TRPC3

Chr 4AD

transient receptor potential cation channel subfamily C member 3

Also known as: SCA41, TRP3

NCBI Gene: 7222 ENSG00000138741 UniProt: Q13507 OMIM: 602345

TRPC3 encodes a membrane protein that forms a receptor-activated calcium-permeable cation channel involved in cellular calcium signaling. Mutations cause autosomal dominant cerebellar ataxia and developmental delay, typically presenting in childhood with progressive neurological symptoms. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to haploinsufficiency.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a membrane protein that can form a non-selective channel permeable to calcium and other cations. The encoded protein appears to be induced to form channels by a receptor tyrosine kinase-activated phosphatidylinositol second messenger system and also by depletion of intracellular calcium stores. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.701 OMIM phenotype

Clinical Summary— TRPC3

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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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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 132 VUS of 225 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 3.01

OE 0.47 (0.33–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.84Z-score

OE missense 0.52 (0.47–0.58)

267 obs / 511.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.47 (0.33–0.70)

0≤0.351.4

Missense OE?0.52 (0.47–0.58)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 18 / 38.0Missense obs/exp: 267 / 511.6Syn Z: 1.37

This gene — mechanism propensity

0.75top 25%

GOF

0.82top 10%

LOF

0.2483th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). 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 · 1 literature citation

LOF1 literature citation

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

DNThey observed that several members of the TRPC family are highly expressed in these neurons, and both calcium elevation and growth cone turning induced by BDNF were abolished by pharmacologic inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6 (603652), or downr1

GOFA gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant.2

LOFTaken together, these data suggest that calcium metabolism abnormalities observed in WBS may be attributable to TFII-I haploinsufficiency and subsequent TRPC3 overexpression, thereby increasing both digestive and renal calcium absorption.3

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

References

ClinVar Variant Classifications

225 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS132

Likely Benign73

Benign15

Pathogenic

132

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	1	0	2
Likely Pathogenic	0	0	0	0	0
VUS	3	126	3	0	132
Likely Benign	0	2	19	52	73
Benign	0	2	4	9	15
Total	4	130	27	61	222

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

22 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap TRPC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →