TRDN

Summary

TRDN (triadin, HGNC:12261) is a protein-coding gene on chromosome 6q22.31, encoding Triadin (Q13061). Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction.

This gene encodes an integral membrane protein found in skeletal and cardiac muscle. The encoded protein plays a role in skeletal muscle excitation-contraction coupling as part of the calcium release complex and is required for normal skeletal muscle strength. This protein indirectly links triads and microtubules in skeletal muscle. Mutations in this gene are associated with cardiac arrythmia syndrome and some variants in this gene may be associated with sudden cardiac death.

Source: NCBI Gene 10345 — RefSeq curated summary.

At a glance

• Gene–disease (curated): catecholaminergic polymorphic ventricular tachycardia (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 1,593 total — 31 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_006073

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12261
Approved symbol	TRDN
Name	triadin
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	TRISK
Ensembl gene	ENSG00000186439
Ensembl biotype	protein_coding
OMIM	603283
Entrez	10345

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 43 protein_coding

ENST00000334268, ENST00000361029, ENST00000422596, ENST00000542443, ENST00000546248, ENST00000628709, ENST00000662930, ENST00000714023, ENST00000714024, ENST00000714025, ENST00000714039, ENST00000714040, ENST00000962652, ENST00000962653, ENST00000962654, ENST00000962655, ENST00000962656, ENST00000962657, ENST00000962658, ENST00000962659, ENST00000962660, ENST00000962661, ENST00000962662, ENST00000962663, ENST00000962664, ENST00000962665, ENST00000962666, ENST00000962667, ENST00000962668, ENST00000962669, ENST00000962670, ENST00000962671, ENST00000962672, ENST00000962673, ENST00000962674, ENST00000962675, ENST00000962676, ENST00000962677, ENST00000962678, ENST00000962679, ENST00000962680, ENST00000962681, ENST00000962682

RefSeq mRNA: 6 — MANE Select: NM_006073 NM_001251987, NM_001256020, NM_001256021, NM_001256022, NM_001407315, NM_006073

CCDS: CCDS55053, CCDS59034, CCDS59035, CCDS75511, CCDS93997

Canonical transcript exons

ENST00000334268 — 41 exons

Exon	Start	End
ENSE00000798552	123547340	123547372
ENSE00001006429	123267707	123267751
ENSE00001006430	123273337	123273363
ENSE00001006431	123382118	123382147
ENSE00001006433	123503719	123503901
ENSE00001006434	123388522	123388551
ENSE00001006436	123265318	123265338
ENSE00001006440	123260612	123260638
ENSE00001006441	123375605	123375631
ENSE00001006443	123366135	123366182
ENSE00001006445	123377716	123377742
ENSE00001006446	123438944	123439003
ENSE00001006448	123224093	123224131
ENSE00001006449	123271139	123271186
ENSE00001006452	123272964	123273011
ENSE00001006454	123316457	123316495
ENSE00001006458	123259624	123259662
ENSE00001006459	123274641	123274670
ENSE00001006464	123255081	123255125
ENSE00001006467	123255867	123255902
ENSE00001084340	123279056	123279082
ENSE00001084354	123278318	123278347
ENSE00001364241	123497193	123497252
ENSE00001370892	123512303	123512362
ENSE00001380521	123530506	123530565
ENSE00001381478	123381370	123381390
ENSE00001381973	123352539	123352586
ENSE00001382178	123331879	123331929
ENSE00001382677	123337619	123337669
ENSE00001389201	123393624	123393677
ENSE00001390889	123377866	123377898
ENSE00001403767	123221487	123221522
ENSE00001404706	123438063	123438122
ENSE00001411958	123464906	123464983
ENSE00001412276	123216339	123218740
ENSE00001447123	123516141	123516206
ENSE00002470503	123570923	123571132
ENSE00002476764	123548454	123548612
ENSE00002507570	123269849	123269866
ENSE00003766474	123252412	123252435
ENSE00003850036	123636754	123636950

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 99.55.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.3301 / max 858.2953, expressed in 167 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75383	2.6459	107
75384	1.2256	81
75385	1.0971	111
75382	0.1083	36
75388	0.0841	23
75381	0.0761	36
75387	0.0446	18
75386	0.0243	13
75389	0.0242	15

Top tissues by expression

275 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.55	gold quality
biceps brachii	UBERON:0001507	99.52	gold quality
gastrocnemius	UBERON:0001388	99.46	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.39	gold quality
vastus lateralis	UBERON:0001379	99.36	gold quality
gluteal muscle	UBERON:0002000	99.30	gold quality
quadriceps femoris	UBERON:0001377	99.24	gold quality
skeletal muscle tissue	UBERON:0001134	99.11	gold quality
apex of heart	UBERON:0002098	99.03	gold quality
body of tongue	UBERON:0011876	98.79	gold quality
triceps brachii	UBERON:0001509	98.66	gold quality
deltoid	UBERON:0001476	98.65	gold quality
diaphragm	UBERON:0001103	98.63	gold quality
muscle organ	UBERON:0001630	98.42	gold quality
right atrium auricular region	UBERON:0006631	98.32	gold quality
tibialis anterior	UBERON:0001385	98.21	gold quality
muscle of leg	UBERON:0001383	98.08	gold quality
cardiac atrium	UBERON:0002081	96.96	gold quality
heart left ventricle	UBERON:0002084	96.86	gold quality
cardiac ventricle	UBERON:0002082	95.97	gold quality
muscle tissue	UBERON:0002385	94.58	gold quality
heart	UBERON:0000948	93.07	gold quality
tongue	UBERON:0001723	90.26	gold quality
left uterine tube	UBERON:0001303	87.38	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.78	gold quality
adenohypophysis	UBERON:0002196	85.71	gold quality
myocardium	UBERON:0002349	83.96	gold quality
superior surface of tongue	UBERON:0007371	82.27	gold quality
popliteal artery	UBERON:0002250	81.42	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	1253.85
E-CURD-11	yes	126.66
E-GEOD-137537	yes	40.35
E-ANND-3	yes	17.54
E-MTAB-6524	no	210.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

130 targeting TRDN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• gene organization and cloning of the major isoform (PMID:12659871)
• Histidine-rich Ca-binding protein may play a key role in the regulation of SR Ca cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross talk between SR Ca uptake and release in the heart. (PMID:17526652)
• The researchers found evidence that TRDN may be a susceptibility or marker gene for IgA nephropathy (PMID:19890582)
• Data show that triadin (TRDN) is a new gene responsible for an autosomal recessive form of ctecholaminergic polymorphic ventricular tachycardia (CPVT). (PMID:22422768)
• TRDN is a novel underlying genetic basis for recessively inherited Long-QT syndrome. (PMID:25922419)
• Common variants in TRDN and CALM1 are associated with increased risk of sudden cardiac death in patients with chronic heart failure. (PMID:26196381)
• We describe a new family with cathecholaminergic polymorphic ventricular tachycardia (CPVT) linked to the Triadin gene. (PMID:26200674)
• A compound heterozygous mutation in the triadin gene resulted in a particularly arrhythmogenic phenotype with with cardiac arrest in two siblings. (PMID:26768964)
• CLIMP-63 (also known as CKAP4), is the partner of triadin, is responsible for this association of triads and microtubules. (PMID:27562070)
• The lncRNA TRDN-AS regulates the balance between cardiac and skeletal isoforms of triadin. (PMID:29126880)
• A novel homozygous mutation in the TRDN gene causes a severe form of pediatric malignant ventricular arrhythmia. (PMID:31437535)
• Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome. (PMID:34415104)
• Association of decreased triadin expression level with apoptosis of dopaminergic cells in Parkinson’s disease mouse model. (PMID:34736417)
• Cardiomyocyte-Specific Long Noncoding RNA Regulates Alternative Splicing of the Triadin Gene in the Heart. (PMID:35862102)
• Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes. (PMID:37163978)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	trdn	ENSDARG00000041779
danio_rerio	si:ch211-266g18.10	ENSDARG00000057903
mus_musculus	Trdn	ENSMUSG00000019787
rattus_norvegicus	Trdn	ENSRNOG00000012609

Protein

Protein identifiers

Triadin — Q13061 (reviewed: Q13061)

All UniProt accessions (10): A0A590UJV0, A0AAQ5BH94, A0AAQ5BH97, A0AAQ5BHB9, A0AAQ5BHC7, A0AAQ5BHD4, Q13061, H0Y6P0, H7BY47, H9ME53

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction. Required for normal organization of the triad junction, where T-tubules and the sarcoplasmic reticulum terminal cisternae are in close contact. Required for normal skeletal muscle strength. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.

Subunit / interactions. Homooligomer of variable subunit number; disulfide-linked. Interacts with CASQ1 and RYR1 in skeletal muscle. Interacts with CASQ2.

Subcellular location. Cell membrane. Sarcoplasmic reticulum membrane.

Post-translational modifications. Phosphorylated by CaMK2. N-glycosylated.

Disease relevance. Cardiac arrhythmia syndrome, with or without skeletal muscle weakness (CARDAR) [MIM:615441] An autosomal recessive cardiac disorder characterized by stress-induced arrhythmias in infancy or early childhood. Patients present with recurrent syncope or cardiac arrest after physical activity or emotional stress. Sudden death may occur in early childhood. Some patients have muscle weakness. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13061-1	1	yes
Q13061-2	2
Q13061-3	3

RefSeq proteins (6): NP_001238916, NP_001242949, NP_001242950, NP_001242951, NP_001394244, NP_006064* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007943	Asp-B-hydro/Triadin_dom	Domain
IPR010798	Triadin	Family

Pfam: PF05279

UniProt features (38 total): compositionally biased region 11, sequence variant 10, splice variant 5, region of interest 4, topological domain 2, glycosylation site 2, disulfide bond 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13061-F1	47.65	0.02

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 270, 691

Glycosylation sites (2): 75, 647

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-5578775	Ion homeostasis

MSigDB gene sets: 296 (showing top): GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, MEF2_02, HNF1_Q6, AAAYRNCTG_UNKNOWN, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION, GOBP_MONOATOMIC_CATION_TRANSPORT, SRF_Q5_01, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_CALCIUM_ION_SIGNALING, GOBP_MAINTENANCE_OF_LOCATION, GOBP_CELL_COMMUNICATION_INVOLVED_IN_CARDIAC_CONDUCTION

GO Biological Process (14): intracellular calcium ion homeostasis (GO:0006874), muscle contraction (GO:0006936), response to bacterium (GO:0009617), regulation of cell communication by electrical coupling (GO:0010649), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), cytoplasmic microtubule organization (GO:0031122), establishment of localization in cell (GO:0051649), heart contraction (GO:0060047), regulation of cardiac muscle cell membrane potential (GO:0086036), endoplasmic reticulum membrane organization (GO:0090158), positive regulation of cell communication by electrical coupling involved in cardiac conduction (GO:1901846), obsolete regulation of sequestering of calcium ion (GO:0051282)

GO Molecular Function (4): signaling receptor binding (GO:0005102), protein-macromolecule adaptor activity (GO:0030674), transmembrane transporter binding (GO:0044325), protein binding (GO:0005515)

GO Cellular Component (10): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), plasma membrane (GO:0005886), junctional sarcoplasmic reticulum membrane (GO:0014701), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), junctional membrane complex (GO:0030314), sarcoplasmic reticulum membrane (GO:0033017), sarcoplasmic reticulum lumen (GO:0033018)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Cardiac conduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
cytoplasm	2
sarcoplasm	2
sarcoplasmic reticulum	2
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
muscle system process	1
response to other organism	1
cell communication by electrical coupling	1
regulation of cell communication	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
microtubule cytoskeleton organization	1
supramolecular fiber organization	1
establishment of localization	1
cellular localization	1
heart process	1
blood circulation	1
regulation of membrane potential	1
endoplasmic reticulum organization	1
membrane organization	1
positive regulation of cell communication by electrical coupling	1
cell communication by electrical coupling involved in cardiac conduction	1
regulation of cell communication by electrical coupling involved in cardiac conduction	1
molecular adaptor activity	1
binding	1
nuclear lumen	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
sarcoplasmic reticulum membrane	1
endoplasmic reticulum	1
protein-containing complex	1
endoplasmic reticulum membrane	1

Protein interactions and networks

STRING

1673 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRDN	ASPH	Q12797	999
TRDN	RYR2	Q92736	998
TRDN	CASQ2	O14958	985
TRDN	CASQ1	P31415	979
TRDN	FKBP1B	P68106	963
TRDN	RYR1	P21817	950
TRDN	CALM1	P02593	949
TRDN	FKBP1A	P20071	929
TRDN	SRI	P30626	913
TRDN	CALML3	P27482	913
TRDN	CALML5	Q9NZT1	913
TRDN	CALML6	Q8TD86	910
TRDN	CALML4	Q96GE6	910
TRDN	HRC	P23327	893
TRDN	JPH2	Q9BR39	852

IntAct

8 interactions, top by confidence:

A	B	Type	Score
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
MTA3	KDM1A	psi-mi:“MI:0914”(association)	0.530
TRDN	NPM1	psi-mi:“MI:0915”(physical association)	0.400
TRDN	AIFM1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (118): TRDN (Two-hybrid), ABCC5 (Affinity Capture-MS), TMEM205 (Affinity Capture-MS), GOLIM4 (Affinity Capture-MS), JPH1 (Affinity Capture-MS), ABCB10 (Affinity Capture-MS), ZFPL1 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), TMEM9B (Affinity Capture-MS), EMC3 (Affinity Capture-MS), VTI1B (Affinity Capture-MS), MANEA (Affinity Capture-MS), EMC4 (Affinity Capture-MS), GOSR2 (Affinity Capture-MS), EMC8 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GR13, A0A571BEE2, A8MU46, E9Q9K5, F1QBY1, O01949, O02828, O43493, P05229, P06719, P08855, P09346, P10156, P12036, P12305, P12675, P20810, P20811, P27321, P29172, P35662, P35663, P38978, P51125, P54938, P57786, P70486, P82179, Q02752, Q05018, Q05019, Q09202, Q09355, Q13061, Q14093, Q27450, Q28092, Q28820, Q54IN6, Q55H65

Diamond homologs: E9Q9K5, P82179, Q13061, Q28820, Q9QX75

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1593 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	23
Uncertain significance	627
Likely benign	676
Benign	122

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070395	NM_006073.4(TRDN):c.22+29A>G	Pathogenic
1403180	NM_006073.4(TRDN):c.439_440del (p.Lys147fs)	Pathogenic
1458047	NM_006073.4(TRDN):c.91del (p.Val31fs)	Pathogenic
1708485	NM_006073.4(TRDN):c.508G>T (p.Gly170Ter)	Pathogenic
1746830	NM_006073.4(TRDN):c.532_533del (p.Glu178fs)	Pathogenic
1749169	NM_006073.4(TRDN):c.57_58insTTTT (p.Lys20delinsPheTer)	Pathogenic
1797791	NM_006073.4(TRDN):c.292delinsAA (p.Glu98fs)	Pathogenic
1798674	NM_006073.4(TRDN):c.2T>C (p.Met1Thr)	Pathogenic
1799347	NM_006073.4(TRDN):c.305G>A (p.Trp102Ter)	Pathogenic
2018973	NM_006073.4(TRDN):c.451C>T (p.Gln151Ter)	Pathogenic
2425490	NC_000006.11:g.(?123539746)(123957920_?)del	Pathogenic
2762883	NM_006073.4(TRDN):c.424G>T (p.Glu142Ter)	Pathogenic
2818604	NM_006073.4(TRDN):c.334del (p.Asp112fs)	Pathogenic
2920531	NC_000006.12:g.123503896TCTGT[1]	Pathogenic
2980846	NM_006073.4(TRDN):c.507dup (p.Gly170fs)	Pathogenic
3245990	NC_000006.11:g.(?123957879)(123957920_?)del	Pathogenic
3245991	NC_000006.11:g.(?123759188)(123957920_?)del	Pathogenic
3245992	NC_000006.11:g.(?123892048)(123957920_?)del	Pathogenic
3673082	NM_006073.4(TRDN):c.587dup (p.Glu197fs)	Pathogenic
408737	NM_006073.4(TRDN):c.618del (p.Ala208fs)	Pathogenic
4279214	GRCh37/hg19 6q22.31(chr6:123875341-123987965)x1	Pathogenic
449691	NM_006073.4(TRDN):c.438_442del (p.Asp146_Lys147insTer)	Pathogenic
463677	NM_006073.4(TRDN):c.232+2T>A	Pathogenic
4712099	NM_006073.4(TRDN):c.521del (p.Val174fs)	Pathogenic
4782180	NM_006073.4(TRDN):c.295dup (p.Thr99fs)	Pathogenic
532312	NM_006073.4(TRDN):c.573dup (p.Lys192fs)	Pathogenic
583099	NM_006073.4(TRDN):c.529A>T (p.Lys177Ter)	Pathogenic
66017	NM_006073.4(TRDN):c.176C>G (p.Thr59Arg)	Pathogenic
685063	GRCh37/hg19 6q22.31(chr6:123815422-123951153)x1	Pathogenic
685818	GRCh37/hg19 6q22.31(chr6:123551934-123597121)x1	Pathogenic

SpliceAI

7151 predictions. Top by Δscore:

Variant	Effect	Δscore
6:123218603:ACTGT:A	donor_gain	1.0000
6:123218604:CTGTC:C	donor_gain	1.0000
6:123224137:G:C	acceptor_gain	1.0000
6:123224137:G:GC	acceptor_gain	1.0000
6:123224140:C:CT	acceptor_gain	1.0000
6:123265316:A:AC	donor_gain	1.0000
6:123265317:C:CC	donor_gain	1.0000
6:123267752:C:CC	acceptor_gain	1.0000
6:123352584:CAG:C	acceptor_gain	1.0000
6:123352587:C:CC	acceptor_gain	1.0000
6:123366192:C:CT	acceptor_gain	1.0000
6:123366195:A:AC	acceptor_gain	1.0000
6:123366195:A:C	acceptor_gain	1.0000
6:123366198:T:C	acceptor_gain	1.0000
6:123366198:T:TC	acceptor_gain	1.0000
6:123377738:CTTTG:C	acceptor_gain	1.0000
6:123377743:C:CC	acceptor_gain	1.0000
6:123377749:C:CT	acceptor_gain	1.0000
6:123377750:A:T	acceptor_gain	1.0000
6:123393679:T:C	acceptor_gain	1.0000
6:123464991:A:AC	acceptor_gain	1.0000
6:123464993:G:C	acceptor_gain	1.0000
6:123464993:G:GC	acceptor_gain	1.0000
6:123464999:G:C	acceptor_gain	1.0000
6:123464999:G:GC	acceptor_gain	1.0000
6:123465006:T:TC	acceptor_gain	1.0000
6:123500587:T:C	donor_gain	1.0000
6:123500618:T:TA	donor_gain	1.0000
6:123503897:CTGTT:C	acceptor_gain	1.0000
6:123503899:GTTC:G	acceptor_loss	1.0000

AlphaMissense

4800 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:123570977:A:G	W60R	1.000
6:123570977:A:T	W60R	1.000
6:123570988:A:G	L56P	0.999
6:123570979:G:T	T59K	0.998
6:123571007:A:G	W50R	0.998
6:123571007:A:T	W50R	0.998
6:123570958:A:T	V66D	0.997
6:123570967:A:T	V63D	0.997
6:123570979:G:C	T59R	0.997
6:123570985:A:T	I57K	0.997
6:123570988:A:T	L56Q	0.997
6:123570991:G:T	A55D	0.997
6:123571000:A:G	L52P	0.997
6:123218720:A:G	C691R	0.996
6:123497236:A:C	C270W	0.996
6:123497237:C:T	C270Y	0.996
6:123497238:A:G	C270R	0.996
6:123570951:A:C	F68L	0.996
6:123570951:A:T	F68L	0.996
6:123570953:A:G	F68L	0.996
6:123570964:G:T	A64D	0.996
6:123570970:G:T	A62D	0.996
6:123570971:C:G	A62P	0.996
6:123570988:A:C	L56R	0.996
6:123218718:A:C	C691W	0.995
6:123218719:C:G	C691S	0.995
6:123218720:A:T	C691S	0.995
6:123497234:C:G	R271P	0.995
6:123570975:C:A	W60C	0.995
6:123570975:C:G	W60C	0.995

dbSNP variants (sampled 300 via entrez): RS1000000374 (6:123607596 AT>A), RS1000004777 (6:123553518 T>C), RS1000007996 (6:123318934 T>C), RS1000009114 (6:123326344 A>T), RS1000013303 (6:123308247 T>C), RS1000013706 (6:123486250 C>G), RS1000015419 (6:123454401 T>C), RS1000022372 (6:123606990 G>A), RS1000026314 (6:123495132 C>A,T), RS1000029059 (6:123472267 G>A,C,T), RS1000031706 (6:123408115 G>A), RS1000037585 (6:123286891 C>T), RS1000047081 (6:123237298 G>A), RS1000049844 (6:123566293 A>G), RS1000051202 (6:123533842 T>C)

Disease associations

OMIM: gene MIM:603283 | disease phenotypes: MIM:600996, MIM:604772, MIM:615441

GenCC curated gene-disease

Disease	Classification	Inheritance
catecholaminergic polymorphic ventricular tachycardia	Definitive	Autosomal recessive
catecholaminergic polymorphic ventricular tachycardia 5	Definitive	Autosomal recessive
familial long QT syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
long QT syndrome	Strong	AR
catecholaminergic polymorphic ventricular tachycardia	Definitive	AR

Mondo (4): catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990), catecholaminergic polymorphic ventricular tachycardia 5 (MONDO:0014191), familial long QT syndrome (MONDO:0019171)

Orphanet (1): Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0002321	Vertigo
HP:0002900	Hypokalemia
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003701	Proximal muscle weakness
HP:0004308	Ventricular arrhythmia
HP:0004755	Supraventricular tachycardia
HP:0004756	Ventricular tachycardia
HP:0004757	Paroxysmal atrial fibrillation
HP:0004758	Effort-induced polymorphic ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0006673	Reduced systolic function
HP:0006682	Premature ventricular contraction

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002928_13	Nickel levels	2.000000e-06
GCST003074_11	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	6.000000e-07
GCST003074_12	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	8.000000e-07
GCST003262_647	Post bronchodilator FEV1	5.000000e-06
GCST003542_149	Night sleep phenotypes	4.000000e-06
GCST004641_19	Borderline personality disorder	7.000000e-06
GCST007100_6	Asthma exacerbations in inhaled corticosteroid treatment	2.000000e-06
GCST007998_13	Intraocular pressure	1.000000e-11
GCST009391_1575	Metabolite levels	2.000000e-07
GCST010796_2712	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_2713	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST012099_7	Hypertrophic cardiomyopathy (sarcomere negative)	2.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004314	forced expiratory volume
EFO:0007614	asthma exacerbation measurement
EFO:0004695	intraocular pressure measurement
EFO:0010517	oxalate measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4897302	TRDN		0.00	0

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
monomethylarsonous acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Triclosan	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	affects expression	1

Clinical trials (associated diseases)

74 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT06658899	PHASE2	RECRUITING	A Phase 2 Study of CRD-4730 in CPVT
NCT07263139	PHASE2	RECRUITING	Safety, Tolerability, and Exploratory Efficacy of AGP100 in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia
NCT06005428	PHASE2	TERMINATED	Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT07148089	PHASE1	RECRUITING	A Study of SGT-501 Gene Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT01117454	Not specified	COMPLETED	Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02927223	Not specified	COMPLETED	Atropine in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT04650009	Not specified	COMPLETED	Physical Activity in Children With Inherited Cardiac Diseases
NCT04712136	Not specified	COMPLETED	Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology