ITPR3

Chr 6AD

inositol 1,4,5-trisphosphate receptor type 3

Also known as: CMT1J, IMD132, IMD133, IP3R, IP3R-3, IP3R3

NCBI Gene: 3710 ENSG00000096433 UniProt: Q14573 OMIM: 147267

The protein functions as an inositol 1,4,5-trisphosphate-gated calcium channel that releases calcium from the endoplasmic reticulum to the cytoplasm, participating in cellular calcium homeostasis. Mutations cause Charcot-Marie-Tooth disease type 1J (demyelinating peripheral neuropathy) and immunodeficiency with ectodermal dysplasia that may include peripheral neuropathy, affecting the immune system, skin/hair/teeth development, and peripheral nervous system. The gene follows autosomal dominant inheritance and is moderately constrained against loss-of-function variants (LOEUF 0.569).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.572 OMIM phenotypes

Clinical Summary— ITPR3

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Gene-Disease Validity (ClinGen)

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

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint

0.57LOEUF

pLI 0.000

Z-score 5.70

OE 0.46 (0.37–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

4.55Z-score

OE missense 0.69 (0.65–0.72)

1144 obs / 1667.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.46 (0.37–0.57)

0≤0.351.4

Missense OE0.69 (0.65–0.72)

0≤0.61.4

Synonymous OE0.92

0≤1.21.6

LoF obs/exp: 59 / 128.8Missense obs/exp: 1144 / 1667.0Syn Z: 1.69

0.6745th %ile

GOF

0.6931th %ile

LOF

0.3355th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant mutations in ITPR3 cause Charcot-Marie-Tooth disease. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 PMID:32949214

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.