Timothy syndrome type 1

Summary

Timothy syndrome type 1 (MONDO:0035678) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Timothy syndrome type 1
Mondo ID	MONDO:0035678
Orphanet	595098
ICD-10-CM	I49.8
UMLS	C5574939
MedGen	1802409
GARD	0022380
Is cancer (heuristic)	no

Also known as: LQT8 type 1 · TS1

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Timothy syndrome › Timothy syndrome, classic type › Timothy syndrome type 1

Related subtypes (1): Timothy syndrome type 2

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699478	NM_000719.7(CACNA1C):c.2530+4C>T	CACNA1C	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1C	Orphanet:101016	Romano-Ward syndrome
CACNA1C	Orphanet:130	Brugada syndrome
CACNA1C	Orphanet:528084	Non-specific syndromic intellectual disability
CACNA1C	Orphanet:595098	Timothy syndrome type 1
CACNA1C	Orphanet:595105	Timothy syndrome type 2
CACNA1C	Orphanet:595109	Atypical Timothy syndrome

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
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu

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
apex of heart	1
muscle layer of sigmoid colon	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1C	3,145

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1C	Q13936	33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Phase 2 - plateau phase	1	761.3×	0.010	CACNA1C
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.010	CACNA1C
Phase 0 - rapid depolarisation	1	346.1×	0.010	CACNA1C
NCAM signaling for neurite out-growth	1	271.9×	0.010	CACNA1C
NCAM1 interactions	1	248.3×	0.010	CACNA1C
Regulation of insulin secretion	1	219.6×	0.010	CACNA1C
Integration of energy metabolism	1	175.7×	0.011	CACNA1C
Cardiac conduction	1	108.8×	0.015	CACNA1C
Muscle contraction	1	77.2×	0.019	CACNA1C
Axon guidance	1	45.1×	0.028	CACNA1C
Nervous system development	1	42.9×	0.028	CACNA1C
Developmental Biology	1	14.5×	0.075	CACNA1C
Metabolism	1	11.6×	0.086	CACNA1C

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
calcium ion transmembrane transport via high voltage-gated calcium channel	1	5617.3×	0.001	CACNA1C
membrane depolarization during atrial cardiac muscle cell action potential	1	5617.3×	0.001	CACNA1C
immune system development	1	4213.0×	0.001	CACNA1C
positive regulation of adenylate cyclase activity	1	3370.4×	0.001	CACNA1C
membrane depolarization during AV node cell action potential	1	3370.4×	0.001	CACNA1C
positive regulation of muscle contraction	1	2407.4×	0.001	CACNA1C
cardiac conduction	1	1685.2×	0.001	CACNA1C
membrane depolarization during cardiac muscle cell action potential	1	1404.3×	0.001	CACNA1C
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.001	CACNA1C
regulation of ventricular cardiac muscle cell action potential	1	1404.3×	0.001	CACNA1C
calcium ion transport into cytosol	1	1203.7×	0.002	CACNA1C
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	CACNA1C
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.002	CACNA1C
calcium ion import across plasma membrane	1	543.6×	0.003	CACNA1C
embryonic forelimb morphogenesis	1	495.6×	0.003	CACNA1C
regulation of heart rate by cardiac conduction	1	374.5×	0.003	CACNA1C
camera-type eye development	1	358.6×	0.003	CACNA1C
calcium ion transmembrane transport	1	210.7×	0.005	CACNA1C
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.009	CACNA1C
heart development	1	78.8×	0.013	CACNA1C

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

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
CACNA1C	REMIFENTANIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1C	85	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C
ASTEMIZOLE	4	CACNA1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1C	575

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

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)
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C
ASTEMIZOLE	4	CACNA1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1C
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	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.