007	GLRB
neuropeptide signaling pathway	1	172.0×	0.009	GLRB
monoatomic ion transport	1	156.0×	0.009	GLRB
visual perception	1	79.5×	0.014	GLRB
chemical synaptic transmission	1	77.3×	0.014	GLRB
nervous system development	1	45.9×	0.022	GLRB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLRB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GLRB	30	Binding:29, Toxicity:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GLRB

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GLRB	30	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.