long QT syndrome 16

Summary

long QT syndrome 16 (MONDO:0032915) is a disease caused by CALM3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CALM3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	long QT syndrome 16
Mondo ID	MONDO:0032915
OMIM	618782
DOID	DOID:0070533
UMLS	C5394068
MedGen	1713991
GARD	0025773
Is cancer (heuristic)	no

Also known as: long QT syndrome 16 · LQT16

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › catecholaminergic polymorphic ventricular tachycardia › long QT syndrome 16

Related subtypes (6): catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 2, catecholaminergic polymorphic ventricular tachycardia 3, catecholaminergic polymorphic ventricular tachycardia 4, catecholaminergic polymorphic ventricular tachycardia 5, ventricular tachycardia, catecholaminergic polymorphic 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

9 retrieved; paginated sample, class counts are floors:

3 benign, 3 pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
409870	NM_005184.4(CALM3):c.286G>C (p.Asp96His)	CALM3	Pathogenic	criteria provided, multiple submitters, no conflicts
812676	NM_005184.4(CALM3):c.389A>G (p.Asp130Gly)	CALM3	Pathogenic	no assertion criteria provided
812678	NM_005184.4(CALM3):c.421G>A (p.Glu141Lys)	CALM3	Pathogenic	criteria provided, multiple submitters, no conflicts
409869	NM_005184.4(CALM3):c.421+4A>G	CALM3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1438531	NM_005184.4(CALM3):c.4-3C>T	CALM3	Uncertain significance	criteria provided, single submitter
839631	NM_005184.4(CALM3):c.179-3del	CALM3	Uncertain significance	criteria provided, multiple submitters, no conflicts
240118	NM_005184.4(CALM3):c.390C>T (p.Asp130=)	CALM3	Benign	criteria provided, multiple submitters, no conflicts
678453	NM_005184.4(CALM3):c.4-73T>C	CALM3	Benign	criteria provided, multiple submitters, no conflicts
678454	NM_005184.4(CALM3):c.178+66T>C	CALM3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CALM3	Definitive	Autosomal dominant	familial long QT syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CALM3	Orphanet:101016	Romano-Ward syndrome
CALM3	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CALM3	HGNC:1449	ENSG00000160014	P0DP25	Calmodulin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CALM3	Calmodulin-3	Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CALM3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CALM3	297	ubiquitous	marker	prefrontal cortex, right frontal lobe, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALM3	15

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM3	P0DP25	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CASP4 inflammasome assembly	1	1268.9×	0.001	CALM3
Enterobacterial factors antagonize host defense	1	815.7×	0.001	CALM3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete establishment of protein localization to mitochondrial membrane	1	16852.0×	0.001	CALM3
negative regulation of high voltage-gated calcium channel activity	1	8426.0×	0.001	CALM3
negative regulation of calcium ion export across plasma membrane	1	4213.0×	0.002	CALM3
presynaptic endocytosis	1	3370.4×	0.002	CALM3
regulation of cardiac muscle cell action potential	1	2808.7×	0.002	CALM3
regulation of cell communication by electrical coupling involved in cardiac conduction	1	1872.4×	0.002	CALM3
calcineurin-mediated signaling	1	1532.0×	0.002	CALM3
detection of calcium ion	1	1123.5×	0.002	CALM3
regulation of calcium-mediated signaling	1	1123.5×	0.002	CALM3
response to corticosterone	1	1123.5×	0.002	CALM3
regulation of cardiac muscle contraction	1	887.0×	0.002	CALM3
regulation of synaptic vesicle endocytosis	1	887.0×	0.002	CALM3
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.002	CALM3
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.002	CALM3
response to amphetamine	1	495.6×	0.003	CALM3
regulation of heart rate	1	468.1×	0.003	CALM3
regulation of synaptic vesicle exocytosis	1	455.5×	0.003	CALM3
regulation of cytokinesis	1	421.3×	0.003	CALM3
substantia nigra development	1	366.4×	0.003	CALM3
response to calcium ion	1	318.0×	0.004	CALM3
G2/M transition of mitotic cell cycle	1	312.1×	0.004	CALM3
long-term synaptic potentiation	1	280.9×	0.004	CALM3
G protein-coupled receptor signaling pathway	1	36.2×	0.028	CALM3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CALM3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CALM3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CALM3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.