TRPV3

Chr 17AD

transient receptor potential cation channel subfamily V member 3

Also known as: FNEPPK2, OLMS, OLMS1, VRL3

NCBI Gene: 162514 ENSG00000167723 UniProt: Q8NET8 OMIM: 607066

TRPV3 encodes a temperature-sensitive calcium-permeable cation channel that is activated by warm temperatures (22-40°C) and regulates keratinocyte proliferation and hair follicle cycling. Mutations cause autosomal dominant Olmsted syndrome and focal nonepidermolytic palmoplantar keratoderma, both affecting skin and hair development. The gene shows low constraint against loss-of-function variants, suggesting the pathogenic variants may work through other mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene product belongs to a family of nonselective cation channels that function in a variety of processes, including temperature sensation and vasoregulation. The thermosensitive members of this family are expressed in subsets of sensory neurons that terminate in the skin, and are activated at distinct physiological temperatures. This channel is activated at temperatures between 22 and 40 degrees C. This gene lies in close proximity to another family member gene on chromosome 17, and the two encoded proteins are thought to associate with each other to form heteromeric channels. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.152 OMIM phenotypes

Clinical Summary— TRPV3

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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

10 unique Pathogenic / Likely Pathogenic· 232 VUS of 489 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 0.82

OE 0.86 (0.65–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.17Z-score

OE missense 0.98 (0.91–1.06)

467 obs / 477.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.86 (0.65–1.15)

0≤0.351.4

Missense OE?0.98 (0.91–1.06)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 33 / 38.5Missense obs/exp: 467 / 477.5Syn Z: -0.31

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedTRPV3-related palmoplantar keratoderma, nonepidermolytic, focalOTHERAD

strongTRPV3-related Olmsted syndromeOTHERAD

This gene — mechanism propensity

0.6259th %ile

GOF

0.77top 25%

LOF

0.3454th %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 · 100% of P/LP are missense

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

GOFMutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 25886873 ↗

ClinVar Variant Classifications

489 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic1

VUS232

Likely Benign72

Benign149

Conflicting19

Pathogenic

Likely Pathogenic

232

VUS

Likely Benign

149

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	9	0	0	9
Likely Pathogenic	0	1	0	0	1
VUS	4	165	62	1	232
Likely Benign	0	12	22	38	72
Benign	1	13	116	19	149
Conflicting	—				19
Total	5	200	200	58	482

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap TRPV3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →