TRPM3

Chr 9AD

transient receptor potential cation channel subfamily M member 3

Also known as: CTRCT50, GON-2, LTRPC3, MLSN2, NEDFSS

NCBI Gene: 80036 ENSG00000083067 UniProt: Q9HCF6 OMIM: 608961

This gene encodes a constitutively active calcium channel that mediates calcium entry into cells and functions in heat sensing, pain sensitivity, and insulin secretion. Mutations cause autosomal dominant neurodevelopmental disorder with hypotonia, dysmorphic features, and skeletal anomalies with or without seizures, as well as cataract with or without glaucoma. The gene is highly constrained against loss-of-function variants (LOEUF 0.453), indicating that such mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.452 OMIM phenotypes

Clinical Summary— TRPM3

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.45LOEUF

pLI 0.000

Z-score 5.64

OE 0.33 (0.24–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.18Z-score

OE missense 0.72 (0.67–0.76)

716 obs / 998.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.33 (0.24–0.45)

0≤0.351.4

Missense OE?0.72 (0.67–0.76)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 27 / 82.2Missense obs/exp: 716 / 998.5Syn Z: 0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTRPM3-related developmental disorderOTHERAD

This gene — mechanism propensity

0.6938th %ile

GOF

0.73top 25%

LOF

0.3455th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction 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

GOFGain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders.1

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

References