autosomal recessive limb-girdle muscular dystrophy type 2K

Summary

autosomal recessive limb-girdle muscular dystrophy type 2K (MONDO:0012248) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Cohort genes: 2
• ClinVar variants: 1,003
• Phenotypes (HPO): 32
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0003551	Difficulty climbing stairs	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003560	Muscular dystrophy	Frequent (30-79%)
HP:0003687	Centrally nucleated skeletal muscle fibers	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003733	Thigh hypertrophy	Frequent (30-79%)
HP:0008981	Calf muscle hypertrophy	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0003325	Limb-girdle muscle weakness	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0003700	Generalized amyotrophy	Occasional (5-29%)
HP:0003803	Type 1 muscle fiber predominance	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)
HP:0031108	Triceps weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2K
Mondo ID	MONDO:0012248
OMIM	609308
Orphanet	86812
DOID	DOID:0110297
NCIT	C133730
SNOMED CT	720523006
UMLS	C1836373
MedGen	332193
GARD	0012535
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in POMT1 · LGMD-POMT1 related · LGMD2K · limb-girdle muscular dystrophy - intellectual disability · limb-girdle muscular dystrophy type 2K · limb-girdle muscular dystrophy-intellectual disability syndrome · MDDGC1 · muscular dystrophy-dystroglycanopathy (Limb-girdle) type C, 1 · muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 · POMT1 autosomal recessive limb-girdle muscular dystrophy

Data availability: 1,003 ClinVar variants · 1 GenCC gene-disease record · 2 cell lines.

Disease family

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

Related subtypes (8): autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8

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

600 retrieved; paginated sample, class counts are floors:

300 likely benign, 163 uncertain significance, 41 conflicting classifications of pathogenicity, 34 pathogenic, 19 benign, 17 pathogenic/likely pathogenic, 15 benign/likely benign, 11 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066221	NM_001077365.2(POMT1):c.1176-2A>G	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067618	NM_001077365.2(POMT1):c.427+1G>A	POMT1	Pathogenic	criteria provided, single submitter
1075349	NM_001077365.2(POMT1):c.1204dup (p.His402fs)	POMT1	Pathogenic	criteria provided, single submitter
1076965	NM_001077365.2(POMT1):c.160_161insTTTTTTTTTTTTTTTNNNNNNNNNNTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCAGTACATCTCTTTTT (p.Tyr54delinsPhePhePhePhePheXaaXaaXaaXaaHisArgPheSerArgAspGlyLeuAspLeuLeuThrSerTer)	POMT1	Pathogenic	criteria provided, single submitter
1192212	NM_001077365.2(POMT1):c.1272+1G>A	POMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323489	NM_001077365.2(POMT1):c.633C>G (p.Tyr211Ter)	POMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1343631	NM_001077365.2(POMT1):c.2040_2050del (p.Val681fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359283	NM_001077365.2(POMT1):c.859_871del (p.Gly287fs)	POMT1	Pathogenic	criteria provided, single submitter
1360015	NM_001077365.2(POMT1):c.270_280delAATTGGAGCAG (p.Gly92fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364191	NM_001077365.2(POMT1):c.58dup (p.Val20fs)	POMT1	Pathogenic	criteria provided, single submitter
1399708	NM_001077365.2(POMT1):c.97C>T (p.Arg33Ter)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451349	NM_001077365.2(POMT1):c.72del (p.Met25fs)	POMT1	Pathogenic	criteria provided, single submitter
1453137	NM_001077365.2(POMT1):c.1364del (p.Lys455fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458255	NM_001077365.2(POMT1):c.130G>A (p.Glu44Lys)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1470886	NM_001077365.2(POMT1):c.605+1G>T	POMT1	Pathogenic	criteria provided, single submitter
1497287	NM_001077365.2(POMT1):c.313C>T (p.Arg105Cys)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1516923	NC_000009.11:g.(?134389752)(134390863_?)del	POMT1	Pathogenic	criteria provided, single submitter
162594	NM_001077365.2(POMT1):c.1478dup (p.Tyr493Ter)	POMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1686087	NM_001077365.2(POMT1):c.986+1G>A	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1930280	NM_001077365.2(POMT1):c.720del (p.Leu240fs)	POMT1	Pathogenic	criteria provided, single submitter
194757	NM_001077365.2(POMT1):c.1657del (p.Leu553fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194859	NM_001077365.2(POMT1):c.1798C>T (p.Arg600Ter)	POMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1997263	NM_001077365.2(POMT1):c.1061G>A (p.Trp354Ter)	POMT1	Pathogenic	criteria provided, single submitter
1998900	NM_001077365.2(POMT1):c.529C>T (p.Gln177Ter)	POMT1	Pathogenic	criteria provided, single submitter
1998907	NM_001077365.2(POMT1):c.2141G>A (p.Trp714Ter)	POMT1	Pathogenic	criteria provided, single submitter
2020409	NM_001077365.2(POMT1):c.145del (p.Gln49fs)	POMT1	Pathogenic	criteria provided, single submitter
2041522	NM_001077365.2(POMT1):c.789_790del (p.Leu263fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2062446	NM_001077365.2(POMT1):c.2113_2119del (p.Ser705fs)	POMT1	Pathogenic	criteria provided, single submitter
212739	NM_001077365.2(POMT1):c.558G>A (p.Trp186Ter)	POMT1	Pathogenic	criteria provided, single submitter
2181474	NM_001077365.2(POMT1):c.1284_1285del (p.Asn428fs)	POMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
POMT1	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POMT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT1	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
POMT1	Orphanet:588	Muscle-eye-brain disease
POMT1	Orphanet:86812	POMT1-related limb-girdle muscular dystrophy R11
POMT1	Orphanet:899	Walker-Warburg syndrome

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
POMT1	HGNC:9202	ENSG00000130714	Q9Y6A1	Protein O-mannosyl-transferase 1	gencc,clinvar
PLPP7	HGNC:28174	ENSG00000160539	Q8NBV4	Inactive phospholipid phosphatase 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POMT1	Protein O-mannosyl-transferase 1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
PLPP7	Inactive phospholipid phosphatase 7	Plays a role as negative regulator of myoblast differentiation, in part through effects on MTOR signaling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POMT1	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like
PLPP7	Other/Unknown	no		PAP2/HPO, PAP2/HPO_sf

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POMT1	264	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PLPP7	195	ubiquitous	yes	apex of heart, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POMT1	1,475
PLPP7	481

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POMT1	Q9Y6A1	88.09
PLPP7	Q8NBV4	80.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	3806.7×	6e-04	POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	3806.7×	6e-04	POMT1
DAG1 core M1 glycosylations	1	2855.0×	6e-04	POMT1
DAG1 core M2 glycosylations	1	2284.0×	6e-04	POMT1
DAG1 core M3 glycosylations	1	1903.3×	6e-04	POMT1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	335.9×	0.003	POMT1

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
negative regulation of myotube differentiation	1	561.7×	0.004	PLPP7
protein O-linked glycosylation via mannose	1	468.1×	0.004	POMT1
protein O-linked glycosylation	1	112.3×	0.012	POMT1
extracellular matrix organization	1	61.1×	0.016	POMT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POMT1	0	0
PLPP7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase

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	1	POMT1
E	Difficult family or no structure, no drug	1	PLPP7

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)
POMT1	0	—
PLPP7	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