Episodic ataxia type 6

Summary

Episodic ataxia type 6 (MONDO:0012982) is a disease caused by SLC1A3 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC1A3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 103
• Phenotypes (HPO): 14
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0002183	Phonophobia	Frequent (30-79%)
HP:0000640	Gaze-evoked nystagmus	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002301	Hemiplegia	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	episodic ataxia type 6
Mondo ID	MONDO:0012982
MeSH	C567207
OMIM	612656
Orphanet	209967
DOID	DOID:0050994
ICD-11	1493336901
SNOMED CT	718753002
UMLS	C2675211
MedGen	390739
GARD	0017107
Is cancer (heuristic)	no

Also known as: EA6 · episodic ataxia type 6 · episodic ataxia, type 6 · hereditary episodic ataxia caused by mutation in SLC1A3 · SLC1A3 hereditary episodic ataxia

Data availability: 103 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › hereditary episodic ataxia › episodic ataxia type 6

Related subtypes (8): episodic ataxia type 2, episodic ataxia type 1, episodic ataxia type 4, episodic ataxia type 3, episodic ataxia type 7, episodic ataxia type 5, episodic ataxia type 8, episodic ataxia, type 9

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

103 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 33 benign, 12 conflicting classifications of pathogenicity, 12 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9441	NM_004172.5(SLC1A3):c.869C>G (p.Pro290Arg)	SLC1A3-AS1	Pathogenic	no assertion criteria provided
9442	NM_004172.5(SLC1A3):c.556T>A (p.Cys186Ser)	SLC1A3-AS1	Pathogenic	no assertion criteria provided
242994	NM_004172.5(SLC1A3):c.1496G>A (p.Arg499Gln)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353307	NM_004172.5(SLC1A3):c.79C>T (p.Leu27Phe)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353310	NM_004172.5(SLC1A3):c.227G>A (p.Arg76Gln)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353316	NM_004172.5(SLC1A3):c.825C>T (p.Asn275=)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353324	NM_004172.5(SLC1A3):c.1284A>C (p.Thr428=)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353341	NM_004172.5(SLC1A3):c.*761G>A	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353348	NM_004172.5(SLC1A3):c.*1206G>A	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805481	NM_004172.5(SLC1A3):c.279G>A (p.Gln93=)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905872	NM_004172.5(SLC1A3):c.297T>G (p.Leu99=)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907389	NM_004172.5(SLC1A3):c.921G>T (p.Met307Ile)	SLC1A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353320	NM_004172.5(SLC1A3):c.985G>A (p.Ala329Thr)	SLC1A3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906385	NM_004172.5(SLC1A3):c.650T>C (p.Val217Ala)	SLC1A3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028197	NM_004172.5(SLC1A3):c.209C>G (p.Pro70Arg)	SLC1A3	Uncertain significance	criteria provided, single submitter
1256120	NM_004172.5(SLC1A3):c.1144G>A (p.Val382Met)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1298988	NM_004172.5(SLC1A3):c.1397C>T (p.Thr466Met)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1341725	NM_004172.5(SLC1A3):c.329C>T (p.Ala110Val)	SLC1A3	Uncertain significance	criteria provided, single submitter
1675981	NM_004172.5(SLC1A3):c.1025G>A (p.Arg342Gln)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805783	NM_004172.5(SLC1A3):c.299T>C (p.Ile100Thr)	SLC1A3	Uncertain significance	criteria provided, single submitter
195211	NM_004172.5(SLC1A3):c.28A>G (p.Lys10Glu)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435982	NM_004172.5(SLC1A3):c.674C>T (p.Thr225Ile)	SLC1A3	Uncertain significance	criteria provided, single submitter
2441631	NM_004172.5(SLC1A3):c.1436G>A (p.Arg479Gln)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2973063	NM_004172.5(SLC1A3):c.397A>G (p.Ile133Val)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3066256	NM_004172.5(SLC1A3):c.1444del (p.Thr482fs)	SLC1A3	Uncertain significance	criteria provided, single submitter
3390941	NM_004172.5(SLC1A3):c.959C>G (p.Thr320Ser)	SLC1A3	Uncertain significance	criteria provided, single submitter
353309	NM_004172.5(SLC1A3):c.212A>G (p.Tyr71Cys)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
353312	NM_004172.5(SLC1A3):c.374T>C (p.Val125Ala)	SLC1A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
353313	NM_004172.5(SLC1A3):c.601G>A (p.Val201Met)	SLC1A3	Uncertain significance	criteria provided, single submitter
353318	NM_004172.5(SLC1A3):c.897G>C (p.Gly299=)	SLC1A3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SLC1A3	Strong	Autosomal dominant	episodic ataxia type 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC1A3	Orphanet:209967	Episodic ataxia type 6
SLC1A3	Orphanet:2131	Alternating hemiplegia of childhood

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC1A3	HGNC:10941	ENSG00000079215	P43003	Excitatory amino acid transporter 1	gencc,clinvar
SLC1A3-AS1	HGNC:56374	ENSG00000250155		SLC1A3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC1A3	Excitatory amino acid transporter 1	Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.

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)
SLC1A3	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
SLC1A3-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	1
corpus callosum	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC1A3	273	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
SLC1A3-AS1	131		yes	corpus callosum, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC1A3	3,201
SLC1A3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC1A3	P43003	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Defective SLC1A3 causes episodic ataxia 6 (EA6)	1	11420.0×	4e-04	SLC1A3
SLC-mediated transport of amino acids	1	2284.0×	7e-04	SLC1A3
Astrocytic Glutamate-Glutamine Uptake And Metabolism	1	1903.3×	7e-04	SLC1A3
Glutamate Neurotransmitter Release Cycle	1	456.8×	0.002	SLC1A3

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
cranial nerve development	1	5617.3×	0.002	SLC1A3
D-aspartate import across plasma membrane	1	3370.4×	0.002	SLC1A3
auditory behavior	1	2808.7×	0.002	SLC1A3
L-glutamate import	1	2808.7×	0.002	SLC1A3
L-aspartate import across plasma membrane	1	2808.7×	0.002	SLC1A3
GABA biosynthetic process	1	2106.5×	0.002	SLC1A3
L-glutamate import across plasma membrane	1	1872.4×	0.002	SLC1A3
cell morphogenesis involved in neuron differentiation	1	1532.0×	0.002	SLC1A3
neurotransmitter uptake	1	1404.3×	0.002	SLC1A3
cellular response to cocaine	1	1296.3×	0.002	SLC1A3
transepithelial transport	1	1203.7×	0.002	SLC1A3
positive regulation of synaptic transmission	1	1123.5×	0.002	SLC1A3
response to light stimulus	1	887.0×	0.002	SLC1A3
L-glutamate transmembrane transport	1	802.5×	0.002	SLC1A3
intracellular sodium ion homeostasis	1	766.0×	0.002	SLC1A3
response to antibiotic	1	702.2×	0.002	SLC1A3
neurotransmitter transport	1	421.3×	0.004	SLC1A3
neuromuscular process controlling balance	1	330.4×	0.004	SLC1A3
chloride transmembrane transport	1	237.3×	0.006	SLC1A3
response to wounding	1	221.7×	0.006	SLC1A3
transport across blood-brain barrier	1	179.3×	0.007	SLC1A3
monoatomic ion transport	1	156.0×	0.008	SLC1A3
potassium ion transmembrane transport	1	135.9×	0.008	SLC1A3
sensory perception of sound	1	100.9×	0.011	SLC1A3
chemical synaptic transmission	1	77.3×	0.013	SLC1A3
response to xenobiotic stimulus	1	69.1×	0.014	SLC1A3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC1A3	2	3
SLC1A3-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ASPARTIC ACID	3	SLC1A3
GLUTAMIC ACID	3	SLC1A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC1A3	47	Binding:38, Functional:9

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

2 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)
ASPARTIC ACID	3	SLC1A3
GLUTAMIC ACID	3	SLC1A3

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	1	SLC1A3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC1A3-AS1

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)
SLC1A3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford