long QT syndrome 14

Summary

long QT syndrome 14 (MONDO:0014548) is a disease caused by CALM1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CALM1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 130

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	long QT syndrome 14
Mondo ID	MONDO:0014548
OMIM	616247
DOID	DOID:0110655
NCIT	C177534
UMLS	C4015671
MedGen	864108
GARD	0016073
Is cancer (heuristic)	no

Also known as: CALM1 long QT syndrome · long QT syndrome 14 · long QT syndrome caused by mutation in CALM1 · long QT syndrome type 14 · LQT14

Data availability: 130 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

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 14

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 15, 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

130 retrieved; paginated sample, class counts are floors:

83 likely benign, 21 uncertain significance, 11 pathogenic, 5 benign/likely benign, 4 benign, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1362982	NM_006888.6(CALM1):c.395A>G (p.Asp132Gly)	CALM1	Pathogenic	criteria provided, single submitter
183230	NM_006888.6(CALM1):c.389A>G (p.Asp130Gly)	CALM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183231	NM_006888.6(CALM1):c.426C>G (p.Phe142Leu)	CALM1	Pathogenic	criteria provided, single submitter
2100843	NM_006888.6(CALM1):c.286G>T (p.Asp96Tyr)	CALM1	Pathogenic	criteria provided, single submitter
39758	NM_006888.6(CALM1):c.293A>G (p.Asn98Ser)	CALM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
426161	NM_006888.6(CALM1):c.424T>C (p.Phe142Leu)	CALM1	Pathogenic	criteria provided, multiple submitters, no conflicts
4785412	NM_006888.6(CALM1):c.270C>G (p.Phe90Leu)	CALM1	Pathogenic	criteria provided, single submitter
4787824	NM_006888.6(CALM1):c.389A>T (p.Asp130Val)	CALM1	Pathogenic	criteria provided, single submitter
639902	NM_006888.6(CALM1):c.394G>A (p.Asp132Asn)	CALM1	Pathogenic	criteria provided, single submitter
948239	NM_006888.6(CALM1):c.395A>T (p.Asp132Val)	CALM1	Pathogenic	criteria provided, single submitter
961658	NM_006888.6(CALM1):c.426C>A (p.Phe142Leu)	CALM1	Pathogenic	criteria provided, single submitter
974612	NM_006888.6(CALM1):c.422A>G (p.Glu141Gly)	CALM1	Pathogenic	criteria provided, single submitter
974613	NM_006888.6(CALM1):c.422A>T (p.Glu141Val)	CALM1	Pathogenic	criteria provided, single submitter
183232	NM_006888.6(CALM1):c.268T>C (p.Phe90Leu)	CALM1	Likely pathogenic	criteria provided, single submitter
542137	NM_006888.6(CALM1):c.398G>A (p.Gly133Glu)	CALM1	Likely pathogenic	criteria provided, single submitter
1086423	NM_006888.6(CALM1):c.4-9T>A	CALM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3826954	NM_006888.6(CALM1):c.4-4A>G	CALM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062650	NC_000014.8:g.(?90870713)(90871071_?)dup	CALM1	Uncertain significance	criteria provided, single submitter
1424459	NM_006888.6(CALM1):c.328A>C (p.Met110Leu)	CALM1	Uncertain significance	criteria provided, single submitter
1718023	NM_006888.6(CALM1):c.358G>A (p.Glu120Lys)	CALM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1740325	NM_006888.6(CALM1):c.4-3T>C	CALM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2061992	NM_006888.6(CALM1):c.70G>A (p.Gly24Ser)	CALM1	Uncertain significance	criteria provided, single submitter
2132986	NM_006888.6(CALM1):c.402C>G (p.Asp134Glu)	CALM1	Uncertain significance	criteria provided, single submitter
2425651	NC_000014.8:g.(?90863575)(90871061_?)dup	CALM1	Uncertain significance	criteria provided, single submitter
2953702	NM_006888.6(CALM1):c.398G>C (p.Gly133Ala)	CALM1	Uncertain significance	criteria provided, single submitter
3244035	NC_000014.8:g.(?90863575)(90871061_?)del	CALM1	Uncertain significance	criteria provided, single submitter
3748203	NM_006888.6(CALM1):c.154A>G (p.Met52Val)	CALM1	Uncertain significance	criteria provided, single submitter
3756961	NM_006888.6(CALM1):c.35-12_35-11delinsCC	CALM1	Uncertain significance	criteria provided, single submitter
3759214	NM_006888.6(CALM1):c.199C>T (p.Pro67Ser)	CALM1	Uncertain significance	criteria provided, single submitter
3759522	NM_006888.6(CALM1):c.35-44_77dup	CALM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
CALM1	Definitive	Autosomal dominant	long QT syndrome 14	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CALM1	Orphanet:101016	Romano-Ward syndrome
CALM1	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
CALM1	HGNC:1442	ENSG00000198668	P0DP23	Calmodulin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CALM1	Calmodulin-1	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)
CALM1	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
lateral nuclear group of thalamus	1
medial globus pallidus	1
parietal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CALM1	295	ubiquitous	marker	lateral nuclear group of thalamus, medial globus pallidus, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALM1	25

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM1	P0DP23	337

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 144. 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
Ionotropic activity of kainate receptors	1	5710.0×	0.006	CALM1
Activation of kainate receptors upon glutamate binding	1	5710.0×	0.006	CALM1
Cam-PDE 1 activation	1	2855.0×	0.006	CALM1
Loss of phosphorylation of MECP2 at T308	1	2855.0×	0.006	CALM1
Metabolism of nitric oxide: NOS3 activation and regulation	1	2284.0×	0.006	CALM1
Metabolism of cofactors	1	1903.3×	0.006	CALM1
Glycogen metabolism	1	1903.3×	0.006	CALM1
CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde	1	1427.5×	0.006	CALM1
Loss of function of MECP2 in Rett syndrome	1	1427.5×	0.006	CALM1
Pervasive developmental disorders	1	1427.5×	0.006	CALM1
Activation of RAC1 downstream of NMDARs	1	1427.5×	0.006	CALM1
Disorders of Developmental Biology	1	1427.5×	0.006	CALM1
Disorders of Nervous System Development	1	1427.5×	0.006	CALM1
Calcineurin activates NFAT	1	1268.9×	0.006	CALM1
The phototransduction cascade	1	1268.9×	0.006	CALM1
CASP4 inflammasome assembly	1	1268.9×	0.006	CALM1
CaMK IV-mediated phosphorylation of CREB	1	1142.0×	0.006	CALM1
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	1142.0×	0.006	CALM1
Activation of Ca-permeable Kainate Receptor	1	1142.0×	0.006	CALM1
Sodium/Calcium exchangers	1	1038.2×	0.006	CALM1
CLEC7A (Dectin-1) induces NFAT activation	1	1038.2×	0.006	CALM1
Reduction of cytosolic Ca++ levels	1	951.7×	0.006	CALM1
Uptake and function of anthrax toxins	1	951.7×	0.006	CALM1
eNOS activation	1	878.5×	0.006	CALM1
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.006	CALM1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	878.5×	0.006	CALM1
Downstream signaling events of B Cell Receptor (BCR)	1	815.7×	0.006	CALM1
Uptake and actions of bacterial toxins	1	815.7×	0.006	CALM1
Enterobacterial factors antagonize host defense	1	815.7×	0.006	CALM1
Glycogen breakdown (glycogenolysis)	1	761.3×	0.006	CALM1

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×	0.001	CALM1
negative regulation of high voltage-gated calcium channel activity	1	8426.0×	0.001	CALM1
regulation of ryanodine-sensitive calcium-release channel activity	1	5617.3×	0.001	CALM1
organelle localization by membrane tethering	1	5617.3×	0.001	CALM1
negative regulation of calcium ion export across plasma membrane	1	4213.0×	0.001	CALM1
presynaptic endocytosis	1	3370.4×	0.001	CALM1
regulation of cardiac muscle cell action potential	1	2808.7×	0.001	CALM1
autophagosome membrane docking	1	2407.4×	0.001	CALM1
obsolete mitochondrion-endoplasmic reticulum membrane tethering	1	2106.5×	0.001	CALM1
regulation of cell communication by electrical coupling involved in cardiac conduction	1	1872.4×	0.001	CALM1
calcineurin-mediated signaling	1	1532.0×	0.002	CALM1
detection of calcium ion	1	1123.5×	0.002	CALM1
regulation of calcium-mediated signaling	1	1123.5×	0.002	CALM1
regulation of cardiac muscle contraction	1	887.0×	0.002	CALM1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.002	CALM1
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.002	CALM1
cellular response to interferon-beta	1	526.6×	0.003	CALM1
regulation of heart rate	1	468.1×	0.003	CALM1
positive regulation of receptor signaling pathway via JAK-STAT	1	432.1×	0.003	CALM1
regulation of cytokinesis	1	421.3×	0.003	CALM1
substantia nigra development	1	366.4×	0.003	CALM1
response to calcium ion	1	318.0×	0.004	CALM1
G2/M transition of mitotic cell cycle	1	312.1×	0.004	CALM1
long-term synaptic potentiation	1	280.9×	0.004	CALM1
cellular response to type II interferon	1	208.1×	0.005	CALM1
G protein-coupled receptor signaling pathway	1	36.2×	0.028	CALM1

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CALM1	CLOZAPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CALM1	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOZAPINE	4	CALM1
TRIFLUOPERAZINE	4	CALM1
PROMETHAZINE	4	CALM1
CHLORPROMAZINE	4	CALM1
HESPERIDIN	3	CALM1
QUERCETIN	3	CALM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CALM1	23	Binding:23

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

6 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.

Compound	Max phase	Cohort target (bioactivity)
CLOZAPINE	4	CALM1
TRIFLUOPERAZINE	4	CALM1
PROMETHAZINE	4	CALM1
CHLORPROMAZINE	4	CALM1
HESPERIDIN	3	CALM1
QUERCETIN	3	CALM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CALM1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.