autosomal recessive limb-girdle muscular dystrophy type 2Y

Summary

autosomal recessive limb-girdle muscular dystrophy type 2Y (MONDO:0014900) is a disease caused by TOR1AIP1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TOR1AIP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 411
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2Y
Mondo ID	MONDO:0014900
OMIM	617072
Orphanet	424261
DOID	DOID:0110289
NCIT	C181000
SNOMED CT	725907002
UMLS	C4511482
MedGen	1385152
GARD	0017708
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in TOR1AIP1 · autosomal recessive muscular dystrophy due to LAP1B deficiency · autosomal recessive muscular dystrophy due to Torsin-1A-interacting protein 1 deficiency · LGMD2Y · muscular dystrophy with progressive weakness, distal contractures and rigid spine · muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures · TOR1AIP1 autosomal recessive limb-girdle muscular dystrophy

Data availability: 411 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › autosomal recessive limb-girdle muscular dystrophy type 2Y

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

411 retrieved; paginated sample, class counts are floors:

191 uncertain significance, 168 likely benign, 14 pathogenic, 13 likely pathogenic, 11 benign, 11 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1356611	NM_015602.4(TOR1AIP1):c.189dup (p.Pro64fs)	LOC112577517	Pathogenic	criteria provided, single submitter
1386750	NM_015602.4(TOR1AIP1):c.349C>T (p.Gln117Ter)	LOC112577517	Pathogenic	criteria provided, single submitter
1388439	NM_015602.4(TOR1AIP1):c.343C>T (p.Arg115Ter)	LOC112577517	Pathogenic	criteria provided, single submitter
1453124	NM_015602.4(TOR1AIP1):c.379del (p.Thr127fs)	LOC112577517	Pathogenic	criteria provided, single submitter
1454229	NM_015602.4(TOR1AIP1):c.149C>A (p.Ser50Ter)	LOC112577517	Pathogenic	criteria provided, single submitter
3668667	NM_015602.4(TOR1AIP1):c.462_463del (p.His155fs)	LOC112577517	Pathogenic	criteria provided, single submitter
4804714	NM_015602.4(TOR1AIP1):c.373C>T (p.Arg125Ter)	LOC112577517	Pathogenic	criteria provided, single submitter
959057	NM_015602.4(TOR1AIP1):c.11_17del (p.Asp4fs)	LOC112577517	Pathogenic	criteria provided, single submitter
583920	NC_000001.11:g.(?179882503)(179904022_?)del	LOC129932003	Pathogenic	criteria provided, single submitter
3023484	NM_015602.4(TOR1AIP1):c.583C>T (p.Arg195Ter)	TOR1AIP1	Pathogenic	criteria provided, single submitter
660593	NM_015602.4(TOR1AIP1):c.646G>T (p.Glu216Ter)	TOR1AIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
862996	NM_015602.4(TOR1AIP1):c.763C>T (p.Gln255Ter)	TOR1AIP1	Pathogenic	criteria provided, single submitter
950989	NM_015602.4(TOR1AIP1):c.663del (p.Glu222fs)	TOR1AIP1	Pathogenic	criteria provided, single submitter
253059	NM_015602.4(TOR1AIP1):c.186del (p.Glu62fs)	TOR1AIP2	Pathogenic	no assertion criteria provided
1466030	NM_015602.4(TOR1AIP1):c.739+1G>A	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
2083769	NM_015602.4(TOR1AIP1):c.838+2T>A	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
2981146	NM_015602.4(TOR1AIP1):c.907+1G>A	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
3377574	NM_015602.4(TOR1AIP1):c.797-2A>G	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
3603577	NM_015602.4(TOR1AIP1):c.476-1G>C	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
3727645	NM_015602.4(TOR1AIP1):c.739+2T>C	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
4749402	NM_015602.4(TOR1AIP1):c.797-1G>T	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
522870	NM_015602.4(TOR1AIP1):c.1427C>T (p.Ala476Val)	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
643973	NM_015602.4(TOR1AIP1):c.906_907+5del	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
644515	NM_015602.4(TOR1AIP1):c.553+1G>A	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
804380	NM_015602.4(TOR1AIP1):c.961C>T (p.Arg321Ter)	TOR1AIP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
843154	NM_015602.4(TOR1AIP1):c.797-2A>T	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
952016	NM_015602.4(TOR1AIP1):c.554-4_554-1delinsAC	TOR1AIP1	Likely pathogenic	criteria provided, single submitter
4738132	NM_015602.4(TOR1AIP1):c.347C>T (p.Pro116Leu)	LOC112577517	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476288	NM_015602.4(TOR1AIP1):c.70C>G (p.Pro24Ala)	LOC112577517	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542852	NM_015602.4(TOR1AIP1):c.155A>T (p.Gln52Leu)	LOC112577517	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TOR1AIP1	Strong	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2Y	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOR1AIP1	Orphanet:424261	TOR1AIP1-related limb-girdle muscular dystrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TOR1AIP1	HGNC:29456	ENSG00000143337	Q5JTV8	Torsin-1A-interacting protein 1	gencc,clinvar
TOR1AIP2	HGNC:24055	ENSG00000169905	Q8NFQ8	Torsin-1A-interacting protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOR1AIP1	Torsin-1A-interacting protein 1	Required for nuclear membrane integrity.
TOR1AIP2	Torsin-1A-interacting protein 2	Required for endoplasmic reticulum integrity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOR1AIP1	Other/Unknown	no		TOIP1/2, LAP1C-like_C_sf, TOIP1/2_C
TOR1AIP2	Other/Unknown	no		TOIP1/2, LAP1C-like_C_sf, TOIP1/2_C

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
choroid plexus epithelium	1
urethra	1
adrenal tissue	1
germinal epithelium of ovary	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOR1AIP1	300	ubiquitous	marker	choroid plexus epithelium, urethra, calcaneal tendon
TOR1AIP2	282	ubiquitous	marker	adrenal tissue, jejunal mucosa, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TOR1AIP1	1,679
TOR1AIP2	1,627

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TOR1AIP2	Q8NFQ8	2
TOR1AIP1	Q5JTV8	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOF GTPase cycle	1	259.6×	0.005	TOR1AIP1
RHOD GTPase cycle	1	203.9×	0.005	TOR1AIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to nuclear envelope	2	2106.5×	1e-06	TOR1AIP1, TOR1AIP2
positive regulation of ATP-dependent activity	2	1404.3×	1e-06	TOR1AIP1, TOR1AIP2
nuclear membrane organization	1	1203.7×	0.002	TOR1AIP1
membrane organization	1	255.3×	0.006	TOR1AIP2
endoplasmic reticulum organization	1	210.7×	0.006	TOR1AIP2
protein localization to nucleus	1	175.5×	0.006	TOR1AIP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TOR1AIP1	0	0
TOR1AIP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TOR1AIP1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TOR1AIP1, TOR1AIP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TOR1AIP1	1	—
TOR1AIP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments