long QT syndrome 15

Summary

long QT syndrome 15 (MONDO:0014550) is a disease caused by CALM2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CALM2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	long QT syndrome 15
Mondo ID	MONDO:0014550
OMIM	616249
DOID	DOID:0110656
UMLS	C4015695
MedGen	864132
GARD	0016074
Is cancer (heuristic)	no

Also known as: CALM2 long QT syndrome · long QT syndrome 15 · long QT syndrome caused by mutation in CALM2 · long QT syndrome type 15 · LQT15

Data availability: 21 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › long QT syndrome › familial long QT syndrome › long QT syndrome 15

Related subtypes (18): Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, cardiac arrhythmia, ankyrin-B-related, Timothy syndrome, long QT syndrome 3, long QT syndrome 9, long QT syndrome 10, long QT syndrome 11, long QT syndrome 12, long QT syndrome 13, long QT syndrome 2, long QT syndrome 6, long QT syndrome 5, long QT syndrome 14, long QT syndrome 8, long QT syndrome 16, long QT syndrome 1, long QT syndrome 4

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

21 retrieved; paginated sample, class counts are floors:

6 pathogenic, 4 uncertain significance, 3 pathogenic/likely pathogenic, 2 benign/likely benign, 2 likely pathogenic, 2 likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
183233	NM_001743.6(CALM2):c.287A>T (p.Asp96Val)	CALM2	Pathogenic	criteria provided, multiple submitters, no conflicts
488476	NM_001743.6(CALM2):c.414C>G (p.Asn138Lys)	CALM2	Pathogenic	criteria provided, single submitter
641544	NM_001743.6(CALM2):c.286G>T (p.Asp96Tyr)	CALM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812710	NM_001743.6(CALM2):c.389A>G (p.Asp130Gly)	CALM2	Pathogenic	criteria provided, single submitter
96720	NM_001743.6(CALM2):c.293A>G (p.Asn98Ser)	CALM2	Pathogenic	criteria provided, multiple submitters, no conflicts
96721	NM_001743.6(CALM2):c.293A>T (p.Asn98Ile)	CALM2	Pathogenic	criteria provided, single submitter
96722	NM_001743.6(CALM2):c.396T>G (p.Asp132Glu)	CALM2	Pathogenic	criteria provided, single submitter
96723	NM_001743.6(CALM2):c.400G>C (p.Asp134His)	CALM2	Pathogenic/Likely pathogenic	no assertion criteria provided
96724	NM_001743.6(CALM2):c.407A>C (p.Gln136Pro)	CALM2	Pathogenic/Likely pathogenic	no assertion criteria provided
2500174	NM_001743.6(CALM2):c.313G>C (p.Glu105Gln)	CALM2	Likely pathogenic	criteria provided, single submitter
448971	NM_001743.6(CALM2):c.400G>A (p.Asp134Asn)	CALM2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1304927	NM_001743.6(CALM2):c.420A>G (p.Glu140=)	CALM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709364	NM_001743.6(CALM2):c.-56G>A	CALM2	Uncertain significance	criteria provided, single submitter
1806166	NM_001305624.1(CALM2):c.8G>A (p.Arg3His)	CALM2	Uncertain significance	criteria provided, single submitter
2500009	NM_001743.6(CALM2):c.104C>A (p.Thr35Asn)	CALM2	Uncertain significance	criteria provided, single submitter
239038	NM_001743.6(CALM2):c.240A>T (p.Thr80=)	CALM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3043763	NC_000002.12:g.47176535G>T	CALM2	Likely benign	criteria provided, single submitter
422684	NM_001743.6(CALM2):c.286-18_286-17del	CALM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
507565	NM_001743.6(CALM2):c.285+16G>T	CALM2	Likely benign	criteria provided, multiple submitters, no conflicts
674615	NM_001743.6(CALM2):c.421+96T>C	CALM2	Benign	criteria provided, multiple submitters, no conflicts
674616	NM_001743.6(CALM2):c.421+97G>C	CALM2	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
CALM2	Definitive	Autosomal dominant	long QT syndrome 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CALM2	Orphanet:101016	Romano-Ward syndrome
CALM2	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
CALM2	HGNC:1445	ENSG00000143933	P0DP24	Calmodulin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CALM2	Calmodulin-2	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)
CALM2	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
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CALM2	310	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALM2	3

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM2	P0DP24	21

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	CALM2
Enterobacterial factors antagonize host defense	1	815.7×	0.001	CALM2

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
negative regulation of ryanodine-sensitive calcium-release channel activity	1	8426.0×	0.002	CALM2
negative regulation of calcium ion export across plasma membrane	1	4213.0×	0.002	CALM2
presynaptic endocytosis	1	3370.4×	0.002	CALM2
regulation of cell communication by electrical coupling involved in cardiac conduction	1	1872.4×	0.002	CALM2
calcineurin-mediated signaling	1	1532.0×	0.002	CALM2
detection of calcium ion	1	1123.5×	0.002	CALM2
regulation of calcium-mediated signaling	1	1123.5×	0.002	CALM2
regulation of cardiac muscle contraction	1	887.0×	0.002	CALM2
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.003	CALM2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.003	CALM2
regulation of heart rate	1	468.1×	0.003	CALM2
regulation of cytokinesis	1	421.3×	0.003	CALM2
substantia nigra development	1	366.4×	0.004	CALM2
response to calcium ion	1	318.0×	0.004	CALM2
G2/M transition of mitotic cell cycle	1	312.1×	0.004	CALM2
long-term synaptic potentiation	1	280.9×	0.004	CALM2
G protein-coupled receptor signaling pathway	1	36.2×	0.028	CALM2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CALM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CALM2	1	Binding:1

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	CALM2

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)
CALM2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.