DOK7

Summary

DOK7 (docking protein 7, HGNC:26594) is a protein-coding gene on chromosome 4p16.3, encoding Protein Dok-7 (Q18PE1). Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.

The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 285489 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital myasthenic syndrome 10 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,301 total — 68 pathogenic, 57 likely-pathogenic
• Phenotypes (HPO): 83
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_173660

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26594
Approved symbol	DOK7
Name	docking protein 7
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33718, FLJ39137, Dok-7
Ensembl gene	ENSG00000175920
Ensembl biotype	protein_coding
OMIM	610285
Entrez	285489

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000340083, ENST00000503688, ENST00000507039, ENST00000511267, ENST00000513995, ENST00000515886, ENST00000643608

RefSeq mRNA: 5 — MANE Select: NM_173660 NM_001164673, NM_001256896, NM_001301071, NM_001363811, NM_173660

CCDS: CCDS3370, CCDS54717, CCDS87205, CCDS87206

Canonical transcript exons

ENST00000340083 — 7 exons

Exon	Start	End
ENSE00001506478	3476342	3476542
ENSE00003502125	3473406	3473636
ENSE00003554733	3492759	3494482
ENSE00003594483	3485539	3485658
ENSE00003612126	3463506	3463551
ENSE00003664759	3489677	3489796
ENSE00003845135	3463306	3463429

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 93.37.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0788 / max 26.2259, expressed in 253 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46714	0.5329	197
46716	0.3365	103
46715	0.2093	122

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	93.37	gold quality
tibialis anterior	UBERON:0001385	90.63	gold quality
right atrium auricular region	UBERON:0006631	89.66	gold quality
heart left ventricle	UBERON:0002084	89.44	gold quality
gastrocnemius	UBERON:0001388	88.96	gold quality
cardiac ventricle	UBERON:0002082	88.91	gold quality
cardiac atrium	UBERON:0002081	88.64	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.54	gold quality
pancreatic ductal cell	CL:0002079	88.43	silver quality
right uterine tube	UBERON:0001302	87.33	gold quality
muscle of leg	UBERON:0001383	86.97	gold quality
heart	UBERON:0000948	84.96	gold quality
germinal epithelium of ovary	UBERON:0001304	84.07	gold quality
pituitary gland	UBERON:0000007	82.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.22	gold quality
cerebellar hemisphere	UBERON:0002245	81.48	gold quality
cerebellar cortex	UBERON:0002129	81.30	gold quality
adenohypophysis	UBERON:0002196	80.97	gold quality
cerebellum	UBERON:0002037	79.93	gold quality
biceps brachii	UBERON:0001507	79.81	gold quality
skeletal muscle tissue	UBERON:0001134	79.76	gold quality
ascending aorta	UBERON:0001496	79.41	gold quality
quadriceps femoris	UBERON:0001377	79.03	silver quality
thoracic aorta	UBERON:0001515	78.85	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	78.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	78.08	gold quality
left ventricle myocardium	UBERON:0006566	77.95	gold quality
vastus lateralis	UBERON:0001379	77.93	silver quality
heart right ventricle	UBERON:0002080	76.85	silver quality
muscle tissue	UBERON:0002385	76.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

19 targeting DOK7, 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-7845-5P	99.88	64.88	771
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-6849-3P	97.25	64.57	1371
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982
HSA-MIR-6769A-3P	94.91	61.36	412

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 35)

• Dok-7 is essential for neuromuscular synaptogenesis through its interaction with MuSK (PMID:16794080)
• findings showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of congenital myasthenic syndromes with proximal muscle weakness (PMID:16917026)
• study of patients with congenital myasthenic syndromes with mutations in DOK7; none with DOK7 mutations had tubular aggregates in muscle biopsy, implying ’limb-girdle myasthenia with tubular aggregates’ may be distinct from CMS caused by DOK7 mutations (PMID:17439981)
• considerable phenotypic variability associated with congenital myasthenic syndrome due to DOK7 mutations (PMID:18161030)
• the COOH-terminal NES and Src homology 2 target motifs play key roles in Dok-7/MuSK signaling for neuromuscular synaptogenesis. (PMID:18165682)
• Dok-7 is essential for not only the size but also the structural integrity of the EP. The structural alterations at the EPs cause the reduced safety margin of neuromuscular transmission. (PMID:18626973)
• Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation. (PMID:19244212)
• whereas incomplete loss of DOK7 function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype (PMID:19261599)
• We report clinical, morphological and molecular data on 15 congenital myasthenic syndrome patients with mutations in DOK7; characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and therapy (PMID:20012313)
• these findings demonstrate that missense mutations in MUSK can result in a severe form of congenital myasthenic syndrome and indicate that the inability of MuSK mutants to interact with Dok-7. (PMID:20371544)
• 6 CMS patients with DOK7 mutations had congenital stridor, bilateral vocal cord palsy and difficulty with feeding (PMID:20554332)
• The crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide representing the Dok7-binding site on MuSK, is presented. (PMID:20603078)
• This study demonistreated that DOK7 mutation casused congenital myasthenic syndrome in French Canadians. (PMID:20610155)
• Sequencing of DOK-7 in seronegative myasthenia gravis patients reveals no mutations. (PMID:21305573)
• The DOK7 gene is highly polymorphic, and within these many variants, a spectrum of mutations that can underlie DOK7 Congenital myasthenic syndromes that will inform in managing this disorder, were defined. (PMID:22661499)
• DOK7 limb-girdle myasthenic syndrome can mimick congenital muscular dystrophy. (PMID:22884442)
• Hypermethylation of DOK7 occurs years before tumor diagnosis, suggesting a role as a powerful epigenetic blood-based biomarker as well as providing insights into breast cancer pathogenesis (PMID:23054610)
• In contrast to AChR deficiency due to epsilon subunit mutations, onset of DOK7 CMS tends to be later–ages two to three years–and in DOK7 CMS eye movements are usually spared and anticholinesterases can exacerbate the weakness (PMID:23278577)
• this study demonistrated that Salbutamol is an effective treatment in patient wity congenital myasthenic syndrome due to DOK7 mutation. (PMID:23790237)
• Individuals with DOK7 congenital myasthenic syndrome displayed stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy pointing to a diagnosis and should lead to neurophysiological and genetic investigation (PMID:23831158)
• Silencing DNMT3A inhibits proliferation and invasion in ESCC cells by inducing demethylation of DOK7. (PMID:28343076)
• DOK7 was reduced in lung cancer and reduced DOK7 expression was associated with poorer survival.DOK7 isoform 1 plays an inhibitory role on the proliferation and migration of lung cancer cells. (PMID:28393246)
• Data identified MuSK activator Dok-7 as a another ROR1-binding protein independently of MuSK interaction. (PMID:29292499)
• Repression of Dok7 expression via DNMT1 mediated DNA methylation promotes glioma cell proliferation. (PMID:29990858)
• Data showed that DOK7 transcript variants 1 (DOK7V1) were decreased in lung cancer, and associated with poor overall survival and progressionfree survival. Its overexpression limited the proliferation and migration, but enhanced the adhesion to the extracellular matrix, of lung cancer cells. Further data indicate that DOK7V1 may inhibit proliferation and migration via negatively regulating the PI3K/AKT/mTOR signaling. (PMID:30431081)
• this study shows hypermethylation of DOK7 gene in DNA from patients affected with breast cancer (PMID:30829272)
• 2 unrelated adult patients who presented with a limb-girdle congenital myasthenic syndrome, caused by 2 compound heterozygous pathogenic sequence variants in DOK7: c.1124_1127dupTGCC (P.Ala378Serfs*30) and c.480C> A (p.Tyr160*) (PMID:31453852)
• Congenital myasthenic syndrome due to DOK7 mutation in a cohort of patients with ‘unexplained’ limb-girdle muscular weakness. (PMID:32238315)
• Hsa_Circ_0001947/MiR-661/DOK7 Axis Restrains Non-Small Cell Lung Cancer Development. (PMID:34528912)
• DOK7 CpG hypermethylation in blood leukocytes as an epigenetic biomarker for acquired tamoxifen resistant in breast cancer. (PMID:36372800)
• Life-Long Steroid Responsive Familial Myopathy With Docking Protein 7 Mutation. (PMID:36409338)
• A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells. (PMID:36579833)
• Congenital Myasthenic Syndrome Caused by DOK7 Mutation in a Quinquagenarian Male with Calf Hypertrophy. (PMID:37611271)
• Delineation of molecular characteristics of congenital myasthenic syndromes in Indian families and review of literature. (PMID:37646703)
• DOK7, a target of miR-299-5p, suppresses the progression of bladder cancer. (PMID:38095644)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dok7b	ENSDARG00000060236
danio_rerio	dok7a	ENSDARG00000105782
mus_musculus	Dok7	ENSMUSG00000044716
rattus_norvegicus	Dok7	ENSRNOG00000022419
caenorhabditis_elegans		WBGENE00017463

Protein

Protein identifiers

Protein Dok-7 — Q18PE1 (reviewed: Q18PE1)

Alternative names: Downstream of tyrosine kinase 7

All UniProt accessions (3): Q18PE1, A0A1W2PRA3, A0A2R8Y701

UniProt curated annotations — full annotation on UniProt →

Function. Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. Induces autophosphorylation of MUSK.

Subunit / interactions. Homodimer. Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via IRS-type PTB domain) with MUSK (via cytoplasmic part); requires MUSK phosphorylation.

Subcellular location. Cell membrane. Synapse.

Tissue specificity. Preferentially expressed in skeletal muscle and heart. Present in thigh muscle, diaphragm and heart but not in the liver or spleen (at protein level).

Disease relevance. Myasthenic syndrome, congenital, 10 (CMS10) [MIM:254300] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS10 is an autosomal recessive, post-synaptic form characterized by a typical ’limb girdle’ pattern of muscle weakness with small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. The disease is caused by variants affecting the gene represented in this entry. Fetal akinesia deformation sequence 3 (FADS3) [MIM:618389] A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. FADS3 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PH domain mediated binding to phospholipids with phosphoinositol headgroups. Affinity is highest for phosphatidyl 3,4,5-trisphosphate, followed by phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate.

Isoforms (4)

UniProt ID	Names	Canonical?
Q18PE1-1	1	yes
Q18PE1-2	2
Q18PE1-4	4
Q18PE1-3	3

RefSeq proteins (5): NP_001158145, NP_001243825, NP_001288000, NP_001350740, NP_775931* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR037746	Dok-7	Family
IPR037747	Dok-7_PH	Domain
IPR037748	Dok-7_PTB	Domain

Pfam: PF02174

UniProt features (53 total): sequence variant 35, splice variant 5, mutagenesis site 4, region of interest 3, compositionally biased region 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q18PE1-F1	65.61	0.38

Functional residue map

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

Mutagenesis-validated functional residues (4):

Position	Phenotype
30	reduced stimulation of musk autophosphorylation.
32	reduced stimulation of musk autophosphorylation.
158	reduced stimulation of musk autophosphorylation; when associated in cis with a-174.
174	reduced stimulation of musk autophosphorylation; when associated in cis with q-158.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 312 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_REGULATION_OF_PHOSPHORYLATION, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_RAC_PROTEIN_SIGNAL_TRANSDUCTION

GO Biological Process (8): enzyme-linked receptor protein signaling pathway (GO:0007167), neuromuscular junction development (GO:0007528), Rac protein signal transduction (GO:0016601), positive regulation of Rac protein signal transduction (GO:0035022), receptor clustering (GO:0043113), positive regulation of protein tyrosine kinase activity (GO:0061098), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), positive regulation of skeletal muscle acetylcholine-gated channel clustering (GO:1904395)

GO Molecular Function (5): protein kinase binding (GO:0019901), phosphatidylinositol binding (GO:0035091), signaling adaptor activity (GO:0035591), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (7): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), neuromuscular junction (GO:0031594), postsynaptic membrane (GO:0045211), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
cell surface receptor signaling pathway	1
synapse organization	1
small GTPase-mediated signal transduction	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
plasma membrane	1
protein localization to membrane	1
protein tyrosine kinase activity	1
positive regulation of protein kinase activity	1
positive regulation of peptidyl-tyrosine phosphorylation	1
regulation of protein tyrosine kinase activity	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
skeletal muscle acetylcholine-gated channel clustering	1
positive regulation of receptor clustering	1
regulation of skeletal muscle acetylcholine-gated channel clustering	1
kinase binding	1
anion binding	1
protein-macromolecule adaptor activity	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
synapse	1
synaptic membrane	1
postsynapse	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

678 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOK7	MUSK	O15146	994
DOK7	AGRN	O00468	991
DOK7	RAPSN	Q13702	983
DOK7	COLQ	Q9Y215	943
DOK7	ACHE	P22303	865
DOK7	CHRNE	Q04844	858
DOK7	BCHE	P06276	798
DOK7	CHRNB1	P11230	786
DOK7	SCN4A	P35499	782
DOK7	CHRND	Q07001	763
DOK7	CHRNA1	P02708	751
DOK7	GFPT1	Q06210	714
DOK7	LRP4	O75096	699
DOK7	DPAGT1	Q9H3H5	686
DOK7	CRK	P46108	685

IntAct

13 interactions, top by confidence:

A	B	Type	Score
EFEMP2	DOK7	psi-mi:“MI:0915”(physical association)	0.560
DOK7	CRK	psi-mi:“MI:0915”(physical association)	0.490
DOK7	APPL1	psi-mi:“MI:0915”(physical association)	0.490
DOK7		psi-mi:“MI:0915”(physical association)	0.490
CRK	DOK7	psi-mi:“MI:0915”(physical association)	0.490
APPL1	DOK7	psi-mi:“MI:0915”(physical association)	0.490
	DOK7	psi-mi:“MI:0915”(physical association)	0.490
DOK7	EFHC1	psi-mi:“MI:0915”(physical association)	0.370
DOK7		psi-mi:“MI:0915”(physical association)	0.370
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
EFEMP2	DOK7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): DOK7 (Two-hybrid), DOK7 (Two-hybrid), MPZL1 (Two-hybrid), EFHC1 (Two-hybrid), YPEL3 (Two-hybrid), DOK7 (Reconstituted Complex), BCAR1 (Affinity Capture-Western), BCAR1 (Far Western), DOK7 (Two-hybrid), DOK7 (Synthetic Lethality), DOK7 (Co-fractionation), DOK7 (Co-fractionation), DOK7 (Affinity Capture-Western)

ESM2 similar proteins: A2ARS0, A5PJP1, A5PKW4, A6QQ91, C9JTQ0, D3ZG83, F1MUS9, O14512, O14559, O75427, O95996, P0C0T2, P46062, Q02779, Q09019, Q12852, Q18PE0, Q18PE1, Q1LZC5, Q2KI85, Q2TAL5, Q2VPJ9, Q3UMT1, Q53LP3, Q566C8, Q5BJT1, Q5DTT2, Q60700, Q63HR2, Q66L42, Q69YU3, Q6GQX6, Q6NSJ2, Q6NXT1, Q6QNY0, Q7TN12, Q80YF9, Q86YV0, Q8C0J6, Q8C2K5

Diamond homologs: Q18PD9, Q18PE0, Q18PE1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
DOK7	up-regulates	MUSK	binding
MUSK	“up-regulates activity”	DOK7	phosphorylation
DOK7	“up-regulates activity”	CRK	binding
DOK7	“up-regulates activity”	CRKL	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1301 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	68
Likely pathogenic	57
Uncertain significance	400
Likely benign	561
Benign	97

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069243	NM_173660.5(DOK7):c.1387G>T (p.Glu463Ter)	Pathogenic
1075034	NM_173660.5(DOK7):c.978_1018del (p.Gln326fs)	Pathogenic
1273	NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)	Pathogenic
1276	NM_173660.5(DOK7):c.1339_1342dup (p.Gly448fs)	Pathogenic
1279	NM_173660.5(DOK7):c.601C>T (p.Arg201Ter)	Pathogenic
1280	NM_173660.5(DOK7):c.55-1G>T	Pathogenic
1332706	NM_173660.5(DOK7):c.930_933del (p.Met311fs)	Pathogenic
1453023	NM_173660.5(DOK7):c.299G>A (p.Trp100Ter)	Pathogenic
1459045	NC_000004.11:g.(?3465103)(3465298_?)del	Pathogenic
1952562	NM_173660.5(DOK7):c.473G>A (p.Arg158Gln)	Pathogenic
198626	NM_173660.5(DOK7):c.957del (p.Lys320fs)	Pathogenic
1994082	NM_173660.5(DOK7):c.429del (p.Asp143fs)	Pathogenic
2059967	NM_173660.5(DOK7):c.1324_1357del (p.Cys442fs)	Pathogenic
209149	NM_173660.5(DOK7):c.1138dup (p.Ala380fs)	Pathogenic
2102209	NM_173660.5(DOK7):c.1257_1269del (p.Ser419fs)	Pathogenic
2203505	NM_173660.5(DOK7):c.1361_1374del (p.Leu454fs)	Pathogenic
2413517	NM_173660.5(DOK7):c.1367dup (p.Met456fs)	Pathogenic
2427510	NC_000004.11:g.(?3494466)(3495228_?)del	Pathogenic
2674884	NM_173660.5(DOK7):c.1378del (p.Gln460fs)	Pathogenic
2674892	NM_173660.5(DOK7):c.1138del (p.Ala380fs)	Pathogenic
2924727	NM_173660.5(DOK7):c.1323dup (p.Cys442fs)	Pathogenic
2925372	NM_173660.5(DOK7):c.1236C>A (p.Cys412Ter)	Pathogenic
2925373	NM_173660.5(DOK7):c.1378C>T (p.Gln460Ter)	Pathogenic
2928747	NM_173660.5(DOK7):c.1310_1320del (p.Gln437fs)	Pathogenic
2932239	NM_173660.5(DOK7):c.894dup (p.Pro299fs)	Pathogenic
2933131	NM_173660.5(DOK7):c.718C>T (p.Gln240Ter)	Pathogenic
2934129	NM_173660.5(DOK7):c.1348del (p.Arg450fs)	Pathogenic
2934155	NM_173660.5(DOK7):c.1296_1311dup (p.Thr438fs)	Pathogenic
2934428	NM_173660.5(DOK7):c.463_466del (p.Ser155fs)	Pathogenic
2936050	NM_173660.5(DOK7):c.1040_1041del (p.Ser347fs)	Pathogenic

SpliceAI

1894 predictions. Top by Δscore:

Variant	Effect	Δscore
4:3473402:GCAGA:G	acceptor_loss	1.0000
4:3473403:CAGAC:C	acceptor_loss	1.0000
4:3473404:A:AG	acceptor_gain	1.0000
4:3473405:G:GA	acceptor_gain	1.0000
4:3473405:GAC:G	acceptor_gain	1.0000
4:3473405:GACT:G	acceptor_gain	1.0000
4:3473633:GAGG:G	donor_gain	1.0000
4:3473635:GG:G	donor_gain	1.0000
4:3473636:GG:G	donor_gain	1.0000
4:3473637:G:GA	donor_loss	1.0000
4:3473637:G:GG	donor_gain	1.0000
4:3473638:T:A	donor_loss	1.0000
4:3485534:T:A	acceptor_gain	1.0000
4:3485534:TGCA:T	acceptor_loss	1.0000
4:3485537:A:AG	acceptor_gain	1.0000
4:3485537:AG:A	acceptor_gain	1.0000
4:3485537:AGG:A	acceptor_gain	1.0000
4:3485537:AGGG:A	acceptor_gain	1.0000
4:3485538:G:GT	acceptor_gain	1.0000
4:3485538:GG:G	acceptor_gain	1.0000
4:3485538:GGG:G	acceptor_gain	1.0000
4:3485538:GGGG:G	acceptor_gain	1.0000
4:3485538:GGGGC:G	acceptor_gain	1.0000
4:3485655:CCAGG:C	donor_loss	1.0000
4:3485656:CAGGT:C	donor_loss	1.0000
4:3485657:AGGT:A	donor_loss	1.0000
4:3485659:G:GC	donor_loss	1.0000
4:3485660:T:G	donor_loss	1.0000
4:3463418:G:GT	donor_gain	0.9900
4:3463423:C:T	donor_gain	0.9900

AlphaMissense

3198 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:3463506:T:A	W19R	0.999
4:3463506:T:C	W19R	0.999
4:3476464:T:A	W152R	0.999
4:3476464:T:C	W152R	0.999
4:3476510:T:C	F167S	0.999
4:3473603:T:A	W100R	0.998
4:3473603:T:C	W100R	0.998
4:3476516:T:C	F169S	0.998
4:3463508:G:C	W19C	0.997
4:3463508:G:T	W19C	0.997
4:3476509:T:C	F167L	0.997
4:3476511:C:A	F167L	0.997
4:3476511:C:G	F167L	0.997
4:3476350:T:C	F114L	0.996
4:3476352:C:A	F114L	0.996
4:3476352:C:G	F114L	0.996
4:3476402:T:C	L131P	0.996
4:3476465:G:C	W152S	0.996
4:3476466:G:C	W152C	0.996
4:3476466:G:T	W152C	0.996
4:3476480:T:A	L157H	0.996
4:3476480:T:C	L157P	0.996
4:3485550:T:C	F182L	0.996
4:3485552:C:A	F182L	0.996
4:3485552:C:G	F182L	0.996
4:3463516:G:T	R22M	0.995
4:3473538:T:C	L78P	0.995
4:3476351:T:C	F114S	0.995
4:3473412:T:C	L36P	0.994
4:3476408:T:C	L133P	0.994

dbSNP variants (sampled 300 via entrez): RS1000002013 (4:3494637 T>A,C), RS1000014743 (4:3469815 A>G,T), RS1000070207 (4:3482595 G>A), RS1000089903 (4:3470789 G>T), RS1000177530 (4:3497274 C>T), RS1000194206 (4:3465614 C>T), RS1000198690 (4:3492541 C>T), RS1000250741 (4:3492444 G>A), RS1000255114 (4:3492568 G>A), RS1000322356 (4:3461418 A>G), RS1000389586 (4:3482004 T>G), RS1000403472 (4:3478197 G>A), RS1000422212 (4:3482167 C>T), RS1000448030 (4:3481273 T>A), RS1000448176 (4:3469664 G>A)

Disease associations

OMIM: gene MIM:610285 | disease phenotypes: MIM:254300, MIM:609456, MIM:208150, MIM:618389, MIM:601462, MIM:300963, MIM:312750

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myasthenic syndrome 10	Definitive	Autosomal recessive
fetal akinesia deformation sequence 3	Strong	Autosomal recessive
postsynaptic congenital myasthenic syndrome	Supportive	Autosomal recessive
fetal akinesia deformation sequence 1	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital myasthenic syndrome 10	Definitive	AR

Mondo (7): congenital myasthenic syndrome 10 (MONDO:0009690), fetal akinesia deformation sequence 1 (MONDO:0100101), fetal akinesia deformation sequence 3 (MONDO:0100103), congenital myasthenic syndrome (MONDO:0018940), Ritscher-Schinzel syndrome 2 (MONDO:0010499), Rett syndrome (MONDO:0010726), postsynaptic congenital myasthenic syndrome (MONDO:0020344)

Orphanet (5): Congenital myasthenic syndrome (Orphanet:590), Fetal akinesia deformation sequence (Orphanet:994), 3C syndrome (Orphanet:7), Atypical Rett syndrome (Orphanet:3095), Rett syndrome (Orphanet:778)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000470	Short neck
HP:0000476	Cystic hygroma
HP:0000494	Downslanted palpebral fissures
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000597	Ophthalmoparesis
HP:0000651	Diplopia
HP:0000961	Cyanosis
HP:0001059	Pterygium
HP:0001262	Excessive daytime somnolence
HP:0001283	Bulbar palsy
HP:0001305	Dandy-Walker malformation
HP:0001315	Reduced tendon reflexes
HP:0001324	Muscle weakness
HP:0001446	Abnormality of the musculature of the upper limbs
HP:0001511	Intrauterine growth retardation
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001838	Rocker bottom foot
HP:0001883	Talipes
HP:0001989	Fetal akinesia sequence
HP:0002089	Pulmonary hypoplasia
HP:0002091	Restrictive ventilatory defect

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004121_26	Fibrinogen levels	3.000000e-11
GCST004122_19	Fibrinogen levels	1.000000e-07
GCST005982_2	Calcium levels	2.000000e-08
GCST008839_33	Height	3.000000e-11
GCST009365_53	LDL cholesterol levels x short total sleep time interaction (2df test)	4.000000e-09
GCST010396_225	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-06
GCST010866_50	Coronary artery disease	2.000000e-08
GCST012616_18	Spondylosis	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
D015518	Rett Syndrome	C10.597.606.360.455.937; C16.320.322.500.937; C16.320.400.525.937
C563716	Muscular Dystrophy, Congenital, Merosin-Positive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, increases reaction	4
Cadmium	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression	1
sulforaphane	increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	affects cotreatment, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Sunitinib	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Endosulfan	increases expression	1
Ethinyl Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Ketoconazole	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00069550	PHASE3	UNKNOWN	Independent Studies of Dextromethorphan and of Donepezil Hydrochloride for Rett Syndrome
NCT00261508	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone Versus Placebo in the Treatment of Children With Autistic Disorder and Other Pervasive Developmental Disorders (PDD)
NCT03848832	PHASE3	TERMINATED	Efficacy and Safety of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome
NCT03941444	PHASE3	COMPLETED	ANAVEX2-73 Study in Patients With Rett Syndrome
NCT04181723	PHASE3	COMPLETED	Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome (LAVENDER™)
NCT04252586	PHASE3	TERMINATED	A Long-term Safety Study of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome
NCT04279314	PHASE3	COMPLETED	Open-Label Extension Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome
NCT04776746	PHASE3	TERMINATED	Open-Label Extension Study of Trofinetide for Rett Syndrome
NCT05606614	PHASE3	RECRUITING	A Phase 1/2/3 Study of TSHA-102 Gene Therapy in Females With Rett Syndrome (REVEAL Pivotal Study)
NCT05898620	PHASE3	RECRUITING	A Novel, Regulated Gene Therapy (NGN-401) Study for Females With Rett Syndrome
NCT06840496	PHASE3	RECRUITING	To Investigate the Efficacy of Treatment With Oral NA-921 (Bionetide) Versus Placebo in Females With Rett Syndrome
NCT07480564	PHASE3	RECRUITING	Safety and Preliminary Efficacy of TSHA-102 Gene Therapy in Pediatric Females Aged >2 to <4 Years With Rett Syndrome
NCT07503444	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study of Fenfluramine Hydrochloride in Rett Syndrome
NCT00593957	PHASE2	TERMINATED	Trial of Dextromethorphan in Rett Syndrome
NCT00990691	PHASE2	COMPLETED	Pilot Study of the Effects of the Desipramine on the Neurovegetative Parameters of the Child With Rett Syndrome
NCT01520363	PHASE2	COMPLETED	Placebo Controlled Trial of Dextromethorphan in Rett Syndrome
NCT01703533	PHASE2	COMPLETED	A Safety Study of NNZ-2566 in Patients With Rett Syndrome
NCT01777542	PHASE2	COMPLETED	Treatment of Rett Syndrome With Recombinant Human IGF-1
NCT01822249	PHASE2	COMPLETED	Phase 2 Study of EPI-743 for Treatment of Rett Syndrome
NCT02153723	PHASE2	COMPLETED	Pharmacological Treatment of Rett Syndrome With Glatiramer Acetate (Copaxone)
NCT02563860	PHASE2	COMPLETED	Pharmacological Treatment of Rett Syndrome With Statins
NCT02696044	PHASE2	UNKNOWN	Treatment of Mitochondrial Dysfunction in Rett Syndrome With Triheptanoin
NCT02715115	PHASE2	COMPLETED	A Safety Study of NNZ-2566 in Pediatric Rett Syndrome
NCT03059160	PHASE2	UNKNOWN	Open Label Trial of Triheptanoin (UX007) in Treatment of Rett Syndrome.
NCT03633058	PHASE2	COMPLETED	A Study to Evaluate Ketamine for the Treatment of Rett Syndrome
NCT03758924	PHASE2	COMPLETED	Study of ANAVEX2-73 in Patients With Rett Syndrome
NCT04041713	PHASE2	NOT_YET_RECRUITING	A Pilot Study of an Antioxidant Cocktail vs. Placebo in the Treatment of Children and Adolescents With Rett Syndrome
NCT05625568	PHASE2	UNKNOWN	Study of VYNT-0126 in the Treatment of Rett Syndrome in Adult Patients
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT01253317	PHASE1	COMPLETED	Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)
NCT02023424	PHASE1	UNKNOWN	An Open Label, Exploratory Study to Investigate the Treatment Effect of Glatiramer Acetate on Girls Woth Rett Syndrome
NCT02562820	PHASE1	TERMINATED	An Exploratory Trial of Ketamine for the Treatment of Rett Syndrome
NCT07150013	PHASE1	RECRUITING	Rett REVOLUTION Trial: An Exploratory Evaluation of the Safety and Efficacy of Vorinostat in Rett Syndrome
NCT00872950	Not specified	APPROVED_FOR_MARKETING	3,4-Diaminopyridine Use in Lambert-Eaton Myasthenic Syndrome(LEMS) and Congenital Myasthenic Syndromes (CMS)
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01474980	Not specified	COMPLETED	Pregnancy Outcomes in Congenital Myasthenie Syndrome
NCT02012933	Not specified	NO_LONGER_AVAILABLE	3,4-Diaminopyridine for Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenia (CM)
NCT02189720	Not specified	APPROVED_FOR_MARKETING	Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome