POPDC1

Summary

POPDC1 (popeye domain cAMP effector 1, HGNC:1152) is a protein-coding gene on chromosome 6q21, encoding Popeye domain-containing protein 1 (Q8NE79). Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity.

This gene encodes a member of the POP family of proteins containing three putative transmembrane domains. This gene is expressed in cardiac and skeletal muscle and may play an important role in development of these tissues. The mouse ortholog may be involved in the regeneration of adult skeletal muscle and may act as a cell adhesion molecule in coronary vasculogenesis. Three transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 11149 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive limb-girdle muscular dystrophy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 117 total — 3 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 49
• MANE Select transcript: NM_001199563

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1152
Approved symbol	POPDC1
Name	popeye domain cAMP effector 1
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	POP1, HBVES
Ensembl gene	ENSG00000112276
Ensembl biotype	protein_coding
OMIM	604577
Entrez	11149

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000314641, ENST00000336775, ENST00000446408, ENST00000932335

RefSeq mRNA: 3 — MANE Select: NM_001199563 NM_001199563, NM_007073, NM_147147

CCDS: CCDS5051

Canonical transcript exons

ENST00000314641 — 8 exons

Exon	Start	End
ENSE00000761264	105124547	105124655
ENSE00000761269	105125391	105125578
ENSE00000761275	105133352	105133588
ENSE00000840278	105129379	105129503
ENSE00001233706	105115686	105115827
ENSE00001233713	105116701	105116868
ENSE00001405776	105096822	105101213
ENSE00002327230	105136969	105137157

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 98.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.9747 / max 340.8976, expressed in 1216 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74869	4.7194	1185
74867	1.0168	504
74868	0.1853	80
74866	0.0532	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	98.16	gold quality
tibialis anterior	UBERON:0001385	97.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.16	gold quality
deltoid	UBERON:0001476	96.08	gold quality
vastus lateralis	UBERON:0001379	95.93	gold quality
quadriceps femoris	UBERON:0001377	95.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.92	gold quality
myocardium	UBERON:0002349	94.65	gold quality
skeletal muscle tissue	UBERON:0001134	94.03	gold quality
biceps brachii	UBERON:0001507	93.75	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.64	gold quality
muscle tissue	UBERON:0002385	92.96	gold quality
skeletal muscle organ	UBERON:0014892	92.03	gold quality
heart right ventricle	UBERON:0002080	91.72	gold quality
gastrocnemius	UBERON:0001388	91.56	gold quality
sperm	CL:0000019	91.43	silver quality
muscle of leg	UBERON:0001383	91.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.95	gold quality
cardiac ventricle	UBERON:0002082	87.80	gold quality
heart left ventricle	UBERON:0002084	87.73	gold quality
secondary oocyte	CL:0000655	85.92	gold quality
smooth muscle tissue	UBERON:0001135	85.18	gold quality
heart	UBERON:0000948	85.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.81	gold quality
oocyte	CL:0000023	83.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.16	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.14	gold quality
lower esophagus	UBERON:0013473	83.07	gold quality
cardiac atrium	UBERON:0002081	82.14	gold quality
apex of heart	UBERON:0002098	81.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

160 targeting POPDC1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-559	99.95	72.28	3609

Literature-anchored findings (GeneRIF, showing 22)

• Methylation of BVES was present in 80% of NSCLC tissues but only 14% of noncancerous tissues. (PMID:18349282)
• Frequent silencing of BVES is associated with promoter hypermethylation in gastric cancer. (PMID:20627872)
• Data suggest that POPDC gene expression is modified in end-stage heart failure in humans in a manner suggesting regulatory and/or functional differences between the three family members and that POPDC1 is particularly susceptible to this condition. (PMID:21069264)
• Bves expression and localization can regulate RhoA and ZONAB/DbpA activity. (PMID:21283798)
• BVES was found to be underexpressed in all stages of colorectal carcinoma and in adenomatous polyps, indicating its suppression occurs early in transformation. (PMID:21911938)
• Low Bves expression is associated with gastric cancer progression. (PMID:22109561)
• Popdc1 (Bves) modulates cardiac pacemaker activity in response to stress and displays high expression levels in the sinus node. The Popeye domain acts as a high-affinity cAMP binding domain and Popdc proteins interact with the ion channel TREK-1. (PMID:22354168)
• Coding sequence and splice junctions of BVES were sequenced in 114 unrelated patients with Tetralogy of Fallot and 400 unrelated healthy individuals.Four novel BVES mutations were identified in patients with TOF but not in the 400 controls. (PMID:23403794)
• These results suggest that down-regulation of BVES in hepatocellular carcinoma induces epithelial-mesenchymal transition, thus promoting invasion and metastasis in HCC cells. (PMID:24442236)
• Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential (PMID:26642364)
• BVES plays a key role in maintaining the integrity of the colonic mucosa and protecting from inflammatory carcinogenesis. Results also suggest that BVES promotes the post-translational degradation of c-Myc. (PMID:28389570)
• Study shows that EGFR negatively regulates POPDC1 expression in breast cancer cell lines and that overexpression of POPDC1 can reduce EGFR-mediated cell migration and proliferation in breast cancer cells. (PMID:28807821)
• recently a novel family of cAMP effector proteins emerged and was termed the Popeye domain containing (POPDC) family, which consists of three members POPDC1, POPDC2 and POPDC3. POPDC proteins are transmembrane proteins, which are abundantly present in striated and smooth muscle cells. POPDC proteins bind cAMP with high affinity comparable to PKA (PMID:28939104)
• Functional suppression of POPDC1 promoted breast cancer cell migration and proliferation, cAMP interacts with POPDC1 and up-regulates its expression in breast cancer cells. (PMID:28954821)
• BVES plays a protective role both in ulcerative and infectious colitis. (PMID:29907869)
• c.385C>T (p.R129W) is a functional SNP of the BVES gene that reduces the transcriptional activity of BVES in vitro and in vivo in TOF tissues. This subsequently affects the transcriptional activities of GATA4 and NKX2.5 related to TOF. These findings suggest that c.385C>T may be associated with the risk of TOF in the Han Chinese population. (PMID:31386585)
• BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis. (PMID:32843646)
• An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs. (PMID:33261556)
• The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation. (PMID:34069715)
• Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1). (PMID:35660068)
• A novel biallelic variant in the Popeye domain-containing protein 1 (POPDC1) underlies limb girdle muscle dystrophy type 25. (PMID:36155908)
• Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking. (PMID:36624536)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	popdc1	ENSDARG00000058548
mus_musculus	Popdc1	ENSMUSG00000071317
rattus_norvegicus	Bves	ENSRNOG00000043199
drosophila_melanogaster	bves	FBGN0031150

Paralogs (2): POPDC2 (ENSG00000121577), POPDC3 (ENSG00000132429)

Protein

Protein identifiers

Popeye domain-containing protein 1 — Q8NE79 (reviewed: Q8NE79)

All UniProt accessions (1): Q8NE79

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity. Involved in the formation and regulation of the tight junction (TJ) paracellular permeability barrier in epithelial cells. Plays a role in VAMP3-mediated vesicular transport and recycling of different receptor molecules through its interaction with VAMP3. Plays a role in the regulation of cell shape and movement by modulating the Rho-family GTPase activity through its interaction with ARHGEF25/GEFT. Induces primordial adhesive contact and aggregation of epithelial cells in a Ca(2+)-independent manner. Also involved in striated muscle regeneration and repair and in the regulation of cell spreading. Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density. Is also a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury.

Subunit / interactions. Homodimer. Homodimerization requires the C-terminus cytoplasmic region. Interacts (via the C-terminus cytoplasmic tail) with TJP1. Interacts (via the C-terminus cytoplasmic tail) with ARHGEF25/GEFT (via the DH domain). Interacts (via the C-terminus cytoplasmic tail) with VAMP3. Interacts with KCNK2; the interaction enhances KCNK2 surface expression and is inhibited by cAMP. Interacts with CAV3.

Subcellular location. Lateral cell membrane. Cell junction. Tight junction. Membrane. Cell membrane. Sarcolemma. Caveola.

Tissue specificity. Expressed in epithelial cells (at protein level). Expressed in fetal and adult heart and skeletal muscle.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal recessive 25 (LGMDR25) [MIM:616812] An autosomal recessive muscular disorder characterized by slowly progressive onset of proximal lower limb weakness in adulthood, syncopal episodes, and markedly increased serum creatine kinase, which can increase further after strenuous exercise. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the popeye family.

RefSeq proteins (3): NP_001186492, NP_009004, NP_671488 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006916	POPDC1-3	Family
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR055272	POPDC1-3_dom	Domain

Pfam: PF04831

UniProt features (27 total): sequence conflict 7, topological domain 4, region of interest 3, sequence variant 3, transmembrane region 3, compositionally biased region 2, modified residue 2, glycosylation site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NE79-F1	76.08	0.49

Functional residue map

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

Post-translational modifications (2): 295, 318

Glycosylation sites (2): 2, 30

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 432 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, WANG_CLIM2_TARGETS_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_NUCLEASE_ACTIVITY, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (21): positive regulation of receptor recycling (GO:0001921), regulation of heart rate (GO:0002027), hematopoietic progenitor cell differentiation (GO:0002244), response to ischemia (GO:0002931), heart development (GO:0007507), muscle organ development (GO:0007517), skeletal muscle tissue development (GO:0007519), regulation of cell shape (GO:0008360), vesicle-mediated transport (GO:0016192), substrate adhesion-dependent cell spreading (GO:0034446), positive regulation of locomotion (GO:0040017), regulation of membrane potential (GO:0042391), regulation of GTPase activity (GO:0043087), obsolete vesicle docking (GO:0048278), striated muscle cell differentiation (GO:0051146), sinoatrial node cell development (GO:0060931), cell migration involved in heart development (GO:0060973), epithelial cell-cell adhesion (GO:0090136), regulation of endocytic recycling (GO:2001135), cell adhesion (GO:0007155), striated muscle tissue development (GO:0014706)

GO Molecular Function (4): structural molecule activity (GO:0005198), cAMP binding (GO:0030552), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), caveola (GO:0005901), bicellular tight junction (GO:0005923), membrane (GO:0016020), lateral plasma membrane (GO:0016328), cell junction (GO:0030054), cell projection membrane (GO:0031253), sarcolemma (GO:0042383), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of biological quality	3
cellular anatomical structure	3
animal organ development	2
cellular process	2
plasma membrane	2
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
regulation of heart contraction	1
hemopoiesis	1
cell differentiation	1
response to stress	1
circulatory system development	1
muscle structure development	1
striated muscle tissue development	1
skeletal muscle organ development	1
regulation of cell morphogenesis	1
transport	1
cell-substrate adhesion	1
locomotion	1
regulation of locomotion	1
positive regulation of biological process	1
monoatomic ion transmembrane transport	1
GTPase activity	1
regulation of hydrolase activity	1
muscle cell differentiation	1
sinoatrial node cell differentiation	1
cardiac pacemaker cell development	1
heart development	1
cell migration	1
cell-cell adhesion	1
regulation of intracellular transport	1
endocytic recycling	1
regulation of vesicle-mediated transport	1
molecular_function	1
cyclic nucleotide binding	1
adenyl ribonucleotide binding	1
anion binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POPDC1	ARHGEF25	Q86VW2	776
POPDC1	KCNK2	O95069	752
POPDC1	PPP2R5A	Q15172	740
POPDC1	DMD	P11532	688
POPDC1	CAV3	P56539	655
POPDC1	DYSF	O75923	646
POPDC1	TJP1	Q07157	640
POPDC1	NDRG4	Q9ULP0	585
POPDC1	TJP2	Q9UDY2	516
POPDC1	TBCCD1	Q9NVR7	476
POPDC1	GATA4	P43694	472
POPDC1	GFOD2	Q3B7J2	449
POPDC1	ANO8	Q9HCE9	424
POPDC1	TMEM214	Q6NUQ4	420
POPDC1	J3KSM2	J3KSM2	413

IntAct

11 interactions, top by confidence:

A	B	Type	Score
HSPB1	POPDC1	psi-mi:“MI:0915”(physical association)	0.370
PB2		psi-mi:“MI:0914”(association)	0.350
POPDC1	RNF123	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
POPDC1	CALM1	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
POPDC1	DCX	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC38A9	SCAMP3	psi-mi:“MI:0914”(association)	0.350
HNRNPC	SBNO1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (19): UBAC1 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), BVES (Two-hybrid), RNF123 (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), BVES (Affinity Capture-RNA), BVES (Affinity Capture-MS), BVES (Affinity Capture-RNA), BVES (Affinity Capture-MS), DCX (Affinity Capture-MS), ITPRIPL1 (Affinity Capture-MS), CPNE2 (Affinity Capture-MS), CALM3 (Affinity Capture-MS), NPW (Affinity Capture-MS), BVES (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P9G0, B1H1G2, B8Q0B2, O18866, O18867, O95259, P29973, P29974, P70604, Q00194, Q00195, Q03041, Q03720, Q08460, Q0IH22, Q12791, Q16280, Q16281, Q21029, Q28204, Q28279, Q28718, Q28EW0, Q29441, Q3BCU4, Q5PQZ7, Q5U2P1, Q60603, Q62398, Q62927, Q62976, Q63472, Q6JWV8, Q8JH92, Q8NCM2, Q8NE79, Q90805, Q90980, Q90ZC7, Q920E3

Diamond homologs: B1H1G2, B8Q0B2, Q0IH22, Q3BCU4, Q5PQZ7, Q6JWV8, Q8JH92, Q8NE79, Q9DG23, Q9DG25, Q9ES81, Q9ES82, Q9ES83, Q9HBU9, Q9HBV1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
BVES	“up-regulates activity”	VAMP3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	7
Uncertain significance	60
Likely benign	17
Benign	22

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1702994	NM_001199563.2(BVES):c.578T>G (p.Ile193Ser)	Pathogenic
626313	NM_001199563.2(BVES):c.816+2T>C	Pathogenic
626315	NM_001199563.2(BVES):c.1A>G (p.Met1Val)	Pathogenic
1163853	NM_001199563.2(POPDC1):c.427A>T (p.Arg143Ter)	Likely pathogenic
1686644	NM_001199563.2(BVES):c.602C>G (p.Ser201Cys)	Likely pathogenic
1723441	NM_001199563.2(POPDC1):c.518dup (p.Ser174fs)	Likely pathogenic
222033	NM_001199563.2(POPDC1):c.602C>T (p.Ser201Phe)	Likely pathogenic
377143	NM_001199563.2(BVES):c.731_734del (p.Phe244fs)	Likely pathogenic
4081212	NM_001199563.2(POPDC1):c.351+1del	Likely pathogenic
624258	NM_001199563.2(POPDC1):c.457C>T (p.Gln153Ter)	Likely pathogenic

SpliceAI

4351 predictions. Top by Δscore:

Variant	Effect	Δscore
6:105101008:AAAAG:A	donor_gain	1.0000
6:105101058:T:A	donor_gain	1.0000
6:105115684:A:AC	donor_gain	1.0000
6:105115685:C:CC	donor_gain	1.0000
6:105115824:CTTT:C	acceptor_gain	1.0000
6:105115826:TT:T	acceptor_gain	1.0000
6:105115828:C:CC	acceptor_gain	1.0000
6:105116694:CACTT:C	donor_loss	1.0000
6:105116695:ACTT:A	donor_loss	1.0000
6:105116697:TTA:T	donor_loss	1.0000
6:105116698:TACTT:T	donor_loss	1.0000
6:105116699:A:AC	donor_gain	1.0000
6:105116699:ACT:A	donor_loss	1.0000
6:105116700:C:CT	donor_gain	1.0000
6:105116700:CTTT:C	donor_gain	1.0000
6:105116700:CTTTA:C	donor_gain	1.0000
6:105125389:A:AC	donor_gain	1.0000
6:105125390:C:CC	donor_gain	1.0000
6:105136968:CCCGG:C	donor_gain	1.0000
8:98123335:GAA:G	acceptor_gain	1.0000
8:98123335:GAAAT:G	acceptor_gain	1.0000
8:98123430:TGTA:T	donor_gain	1.0000
8:98128363:A:AG	acceptor_gain	1.0000
8:98128364:G:GG	acceptor_gain	1.0000
8:98128538:GAG:G	donor_gain	1.0000
8:98128538:GAGG:G	donor_loss	1.0000
8:98130224:CAGGT:C	donor_loss	1.0000
8:98130225:AGGT:A	donor_loss	1.0000
8:98130226:GGTG:G	donor_loss	1.0000
8:98130227:GTG:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000038949 (6:105101744 G>A), RS1000050551 (6:105138565 T>C), RS1000062331 (6:105123767 C>T), RS1000113547 (6:105116102 A>C,G), RS1000601653 (6:105100621 A>G), RS1000643553 (6:105105261 C>G), RS1000701751 (6:105099702 C>T), RS1000733868 (6:105136668 G>A), RS1001100353 (6:105110676 G>A), RS1001197528 (6:105100259 C>T), RS1001250976 (6:105129356 TATTA>T), RS1001309651 (6:105122697 G>C,T), RS1001325271 (6:105124819 A>C), RS1001345823 (6:105115424 C>G), RS1001365943 (6:105103751 C>T)

Disease associations

OMIM: gene MIM:604577 | disease phenotypes: MIM:616812

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy type 2X	Strong	Autosomal recessive
tetralogy of fallot	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy	Definitive	AR

Mondo (3): autosomal recessive limb-girdle muscular dystrophy type 2X (MONDO:0014782), limb-girdle muscular dystrophy (MONDO:0016971), tetralogy of fallot (MONDO:0008542)

Orphanet (2): BVES-related limb-girdle muscular dystrophy (Orphanet:476084), Limb-girdle muscular dystrophy (Orphanet:263)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000470	Short neck
HP:0000668	Hypodontia
HP:0000914	Shield chest
HP:0001156	Brachydactyly
HP:0001279	Syncope
HP:0001288	Gait disturbance
HP:0001371	Flexion contracture
HP:0001511	Intrauterine growth retardation
HP:0001688	Sinus bradycardia
HP:0001792	Small nail
HP:0001962	Palpitations
HP:0002164	Nail dysplasia
HP:0002505	Loss of ambulation
HP:0002673	Coxa valga
HP:0002680	J-shaped sella turcica
HP:0002750	Delayed skeletal maturation
HP:0002812	Coxa vara
HP:0002967	Cubitus valgus
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003300	Ovoid vertebral bodies
HP:0003307	Hyperlordosis
HP:0003325	Limb-girdle muscle weakness
HP:0003326	Myalgia
HP:0003423	Thoracolumbar kyphoscoliosis
HP:0003546	Exercise intolerance
HP:0003557	Increased variability in muscle fiber diameter
HP:0003560	Muscular dystrophy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000175_14	Height	8.000000e-07
GCST000400_1	Menarche (age at onset)	2.000000e-14
GCST005171_45	QT interval	2.000000e-06
GCST006014_11	Creatine kinase levels	4.000000e-18

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004682	QT interval
EFO:0004534	creatine kinase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
bisphenol A	decreases methylation, increases expression	2
trichostatin A	increases expression	2
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
entinostat	increases expression	1
nutlin 3	increases expression, affects cotreatment	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Gold	increases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Urethane	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT02010905	PHASE2	UNKNOWN	Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT00573066	PHASE1	COMPLETED	Understanding Dexmedetomidine In Infants Post-Operative From Cardiac Surgery
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT04713657	PHASE1	RECRUITING	Beta-blocker Administration for Cardiomyocyte Division
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
NCT02050776	PHASE1	WITHDRAWN	Stem Cell Therapy in Limb Girdle Muscular Dystrophy
NCT02245711	PHASE1	WITHDRAWN	Cell Therapy in Limb Girdle Muscular Dystrophy
NCT05876780	PHASE1	ACTIVE_NOT_RECRUITING	A Gene Transfer Single Dose Study to Evaluate the Safety, Tolerability and Efficacy of SRP-9003 in Non-Ambulatory and Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2E/R4 (Beta-Sarcoglycan [β-SG] Deficiency)
NCT05906251	PHASE1	TERMINATED	A Gene Transfer Study to Evaluate the Safety, Tolerability and Efficacy of SRP-6004 in Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2B/R2 (LGMD2B/R2, Dysferlin [DYSF] Related)
NCT06747273	PHASE1	TERMINATED	Study to Evaluate the Safety, Tolerability, and Efficacy of SRP-9004 Administered by Systemic Infusion in Limb Girdle Muscular Dystrophy Type 2D/R3 Participants in the United States
NCT02590679	PHASE2/PHASE3	UNKNOWN	Multi-center Trial of Percutaneous Pulmonary Valve Implantation With Venus-p
NCT05579964	PHASE2/PHASE3	COMPLETED	The Role of Dexmedetomidine as Myocardial Protector in Pediatric Cardiac Surgery Total Correction of Tetralogy of Fallot
NCT05186415	PHASE1/PHASE2	COMPLETED	Contrast Enhanced 3D Echocardiographic Quantification of Right Ventricular Volumes in Repaired CHD
NCT07194304	EARLY_PHASE1	COMPLETED	Effect of Parenteral Alpha-Tocopherol in the Definitive Surgery of Tetralogy of Fallot
NCT00004361	Not specified	COMPLETED	Study of the Relationship Between Calcium Levels and Intact Parathyroid Hormone (iPTH) in Adults With Repaired or Palliated Conotruncal Cardiac Defects
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00112320	Not specified	COMPLETED	Comparison of Two Pulmonary Valve Replacement Methods to Treat Tetralogy of Fallot
NCT00155428	Not specified	UNKNOWN	Biomodel in Tetralogy of Fallot
NCT00243776	Not specified	RECRUITING	Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development
NCT00266188	Not specified	COMPLETED	Follow up of Post-repair Tetralogy of Fallot
NCT00412685	Not specified	COMPLETED	Myocardial Contrast Echocardiography in Congenital Heart Disease
NCT00536432	Not specified	COMPLETED	Early Re-intervention in Infants and Small Children After Correction of Tetralogy of Fallot
NCT00860327	Not specified	TERMINATED	Examining Developmental Changes in Heart Contractions of Children With Congenital Heart Defects
NCT01419756	Not specified	COMPLETED	Assessment of Right Ventricular Volume in Tetralogy of Fallott (TOF) Patients
NCT01762124	Not specified	COMPLETED	Study of the Native Outflow Tract Transcatheter Pulmonary Valve (TPV)
NCT01824160	Not specified	COMPLETED	Pulmonary Artery Repair With Covered Stents
NCT01941576	Not specified	COMPLETED	Effects of rhBNP in Pediatrics After Corrective Repair of Tetralogy Of Fallot
NCT02161471	Not specified	COMPLETED	Haemodynamics and Function of the Atria in Congenital Heart Disease by Cardiovascular Magnetic Resonance
NCT02364934	Not specified	UNKNOWN	Pharmacokinetics and Pharmacodynamics of Rocuronium in Closed-Loop Infusion System
NCT02534792	Not specified	COMPLETED	Early Revalvulation After Fallot Repair Improves Clinical Outcome
NCT02586740	Not specified	COMPLETED	Retrospective Review of Anesthetic Considerations for Pulmonary Artery Rehabilitation
NCT02643810	Not specified	COMPLETED	Exercise Training in Adults With Corrected Tetralogy of Fallot
NCT02967315	Not specified	COMPLETED	Effects of Changes in Fluid Status on Right Ventricular Volumes and Function