short QT syndrome type 3

Summary

short QT syndrome type 3 (MONDO:0012314) is a disease caused by KCNJ2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KCNJ2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 520

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short QT syndrome type 3
Mondo ID	MONDO:0012314
MeSH	C566504
OMIM	609622
UMLS	C1865018
MedGen	400662
GARD	0018635
Is cancer (heuristic)	no

Also known as: KCNJ2 short QT syndrome · short QT syndrome 3 · short QT syndrome caused by mutation in KCNJ2 · short QT syndrome type 3 · SQT3

Data availability: 520 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › short QT syndrome › short QT syndrome type 3

Related subtypes (3): short QT syndrome type 1, short QT syndrome type 2, short QT syndrome 7

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

520 retrieved; paginated sample, class counts are floors:

249 uncertain significance, 123 likely benign, 63 conflicting classifications of pathogenicity, 30 pathogenic, 23 benign/likely benign, 14 benign, 11 likely pathogenic, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1480008	NM_000891.3(KCNJ2):c.636G>A (p.Trp212Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
190820	NM_000891.3(KCNJ2):c.935G>A (p.Arg312His)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020840	NM_000891.3(KCNJ2):c.224C>A (p.Thr75Lys)	KCNJ2	Pathogenic	criteria provided, single submitter
2036326	NM_000891.3(KCNJ2):c.232G>A (p.Asp78Asn)	KCNJ2	Pathogenic	criteria provided, single submitter
234729	NM_000891.3(KCNJ2):c.902T>G (p.Met301Arg)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
2682647	NM_000891.3(KCNJ2):c.902T>A (p.Met301Lys)	KCNJ2	Pathogenic	no assertion criteria provided
3243061	NC_000017.10:g.(?68166871)(68171602_?)del	KCNJ2	Pathogenic	criteria provided, single submitter
3755832	NM_000891.3(KCNJ2):c.1044C>G (p.Tyr348Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
403974	NM_000891.3(KCNJ2):c.682C>T (p.Arg228Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
463523	NM_000891.3(KCNJ2):c.715G>T (p.Glu239Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
4784294	NM_000891.3(KCNJ2):c.351del (p.Glu118fs)	KCNJ2	Pathogenic	criteria provided, single submitter
519476	NM_000891.3(KCNJ2):c.919A>G (p.Met307Val)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
569363	NM_000891.3(KCNJ2):c.1102del (p.Leu368fs)	KCNJ2	Pathogenic	criteria provided, single submitter
67560	NM_000891.3(KCNJ2):c.200G>A (p.Arg67Gln)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67565	NM_000891.3(KCNJ2):c.224C>T (p.Thr75Met)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67566	NM_000891.3(KCNJ2):c.232G>T (p.Asp78Tyr)	KCNJ2	Pathogenic	criteria provided, single submitter
67568	NM_000891.3(KCNJ2):c.244C>T (p.Arg82Trp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67569	NM_000891.3(KCNJ2):c.245G>A (p.Arg82Gln)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67573	NM_000891.3(KCNJ2):c.430G>A (p.Gly144Ser)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67574	NM_000891.3(KCNJ2):c.431G>A (p.Gly144Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67575	NM_000891.3(KCNJ2):c.431G>C (p.Gly144Ala)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67576	NM_000891.3(KCNJ2):c.436G>A (p.Gly146Ser)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67583	NM_000891.3(KCNJ2):c.644G>A (p.Gly215Asp)	KCNJ2	Pathogenic	criteria provided, single submitter
67585	NM_000891.3(KCNJ2):c.653G>A (p.Arg218Gln)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67588	NM_000891.3(KCNJ2):c.899G>A (p.Gly300Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67591	NM_000891.3(KCNJ2):c.913A>G (p.Thr305Ala)	KCNJ2	Pathogenic	criteria provided, single submitter
67593	NM_000891.3(KCNJ2):c.926C>T (p.Thr309Ile)	KCNJ2	Pathogenic	criteria provided, single submitter
67594	NM_000891.3(KCNJ2):c.934C>T (p.Arg312Cys)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
858285	NM_000891.3(KCNJ2):c.434A>G (p.Tyr145Cys)	KCNJ2	Pathogenic	criteria provided, single submitter
8918	NM_000891.3(KCNJ2):c.212A>T (p.Asp71Val)	KCNJ2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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
KCNJ2	Strong	Autosomal dominant	short QT syndrome type 3	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome

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
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N

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
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNJ2	65

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNJ2	P63252	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Sensory perception of sour taste	1	5710.0×	0.003	KCNJ2
Classical Kir channels	1	2855.0×	0.003	KCNJ2
G protein gated Potassium channels	1	1142.0×	0.005	KCNJ2
Inwardly rectifying K+ channels	1	713.8×	0.005	KCNJ2
Phase 4 - resting membrane potential	1	601.0×	0.005	KCNJ2
Activation of GABAB receptors	1	601.0×	0.005	KCNJ2
GABA B receptor activation	1	543.8×	0.005	KCNJ2
Activation of G protein gated Potassium channels	1	393.8×	0.005	KCNJ2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	393.8×	0.005	KCNJ2
Sensory perception of taste	1	335.9×	0.005	KCNJ2
GABA receptor activation	1	317.2×	0.005	KCNJ2
Potassium Channels	1	134.3×	0.011	KCNJ2
Cardiac conduction	1	108.8×	0.013	KCNJ2
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.013	KCNJ2
Sensory Perception	1	95.2×	0.013	KCNJ2
Muscle contraction	1	77.2×	0.014	KCNJ2
Transmission across Chemical Synapses	1	76.1×	0.014	KCNJ2
Neuronal System	1	44.3×	0.023	KCNJ2

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
regulation of skeletal muscle contraction via regulation of action potential	1	16852.0×	0.001	KCNJ2
relaxation of skeletal muscle	1	5617.3×	0.002	KCNJ2
membrane repolarization during action potential	1	1685.2×	0.002	KCNJ2
membrane repolarization during cardiac muscle cell action potential	1	1685.2×	0.002	KCNJ2
membrane depolarization during cardiac muscle cell action potential	1	1404.3×	0.002	KCNJ2
relaxation of cardiac muscle	1	1296.3×	0.002	KCNJ2
regulation of resting membrane potential	1	1296.3×	0.002	KCNJ2
regulation of membrane repolarization	1	1296.3×	0.002	KCNJ2
magnesium ion transport	1	1203.7×	0.002	KCNJ2
regulation of cardiac muscle cell contraction	1	1123.5×	0.002	KCNJ2
intracellular potassium ion homeostasis	1	991.3×	0.002	KCNJ2
positive regulation of potassium ion transmembrane transport	1	991.3×	0.002	KCNJ2
regulation of monoatomic ion transmembrane transport	1	732.7×	0.002	KCNJ2
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	KCNJ2
regulation of heart rate by cardiac conduction	1	374.5×	0.003	KCNJ2
potassium ion import across plasma membrane	1	366.4×	0.003	KCNJ2
protein homotetramerization	1	237.3×	0.005	KCNJ2
cellular response to mechanical stimulus	1	216.1×	0.005	KCNJ2
potassium ion transport	1	191.5×	0.005	KCNJ2
potassium ion transmembrane transport	1	135.9×	0.007	KCNJ2

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
KCNJ2	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
KCNJ2	31	Binding:23, ADMET:8

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	1	KCNJ2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KCNJ2	31	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.