Hyperekplexia 3

Summary

Hyperekplexia 3 (MONDO:0013827) is a disease caused by SLC6A5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: SLC6A5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 776

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperekplexia 3
Mondo ID	MONDO:0013827
OMIM	614618
DOID	DOID:0060698
UMLS	C3553288
MedGen	766202
GARD	0015825
Is cancer (heuristic)	no

Also known as: hereditary hyperekplexia caused by mutation in SLC6A5 · HKPX3 · hyperekplexia 3 · hyperekplexia type 3 · SLC6A5 hereditary hyperekplexia

Data availability: 776 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 3

Related subtypes (4): hyperekplexia 1, developmental and epileptic encephalopathy, 8, hyperekplexia 2, 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

600 retrieved; paginated sample, class counts are floors:

273 likely benign, 255 uncertain significance, 19 conflicting classifications of pathogenicity, 19 pathogenic, 18 benign, 12 likely pathogenic, 3 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323615	NM_004211.5(SLC6A5):c.1315C>T (p.Arg439Ter)	SLC6A5	Pathogenic	criteria provided, multiple submitters, no conflicts
1353821	NM_004211.5(SLC6A5):c.2124C>A (p.Tyr708Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
1373505	NM_004211.5(SLC6A5):c.1266_1267dup (p.Tyr423fs)	SLC6A5	Pathogenic	criteria provided, single submitter
1394178	NM_004211.5(SLC6A5):c.997_998del (p.Ile333fs)	SLC6A5	Pathogenic	criteria provided, single submitter
1437471	NM_004211.5(SLC6A5):c.1621C>T (p.Gln541Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
1453382	NC_000011.9:g.(?20621219)(20668500_?)del	SLC6A5	Pathogenic	criteria provided, single submitter
1454424	NM_004211.5(SLC6A5):c.1759del (p.Ile586_Val587insTer)	SLC6A5	Pathogenic	criteria provided, single submitter
1455981	NM_004211.5(SLC6A5):c.1680_1681dup (p.Pro561fs)	SLC6A5	Pathogenic	criteria provided, single submitter
1457616	NC_000011.9:g.(?20668360)(20668500_?)del	SLC6A5	Pathogenic	criteria provided, single submitter
1458893	NM_004211.5(SLC6A5):c.90C>A (p.Cys30Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
1971213	NM_004211.5(SLC6A5):c.811+1G>T	SLC6A5	Pathogenic	criteria provided, single submitter
2015912	NM_004211.5(SLC6A5):c.342del (p.Gly115fs)	SLC6A5	Pathogenic	criteria provided, single submitter
2018966	NM_004211.5(SLC6A5):c.769C>T (p.Gln257Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
2059727	NM_004211.5(SLC6A5):c.677del (p.Gly226fs)	SLC6A5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2079085	NM_004211.5(SLC6A5):c.1969+1G>A	SLC6A5	Pathogenic	criteria provided, single submitter
2087072	NM_004211.5(SLC6A5):c.1374G>A (p.Trp458Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
2149851	NM_004211.5(SLC6A5):c.1286C>T (p.Pro429Leu)	SLC6A5	Pathogenic	criteria provided, multiple submitters, no conflicts
2425045	NC_000011.9:g.(?20612464)(20622873_?)del	SLC6A5	Pathogenic	criteria provided, single submitter
2858966	NM_004211.5(SLC6A5):c.31A>T (p.Lys11Ter)	SLC6A5	Pathogenic	criteria provided, single submitter
2991866	NM_004211.5(SLC6A5):c.1680_1681del (p.Pro561fs)	SLC6A5	Pathogenic	criteria provided, single submitter
1067229	NM_004211.5(SLC6A5):c.1260+1G>T	SLC6A5	Likely pathogenic	criteria provided, single submitter
1464961	NM_004211.5(SLC6A5):c.1641T>G (p.Phe547Leu)	SLC6A5	Likely pathogenic	criteria provided, single submitter
1470289	NM_004211.5(SLC6A5):c.710T>C (p.Leu237Pro)	SLC6A5	Likely pathogenic	criteria provided, single submitter
1931559	NM_004211.5(SLC6A5):c.728C>G (p.Pro243Arg)	SLC6A5	Likely pathogenic	criteria provided, single submitter
1993983	NM_004211.5(SLC6A5):c.985+1G>A	SLC6A5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2074189	NM_004211.5(SLC6A5):c.3+1G>T	SLC6A5	Likely pathogenic	criteria provided, single submitter
2425043	NC_000011.9:g.(?20668360)(20668500_?)dup	SLC6A5	Likely pathogenic	criteria provided, single submitter
2441905	NM_004211.5(SLC6A5):c.1436_1737+314del	SLC6A5	Likely pathogenic	criteria provided, single submitter
2498225	NM_004211.5(SLC6A5):c.975del (p.Lys325fs)	SLC6A5	Likely pathogenic	criteria provided, single submitter
2582175	NM_004211.5(SLC6A5):c.727C>A (p.Pro243Thr)	SLC6A5	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 2 · 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
SLC6A2	Definitive	Autosomal recessive	hyperekplexia 3	9
SLC6A5	Definitive	Autosomal recessive	hyperekplexia 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A2	Orphanet:443236	Postural orthostatic tachycardia syndrome due to NET deficiency
SLC6A5	Orphanet:3197	Hereditary hyperekplexia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC6A2	HGNC:11048	ENSG00000103546	P23975	Sodium-dependent noradrenaline transporter	gencc,clinvar
SLC6A5	HGNC:11051	ENSG00000165970	Q9Y345	Sodium- and chloride-dependent glycine transporter 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A2	Sodium-dependent noradrenaline transporter	Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline), the primary signaling neurotransmitter in the autonomic sympathetic nervous system.
SLC6A5	Sodium- and chloride-dependent glycine transporter 2	Sodium- and chloride-dependent glycine transporter.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A2	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_noradrenaline, SNS_sf
SLC6A5	Other/Unknown	no		Na/ntran_symport, SNS_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
decidua	1
placenta	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A2	121	ubiquitous	marker	placenta, buccal mucosa cell, decidua
SLC6A5	36	ubiquitous	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC6A5	1,314
SLC6A2	1,213

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A2	P23975	36
SLC6A5	Q9Y345	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SLC-mediated transport of neurotransmitters	2	407.9×	5e-05	SLC6A2, SLC6A5
SLC transporter disorders	2	203.9×	9e-05	SLC6A2, SLC6A5
R-HSA-425366	2	181.3×	9e-05	SLC6A2, SLC6A5
Disorders of transmembrane transporters	2	139.3×	1e-04	SLC6A2, SLC6A5
SLC-mediated transmembrane transport	2	59.2×	5e-04	SLC6A2, SLC6A5
Defective SLC6A5 causes hyperekplexia 3 (HKPX3)	1	2855.0×	5e-04	SLC6A5
Defective SLC6A2 causes orthostatic intolerance (OI)	1	1427.5×	9e-04	SLC6A2
Transport of small molecules	2	25.1×	0.002	SLC6A2, SLC6A5
Disease	2	13.1×	0.006	SLC6A2, SLC6A5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neurotransmitter transport	2	421.3×	7e-05	SLC6A2, SLC6A5
sodium ion transmembrane transport	2	203.0×	2e-04	SLC6A2, SLC6A5
chemical synaptic transmission	2	77.3×	7e-04	SLC6A2, SLC6A5
synaptic transmission, glycinergic	1	2106.5×	0.002	SLC6A5
glycine import across plasma membrane	1	1203.7×	0.002	SLC6A5
obsolete norepinephrine transport	1	936.2×	0.002	SLC6A2
dopamine uptake involved in synaptic transmission	1	936.2×	0.002	SLC6A2
norepinephrine uptake	1	936.2×	0.002	SLC6A2
obsolete monoamine transport	1	601.9×	0.002	SLC6A2
response to pain	1	443.5×	0.003	SLC6A2
neuron cellular homeostasis	1	227.7×	0.005	SLC6A2
amino acid transport	1	156.0×	0.007	SLC6A2
response to xenobiotic stimulus	1	34.5×	0.029	SLC6A2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC6A2	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A2	471	4
SLC6A5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	SLC6A2
BEPRIDIL	4	SLC6A2
CANDESARTAN CILEXETIL	4	SLC6A2
BEXAROTENE	4	SLC6A2
CLOTRIMAZOLE	4	SLC6A2
AMINOCAPROIC ACID	4	SLC6A2
SIMVASTATIN	4	SLC6A2
NABUMETONE	4	SLC6A2
METAXALONE	4	SLC6A2
ACETOPHENAZINE	4	SLC6A2
MESORIDAZINE	4	SLC6A2
PHENELZINE	4	SLC6A2
NIRAPARIB	4	SLC6A2
INDACATEROL	4	SLC6A2
IMIPRAMINE	4	SLC6A2
EPINASTINE	4	SLC6A2
RIMONABANT	4	SLC6A2
ARIPIPRAZOLE	4	SLC6A2
AMOXAPINE	4	SLC6A2
IDARUBICIN	4	SLC6A2
DESVENLAFAXINE	4	SLC6A2
EZETIMIBE	4	SLC6A2
PONATINIB	4	SLC6A2
DESLORATADINE	4	SLC6A2
RUCAPARIB	4	SLC6A2
DULOXETINE	4	SLC6A2
CELECOXIB	4	SLC6A2
UMECLIDINIUM	4	SLC6A2
TRIMETREXATE	4	SLC6A2
PHENIRAMINE	4	SLC6A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A2	929	Binding:885, ADMET:25, Functional:15, Toxicity:3, Unclassified:1
SLC6A5	54	Binding:50, Functional:4

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SLC6A2	929

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
CETIRIZINE	4	SLC6A2
BEPRIDIL	4	SLC6A2
CANDESARTAN CILEXETIL	4	SLC6A2
BEXAROTENE	4	SLC6A2
CLOTRIMAZOLE	4	SLC6A2
AMINOCAPROIC ACID	4	SLC6A2
SIMVASTATIN	4	SLC6A2
NABUMETONE	4	SLC6A2
METAXALONE	4	SLC6A2
ACETOPHENAZINE	4	SLC6A2
MESORIDAZINE	4	SLC6A2
PHENELZINE	4	SLC6A2
NIRAPARIB	4	SLC6A2
INDACATEROL	4	SLC6A2
IMIPRAMINE	4	SLC6A2
EPINASTINE	4	SLC6A2
RIMONABANT	4	SLC6A2
ARIPIPRAZOLE	4	SLC6A2
AMOXAPINE	4	SLC6A2
IDARUBICIN	4	SLC6A2
DESVENLAFAXINE	4	SLC6A2
EZETIMIBE	4	SLC6A2
PONATINIB	4	SLC6A2
DESLORATADINE	4	SLC6A2
RUCAPARIB	4	SLC6A2
DULOXETINE	4	SLC6A2
CELECOXIB	4	SLC6A2
UMECLIDINIUM	4	SLC6A2
TRIMETREXATE	4	SLC6A2
PHENIRAMINE	4	SLC6A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC6A2
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	SLC6A5

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)
SLC6A5	54	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.