Autosomal recessive spinocerebellar ataxia 13

Summary

Autosomal recessive spinocerebellar ataxia 13 (MONDO:0013905) is a disease caused by GRM1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GRM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0003698	Difficulty standing	Very frequent (80-99%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0000571	Hypometric saccades	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002406	Limb dysmetria	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0011347	Abnormality of ocular abduction	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001271	Polyneuropathy	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0007979	Gaze-evoked horizontal nystagmus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 13
Mondo ID	MONDO:0013905
OMIM	614831
Orphanet	324262
DOID	DOID:0080062
UMLS	C3553816
MedGen	766730
GARD	0017481
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome caused by mutation in GRM1 · autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome caused by mutation in GRM1 · autosomal recessive congenital cerebellar ataxia due to metabotropic glutamate receptor 1 deficiency · autosomal recessive spinocerebellar ataxia 13 · autosomal recessive spinocerebellar ataxia type 13 · GRM1 autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome · GRM1 autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome · SCAR13 · spinocerebellar ataxia, autosomal recessive 13 · spinocerebellar ataxia, autosomal recessive type 13

Data availability: 30 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome › autosomal recessive spinocerebellar ataxia 13

Related subtypes (1): autosomal recessive spinocerebellar ataxia 18

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

30 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 benign/likely benign, 5 benign, 5 pathogenic, 1 not provided, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4813112	NM_001278064.1(GRM1):c.[2652_2654delGAA;2660+2T>G]		Pathogenic	no assertion criteria provided
2572460	NM_001278064.2(GRM1):c.1715del (p.Asn572fs)	GRM1	Pathogenic	criteria provided, single submitter
4532016	NM_001278064.2(GRM1):c.2238C>A (p.Cys746Ter)	GRM1	Pathogenic	criteria provided, single submitter
626248	NM_001278064.2(GRM1):c.889C>T (p.Arg297Ter)	GRM1	Pathogenic	criteria provided, single submitter
818224	NM_001278064.2(GRM1):c.26dup (p.Ala11fs)	GRM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984959	NM_001278064.2(GRM1):c.1360C>T (p.Leu454Phe)	GRM1	Pathogenic	no assertion criteria provided
3362552	NM_001278064.2(GRM1):c.1145del (p.Gly382fs)	GRM1	Likely pathogenic	criteria provided, single submitter
2059560	NM_001278064.2(GRM1):c.950+8TC[22]	GRM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335648	NM_001278064.2(GRM1):c.2909C>T (p.Pro970Leu)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362622	NM_001278064.2(GRM1):c.1569G>T (p.Val523=)	GRM1	Uncertain significance	criteria provided, single submitter
3593214	NM_001278064.2(GRM1):c.3188G>T (p.Arg1063Leu)	GRM1	Uncertain significance	criteria provided, single submitter
3593215	NM_001278064.2(GRM1):c.3461C>T (p.Ser1154Leu)	GRM1	Uncertain significance	criteria provided, single submitter
3779712	NM_001278064.2(GRM1):c.951-3dup	GRM1	Uncertain significance	criteria provided, single submitter
447469	NM_001278064.2(GRM1):c.829C>A (p.Leu277Ile)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
560384	NM_001278064.2(GRM1):c.951-6T>A	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
804887	NM_001278064.2(GRM1):c.827A>C (p.Lys276Thr)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
994892	NM_001278064.2(GRM1):c.1073G>A (p.Arg358Lys)	GRM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
129209	NM_001278064.2(GRM1):c.2793G>A (p.Lys931=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129210	NM_001278064.2(GRM1):c.2977T>C (p.Ser993Pro)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129211	NM_001278064.2(GRM1):c.3168T>G (p.Gly1056=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129212	NM_001278064.2(GRM1):c.3213T>G (p.Pro1071=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
129213	NM_001278064.2(GRM1):c.3495C>A (p.Pro1165=)	GRM1	Benign	criteria provided, multiple submitters, no conflicts
445990	NM_001278064.2(GRM1):c.3214C>G (p.Pro1072Ala)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
447463	NM_001278064.2(GRM1):c.3161G>A (p.Gly1054Asp)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585954	NM_001278064.2(GRM1):c.2007G>T (p.Ala669=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585955	NM_001278064.2(GRM1):c.2043T>C (p.Arg681=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585957	NM_001278064.2(GRM1):c.2364G>C (p.Ala788=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
585958	NM_001278064.2(GRM1):c.2496T>C (p.Thr832=)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
995113	NM_001278064.2(GRM1):c.2651G>A (p.Gly884Glu)	GRM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1339870	NM_001278064.2(GRM1):c.1602G>A (p.Lys534=)	GRM1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
GRM1	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 13	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRM1	Orphanet:324262	Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency
GRM1	Orphanet:404507	Chondromyxoid fibroma
GRM1	Orphanet:631095	Spinocerebellar ataxia type 44

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
GRM1	HGNC:4593	ENSG00000152822	Q13255	Metabotropic glutamate receptor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRM1	Metabotropic glutamate receptor 1	G-protein coupled receptor for glutamate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRM1	GPCR	yes		GPCR_3_mtglu_rcpt, GPCR_3, GPCR_3_mGluR1

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
cerebellar vermis	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRM1	94	tissue_specific	marker	lateral nuclear group of thalamus, cerebellar vermis, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRM1	2,814

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRM1	Q13255	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	292.8×	0.007	GRM1
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.007	GRM1
Neurexins and neuroligins	1	196.9×	0.007	GRM1
G alpha (q) signalling events	1	57.4×	0.017	GRM1

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
phospholipase C-activating G protein-coupled glutamate receptor signaling pathway	1	4213.0×	0.002	GRM1
L-glutamate import across plasma membrane	1	1872.4×	0.002	GRM1
synaptic signaling via neuropeptide	1	1532.0×	0.002	GRM1
cellular response to electrical stimulus	1	1296.3×	0.002	GRM1
G protein-coupled glutamate receptor signaling pathway	1	1053.2×	0.002	GRM1
regulation of sensory perception of pain	1	991.3×	0.002	GRM1
regulation of synaptic transmission, glutamatergic	1	510.7×	0.004	GRM1
sensory perception of pain	1	374.5×	0.004	GRM1
locomotory behavior	1	179.3×	0.008	GRM1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.010	GRM1
positive regulation of MAPK cascade	1	80.6×	0.014	GRM1
chemical synaptic transmission	1	77.3×	0.014	GRM1
G protein-coupled receptor signaling pathway	1	36.2×	0.028	GRM1

Therapeutics

Drug target analysis

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

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
GRM1	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GLUTAMIC ACID	3	GRM1
FENOBAM ANHYDROUS	2	GRM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GRM1	284	Functional:177, Binding:107

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GRM1	284

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)
GLUTAMIC ACID	3	GRM1
FENOBAM ANHYDROUS	2	GRM1

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	GRM1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.