Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Summary

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (MONDO:0024542) is a disease caused by VLDLR (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: VLDLR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 147

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1
Mondo ID	MONDO:0024542
OMIM	224050
DOID	DOID:0070556
UMLS	C4551552
MedGen	1639436
GARD	0025423
Is cancer (heuristic)	no

Also known as: CAMRQ1 · cerebellar ataxia and mental retardation with or without quadrupedal locomotion 1 · cerebellar ataxia, congenital, and mental retardation, autosomal recessive · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 1 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome 1 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 1 · cerebellar hypoplasia and mental retardation with or without quadrupedal locomotion 1 · dysequilibrium syndrome caused by mutation in VLDLR · VLDLR dysequilibrium syndrome

Data availability: 147 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › cerebellar ataxia, intellectual disability, and dysequilibrium › cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Related subtypes (3): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 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

147 retrieved; paginated sample, class counts are floors:

62 uncertain significance, 25 conflicting classifications of pathogenicity, 17 likely pathogenic, 15 benign/likely benign, 12 pathogenic, 10 benign, 3 likely benign, 2 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
12200	NG_012741.1:g.(?5001)(37693_?)del	LOC130001469	Pathogenic	no assertion criteria provided
12201	NM_003383.5(VLDLR):c.769C>T (p.Arg257Ter)	VLDLR	Pathogenic	criteria provided, single submitter
12202	NM_003383.5(VLDLR):c.2339del (p.Ile780fs)	VLDLR	Pathogenic	no assertion criteria provided
1223471	NM_003383.5(VLDLR):c.835C>T (p.Arg279Ter)	VLDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
1325339	NM_003383.5(VLDLR):c.2465G>A (p.Trp822Ter)	VLDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212565	NM_003383.5(VLDLR):c.83-1G>A	VLDLR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21381	NM_003383.5(VLDLR):c.1342C>T (p.Arg448Ter)	VLDLR	Pathogenic	no assertion criteria provided
2577844	NM_003383.5(VLDLR):c.901C>T (p.Arg301Ter)	VLDLR	Pathogenic	criteria provided, single submitter
2577846	NM_003383.5(VLDLR):c.149G>A (p.Trp50Ter)	VLDLR	Pathogenic	no assertion criteria provided
2577847	NM_003383.5(VLDLR):c.1961A>G (p.Glu654Gly)	VLDLR	Pathogenic	no assertion criteria provided
2577848	NM_003383.5(VLDLR):c.1724G>A (p.Trp575Ter)	VLDLR	Pathogenic	no assertion criteria provided
3255613	NM_003383.5(VLDLR):c.821-1G>A	VLDLR	Pathogenic	criteria provided, single submitter
55852	NM_003383.5(VLDLR):c.1249_1255del (p.Tyr417fs)	VLDLR	Pathogenic	no assertion criteria provided
64373	NM_003383.5(VLDLR):c.2117G>T (p.Cys706Phe)	VLDLR	Pathogenic	criteria provided, single submitter
1333255	NM_003383.5(VLDLR):c.262dup (p.Arg88fs)	VLDLR	Likely pathogenic	criteria provided, single submitter
1679407	NM_003383.5(VLDLR):c.1666C>T (p.Arg556Ter)	VLDLR	Likely pathogenic	criteria provided, single submitter
1705671	NM_003383.5(VLDLR):c.376C>T (p.Gln126Ter)	VLDLR	Likely pathogenic	criteria provided, single submitter
1705926	NM_003383.5(VLDLR):c.2144G>A (p.Cys715Tyr)	VLDLR	Likely pathogenic	criteria provided, single submitter
212557	NM_003383.5(VLDLR):c.2T>C (p.Met1Thr)	VLDLR	Likely pathogenic	criteria provided, single submitter
2231752	NM_003383.5(VLDLR):c.820+1G>A	VLDLR	Likely pathogenic	criteria provided, single submitter
2444129	NM_003383.5(VLDLR):c.325+1del	VLDLR	Likely pathogenic	criteria provided, single submitter
2445903	NM_003383.5(VLDLR):c.325+1G>A	VLDLR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2892838	NM_003383.5(VLDLR):c.449-2A>T	VLDLR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2904136	NM_003383.5(VLDLR):c.2252-2A>C	VLDLR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3597243	NM_003383.5(VLDLR):c.436del (p.Glu146fs)	VLDLR	Likely pathogenic	criteria provided, single submitter
3597244	NM_003383.5(VLDLR):c.1200C>A (p.Cys400Ter)	VLDLR	Likely pathogenic	criteria provided, single submitter
3597245	NM_003383.5(VLDLR):c.1441C>T (p.Gln481Ter)	VLDLR	Likely pathogenic	criteria provided, single submitter
3597246	NM_003383.5(VLDLR):c.2158del (p.Leu720fs)	VLDLR	Likely pathogenic	criteria provided, single submitter
3597247	NM_003383.5(VLDLR):c.2417-1G>T	VLDLR	Likely pathogenic	criteria provided, single submitter
4847965	NM_003383.5(VLDLR):c.2252-2A>G	VLDLR	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
VLDLR	Definitive	Autosomal recessive	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VLDLR	Orphanet:1766	Dysequilibrium syndrome

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
VLDLR	HGNC:12698	ENSG00000147852	P98155	Very low-density lipoprotein receptor	gencc,clinvar
VLDLR-AS1	HGNC:49621	ENSG00000236404		VLDLR antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VLDLR	Very low-density lipoprotein receptor	Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism.

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)
VLDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
VLDLR-AS1	Other/Unknown	no

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
left ovary	2
heart right ventricle	1
right ovary	1
apex of heart	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VLDLR	273	ubiquitous	marker	heart right ventricle, left ovary, right ovary
VLDLR-AS1	159	broad	marker	oocyte, apex of heart, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VLDLR	1,817
VLDLR-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VLDLR	P98155	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Reelin signalling pathway	1	1903.3×	8e-04	VLDLR
VLDL clearance	1	1903.3×	8e-04	VLDLR
VLDLR internalisation and degradation	1	713.8×	0.001	VLDLR

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
glycoprotein transport	1	5617.3×	0.002	VLDLR
very-low-density lipoprotein particle clearance	1	3370.4×	0.002	VLDLR
ventral spinal cord development	1	1872.4×	0.002	VLDLR
reelin-mediated signaling pathway	1	1203.7×	0.003	VLDLR
positive regulation of dendrite development	1	991.3×	0.003	VLDLR
regulation of synapse assembly	1	702.2×	0.003	VLDLR
dendrite morphogenesis	1	432.1×	0.004	VLDLR
lipid transport	1	263.3×	0.006	VLDLR
receptor-mediated endocytosis	1	221.7×	0.006	VLDLR
cholesterol metabolic process	1	195.9×	0.006	VLDLR
memory	1	183.2×	0.006	VLDLR
nervous system development	1	45.9×	0.024	VLDLR
signal transduction	1	16.1×	0.062	VLDLR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VLDLR	0	0
VLDLR-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	2	VLDLR, VLDLR-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VLDLR	0	—
VLDLR-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.