Charcot-Marie-Tooth disease, demyelinating, type 1J

Summary

Charcot-Marie-Tooth disease, demyelinating, type 1J (MONDO:0859311) is a disease caused by ITPR3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ITPR3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, demyelinating, type 1J
Mondo ID	MONDO:0859311
OMIM	620111
UMLS	C5774249
MedGen	1824022
GARD	0026691
Is cancer (heuristic)	no

Data availability: 27 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, demyelinating, type 1J

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, demyelinating, IIA 1H, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

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

27 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 3 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1722508	NM_002224.4(ITPR3):c.1843G>A (p.Val615Met)	ITPR3	Pathogenic	no assertion criteria provided
1722510	NM_002224.4(ITPR3):c.4271C>T (p.Thr1424Met)	ITPR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722509	NM_002224.4(ITPR3):c.7570C>T (p.Arg2524Cys)	ITPR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2345476	NM_002224.4(ITPR3):c.4218C>G (p.Ile1406Met)	ITPR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2578246	NM_002224.4(ITPR3):c.445C>T (p.Arg149Trp)	ITPR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2388613	NM_002224.4(ITPR3):c.2007G>C (p.Glu669Asp)	ITPR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2430203	NM_002224.4(ITPR3):c.6391C>T (p.Arg2131Cys)	ITPR3	Uncertain significance	no assertion criteria provided
2534518	NM_002224.4(ITPR3):c.4054G>A (p.Ala1352Thr)	ITPR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689266	NM_002224.4(ITPR3):c.5138-8G>A	ITPR3	Uncertain significance	criteria provided, single submitter
3068221	NM_002224.4(ITPR3):c.730T>C (p.Phe244Leu)	ITPR3	Uncertain significance	criteria provided, single submitter
3360604	NM_002224.4(ITPR3):c.5903A>T (p.Asp1968Val)	ITPR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3530928	NM_002224.4(ITPR3):c.3254G>T (p.Arg1085Leu)	ITPR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3776040	NM_002224.4(ITPR3):c.2756G>T (p.Gly919Val)	ITPR3	Uncertain significance	criteria provided, single submitter
4040466	NM_002224.4(ITPR3):c.1076A>G (p.His359Arg)	ITPR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
4079026	NM_002224.4(ITPR3):c.2163C>A (p.His721Gln)	ITPR3	Uncertain significance	criteria provided, single submitter
4079027	NM_002224.4(ITPR3):c.7972dup (p.Gln2658fs)	ITPR3	Uncertain significance	criteria provided, single submitter
4079028	NM_002224.4(ITPR3):c.1480C>G (p.Leu494Val)	ITPR3	Uncertain significance	criteria provided, single submitter
4079029	NM_002224.4(ITPR3):c.2791C>G (p.Arg931Gly)	ITPR3	Uncertain significance	criteria provided, single submitter
4277688	NM_002224.4(ITPR3):c.6785G>A (p.Arg2262His)	ITPR3	Uncertain significance	criteria provided, single submitter
4537368	NM_002224.4(ITPR3):c.5529G>T (p.Ser1843=)	ITPR3	Uncertain significance	criteria provided, single submitter
4537403	NM_002224.4(ITPR3):c.5046G>C (p.Arg1682=)	ITPR3	Uncertain significance	criteria provided, single submitter
4688014	NM_002224.4(ITPR3):c.104G>A (p.Arg35His)	ITPR3	Uncertain significance	criteria provided, single submitter
4688149	NM_002224.4(ITPR3):c.3928G>A (p.Glu1310Lys)	ITPR3	Uncertain significance	criteria provided, single submitter
4796803	NM_002224.4(ITPR3):c.7976G>A (p.Arg2659His)	ITPR3	Uncertain significance	criteria provided, single submitter
4813625	NM_002224.4(ITPR3):c.404T>C (p.Val135Ala)	ITPR3	Uncertain significance	criteria provided, single submitter
4819931	NM_002224.4(ITPR3):c.4220C>T (p.Thr1407Ile)	ITPR3	Uncertain significance	criteria provided, single submitter
4845339	NM_002224.4(ITPR3):c.1317C>G (p.Ile439Met)	ITPR3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 0 · 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
ITPR3	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease, demyelinating, type 1J	6

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
ITPR3	HGNC:6182	ENSG00000096433	Q14573	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3	Inositol 1,4,5-trisphosphate-gated calcium channel that, upon 1D-myo-inositol 1,4,5-trisphosphate binding, transports calcium from the endoplasmic reticulum lumen to cytoplasm, thus releasing the intracellular calcium and therefore partici…

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)
ITPR3	Ion channel	yes		InsP3_rcpt, RIH_dom, Ion_trans_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
cartilage tissue	1
pylorus	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITPR3	262	ubiquitous	marker	cartilage tissue, pylorus, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITPR3	3,135

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITPR3	Q14573	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. 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
CLEC7A (Dectin-1) induces NFAT activation	1	1038.2×	0.009	ITPR3
Elevation of cytosolic Ca2+ levels	1	713.8×	0.009	ITPR3
Platelet calcium homeostasis	1	713.8×	0.009	ITPR3
VEGFR2 mediated cell proliferation	1	571.0×	0.009	ITPR3
Effects of PIP2 hydrolysis	1	456.8×	0.009	ITPR3
Role of phospholipids in phagocytosis	1	456.8×	0.009	ITPR3
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.009	ITPR3
Leishmania parasite growth and survival	1	393.8×	0.009	ITPR3
FCERI mediated Ca+2 mobilization	1	356.9×	0.009	ITPR3
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.009	ITPR3
Signaling by the B Cell Receptor (BCR)	1	346.1×	0.009	ITPR3
Sensory perception of taste	1	335.9×	0.009	ITPR3
G-protein mediated events	1	326.3×	0.009	ITPR3
DAG and IP3 signaling	1	317.2×	0.009	ITPR3
Beta-catenin independent WNT signaling	1	292.8×	0.009	ITPR3
FCGR3A-mediated IL10 synthesis	1	292.8×	0.009	ITPR3
Fcgamma receptor (FCGR) dependent phagocytosis	1	278.5×	0.009	ITPR3
Platelet homeostasis	1	278.5×	0.009	ITPR3
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.009	ITPR3
Fc epsilon receptor (FCERI) signaling	1	271.9×	0.009	ITPR3
Opioid Signalling	1	265.6×	0.009	ITPR3
PLC beta mediated events	1	265.6×	0.009	ITPR3
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.009	ITPR3
C-type lectin receptors (CLRs)	1	237.9×	0.009	ITPR3
Signaling by VEGF	1	219.6×	0.009	ITPR3
Regulation of insulin secretion	1	219.6×	0.009	ITPR3
Ion homeostasis	1	203.9×	0.009	ITPR3
Ca2+ pathway	1	178.4×	0.010	ITPR3
Integration of energy metabolism	1	175.7×	0.010	ITPR3
Leishmania infection	1	163.1×	0.010	ITPR3

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
sensory perception of bitter taste	1	2808.7×	0.002	ITPR3
sensory perception of sweet taste	1	2407.4×	0.002	ITPR3
sensory perception of umami taste	1	2407.4×	0.002	ITPR3
sensory perception of taste	1	1123.5×	0.003	ITPR3
calcium ion homeostasis	1	443.5×	0.005	ITPR3
release of sequestered calcium ion into cytosol	1	343.9×	0.005	ITPR3
response to calcium ion	1	318.0×	0.005	ITPR3
long-term synaptic potentiation	1	280.9×	0.005	ITPR3
platelet activation	1	267.5×	0.005	ITPR3
protein homotetramerization	1	237.3×	0.005	ITPR3
memory	1	183.2×	0.006	ITPR3
positive regulation of cytosolic calcium ion concentration	1	117.0×	0.009	ITPR3
G protein-coupled receptor signaling pathway	1	36.2×	0.028	ITPR3

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
ITPR3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ITPR3	11	Binding:9, Functional:2

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	ITPR3
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)
ITPR3	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.