TRPM3

protein-coding

transient receptor potential cation channel subfamily M member 3, the group of MicroRNA protein coding host genes|Transient receptor potential cation channels

Gene summary

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]

MANE transcript

NM_001366145.2

Inheritance

ClinVar variants

P:11U:404B:78

Top phenotype

Cataract 50 with or without glaucoma

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr9:70,529,060-71,446,977

External References & Databases

Ensembl (ENSG00000083067)

Transcript & Mutation Effects

hg38 • Region Span ~917.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

schizophreniaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005090

Submitter: Labcorp Genetics (formerly Invitae)

schizophreniaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005090

Submitter: Ambry Genetics

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859365

Submitter: G2P

cataract-glaucoma syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015567

Submitter: Ambry Genetics

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*TRPM3* was first reported in relation to autosomal dominant intellectual disability and epilepsy in 2019 (Dyment et al., PMID: 31278393). Phenotypic features include congenital hypotonia, global developmental delays, variable intellectual disability, ophthalmologic findings including strabismus and nystagmus, musculoskeletal findings including hip dysplasia, scoliosis, and club foot, variable seizure and epilepsy classifications, MRI abnormalities, and distinctive dysmorphic features. This curation includes 12 heterozygous missense variants reported in 12 probands with phenotypic similarity (PMIDs: 31278393, 34074259, 36648066, 37684057). Of these 12 heterozygous missense variants, 9 have functional data to support a gain of function effect. All distinct variants available in the literature are scored. Additional probands are reported in the literature, but all harbor variants already included in the curation. As the maximum score for genetic evidence (12 points) has already been reached, those individuals were not included in this curation. In summary, there is definitive evidence supporting the relationship between *TRPM3* and autosomal dominant syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in the clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on the meeting date May 23, 2024 (SOP Version 10).

neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859365

Submitter: PanelApp Australia

cataract 50 with or without glaucomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859382

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859365

Submitter: Ambry Genetics

cataract 50 with or without glaucomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859382

Submitter: Labcorp Genetics (formerly Invitae)

cataract 50 with or without glaucomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859382

Submitter: ClinGen

TRPM3 encodes a protein, transient receptor potential cation channel subfamily M member 3, which is temperature- and neurosteroid-sensitive. The first study by Bennett et al in 2014 (PMID: 25090642). reported TRPM3 in relationship to autosomal dominant cataract with or without high pressure glaucoma in a 5-generation Caucasian-American pedigree. Genome-wide linkage analysis mapped the cataract locus to the pericentric region of human chromosome 9, and exome sequencing of the linked region identified a heterozygous substitution of isoleucine-to-methionine at codon 65 (c.195A>G, p.Ile65Met) in TRPM3 transcript NM_001007471.2. This variant segregated fully with the cataract in the family. Functional studies of the human p.Ile65M knock-in mice model showed that heterozygous Trpm3-mutant mice developed cataract (2021, PMID: 33484482) and lens from the Trpm3-mutation mice displayed elevated cytosolic Ca2+ levels and an imbalance of sodium (Na+) and potassium (K+) ions, coupled with increased water content, suggesting failure of Trpm3-mutant lens to osmoregulation and gain-of-function as the disease mechanism (2024, PMID: 38334649). The second study by Li et al in 2018 (PMID: 29914532) sequenced 80 cataract-associated genes for a cohort of 39 Chinese pediatric cataract cases and detected a heterozygous variant, c.3920G>C, p.Arg1307Thr in TRPM3 transcript NM_206944.4, in one family. This variant segregated with the cataract in the family. No data of functional study is available for this variant. As of this curation, only two above-mentioned variants in TRPM3 have been linked to inherited form of cataract in two families. As of the genetic evidence, the case level and segregation data were scored up to 3.6 points. The functional experimental data from the human p.Ile65Met knock-in mouse model was scored up to 3.25 points. Taking together 6.85 points is scored in total with moderate evidence to support the TRPM3-cataract relationship. While more evidence is needed to establish this relationship definitively, no contradictory evidence has merged. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel (SOP Version 10).

neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859365

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cataract 50 with or without glaucomaAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Ophthalmologic

Rationale: The condition can include risk of glaucoma, and awareness may allow surveillance and early management

Refs: 25090642,; 31278393; 32343227; 32439617; 32427099; 33484482; 34438093; 35146895

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRPM3 variants in ClinVar

22 Conditions Cataloged

not providedTotal: 240

Inborn genetic diseasesTotal: 193

not specifiedTotal: 61

TRPM3-related disorderTotal: 50

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizuresTotal: 35

Cataract 50 with or without glaucomaTotal: 6

Neurodevelopmental disorderTotal: 3

Global developmental delayTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366145.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	44 clinvar	5 clinvar	53
missense		10 clinvar	381 clinvar	26 clinvar	3 clinvar	420
nonsense			8 clinvar			8
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)		1 clinvar	7 clinvar			8
Total	0	11	404	70	8	493

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366145.2	RefSeq	NP_001353074.1	26	MANE Select
ENST00000677713.2	Ensembl	ENSP00000503830.2	26	MANE Select
NM_001007470.3	RefSeq	NP_001007471.1	6	Standard
NM_001007471.4	RefSeq	NP_001007472.2	25	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules
TRP channels

Biological Process

cation transport
detection of temperature stimulus
sensory perception of temperature stimulus
protein tetramerization
calcium ion transmembrane transport

Molecular Function

calcium activated cation channel activity
cation channel activity
calcium channel activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377110
Coding exons: 25
Length: 917842
Individuals with no LoFs: 125670
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125748
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.18	716	998	0.717	0.0000576	11294
Missense (PolyPhen)		289	471.78	0.61257		5303
Synonymous	0.133	374	377	0.991	0.0000230	3243
Loss of Function	5.64	27	82.2	0.329	0.00000471	917

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00071	0.00069	rare
East Asian	0	0.0	absent
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00033	0.00033	rare
South Asian	0.00037	0.00036	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium channel mediating constitutive calcium ion entry. Its activity is increased by reduction in extracellular osmolarity, by store depletion and muscarinic receptor activation. {ECO:0000269|PubMed:12672799, ECO:0000269|PubMed:12672827}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.767
RVIS EVS: -1.09
RVIS percentile EVS: 6.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0628

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	High	Medium	High