Dystonia 27

Summary

Dystonia 27 (MONDO:0014627) is a disease caused by COL6A3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL6A3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 94
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0012048	Oromandibular dystonia	Very frequent (80-99%)
HP:0012049	Laryngeal dystonia	Very frequent (80-99%)
HP:0002345	Action tremor	Frequent (30-79%)
HP:0002356	Writer’s cramp	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0002530	Axial dystonia	Frequent (30-79%)
HP:0004373	Focal dystonia	Frequent (30-79%)
HP:0007351	Upper limb postural tremor	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 27
Mondo ID	MONDO:0014627
OMIM	616411
Orphanet	464440
DOID	DOID:0090050
UMLS	C4225336
MedGen	907580
GARD	0017819
Is cancer (heuristic)	no

Also known as: COL6A3 dystonic disorder · dystonia 27 · dystonia type 27 · dystonic disorder caused by mutation in COL6A3 · DYT27

Data availability: 94 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › segmental dystonia › dystonia 27

Related subtypes (1): adult-onset segmental dystonia

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

94 retrieved; paginated sample, class counts are floors:

48 conflicting classifications of pathogenicity, 16 uncertain significance, 11 benign/likely benign, 11 benign, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
192263	NM_004369.4(COL6A3):c.8966-1G>C	COL6A3	Pathogenic	criteria provided, multiple submitters, no conflicts
196977	NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)	COL6A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2187695	NM_004369.4(COL6A3):c.5992C>T (p.Arg1998Ter)	COL6A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
417888	NM_004369.4(COL6A3):c.7669-2del	COL6A3	Pathogenic/Likely pathogenic	no assertion criteria provided
419449	NM_004369.4(COL6A3):c.2506C>T (p.Arg836Ter)	COL6A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338441	GRCh37/hg19 2q37.3(chr2:238234151-238234418)x0	COL6A3	Likely pathogenic	no assertion criteria provided
3376833	NM_004369.4(COL6A3):c.8966-2A>G	COL6A3	Likely pathogenic	criteria provided, single submitter
4081277	NM_004369.4(COL6A3):c.3071-2A>G	COL6A3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1004320	NM_004369.4(COL6A3):c.1268C>T (p.Ala423Val)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021944	NM_004369.4(COL6A3):c.3196C>T (p.Arg1066Cys)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051564	NM_004369.4(COL6A3):c.5230C>T (p.Pro1744Ser)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128822	NM_004369.4(COL6A3):c.8009C>T (p.Ala2670Val)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1575428	NM_004369.4(COL6A3):c.7051A>C (p.Ile2351Leu)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162547	NM_004369.4(COL6A3):c.3040A>G (p.Lys1014Glu)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162548	NM_004369.4(COL6A3):c.4912G>A (p.Ala1638Thr)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192260	NM_004369.4(COL6A3):c.7660G>A (p.Ala2554Thr)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
192264	NM_004369.4(COL6A3):c.7502G>A (p.Arg2501His)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193877	NM_004369.4(COL6A3):c.5341A>G (p.Ile1781Val)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197761	NM_004369.4(COL6A3):c.1478T>C (p.Val493Ala)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
224687	NM_004369.4(COL6A3):c.2218C>T (p.Arg740Cys)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281820	NM_004369.4(COL6A3):c.5833G>C (p.Val1945Leu)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282445	NM_004369.4(COL6A3):c.958G>A (p.Ala320Thr)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282774	NM_004369.4(COL6A3):c.3902G>A (p.Arg1301Gln)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284495	NM_004369.4(COL6A3):c.3852C>A (p.Phe1284Leu)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284966	NM_004369.4(COL6A3):c.3499A>T (p.Ile1167Phe)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285594	NM_004369.4(COL6A3):c.3118G>A (p.Val1040Ile)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285987	NM_004369.4(COL6A3):c.4900+9C>T	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285998	NM_004369.4(COL6A3):c.8632A>G (p.Thr2878Ala)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288419	NM_004369.4(COL6A3):c.3055G>A (p.Gly1019Arg)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288602	NM_004369.4(COL6A3):c.1065C>T (p.Ala355=)	COL6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
COL6A3	Strong	Autosomal recessive	dystonia 27	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL6A3	Orphanet:464440	Primary dystonia, DYT27 type
COL6A3	Orphanet:610	Bethlem muscular dystrophy
COL6A3	Orphanet:646113	Intermediate collagen VI-related muscular dystrophy
COL6A3	Orphanet:75840	Ullrich congenital muscular dystrophy

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
COL6A3	HGNC:2213	ENSG00000163359	P12111	Collagen alpha-3(VI) chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL6A3	Collagen alpha-3(VI) chain	Collagen VI acts as a cell-binding protein.

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL6A3	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom

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
skin of hip	1
stromal cell of endometrium	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL6A3	264	broad	marker	stromal cell of endometrium, visceral pleura, skin of hip

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL6A3	2,267

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL6A3	P12111	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Collagen chain trimerization	1	259.6×	0.007	COL6A3
Signaling by PDGF	1	253.8×	0.007	COL6A3
NCAM1 interactions	1	248.3×	0.007	COL6A3
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.007	COL6A3
Collagen degradation	1	175.7×	0.007	COL6A3
Collagen biosynthesis and modifying enzymes	1	170.4×	0.007	COL6A3
ECM proteoglycans	1	150.3×	0.007	COL6A3
Integrin cell surface interactions	1	134.3×	0.007	COL6A3

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
response to UV	1	366.4×	0.007	COL6A3
response to glucose	1	255.3×	0.007	COL6A3
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	COL6A3
neuron apoptotic process	1	185.2×	0.007	COL6A3
muscle organ development	1	166.8×	0.007	COL6A3
cell adhesion	1	37.5×	0.027	COL6A3

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
COL6A3	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	1	COL6A3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
COL6A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.