Muscular dystrophy, limb-girdle, autosomal recessive 28

Summary

Muscular dystrophy, limb-girdle, autosomal recessive 28 (MONDO:0957270) is a disease caused by HMGCR (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HMGCR (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy, limb-girdle, autosomal recessive 28
Mondo ID	MONDO:0957270
OMIM	620375
Orphanet	653725
DOID	DOID:0061130
UMLS	C5830518
MedGen	1841154
GARD	0026805
Is cancer (heuristic)	no

Data availability: 11 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive limb-girdle muscular dystrophy › muscular dystrophy, limb-girdle, autosomal recessive 28

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2H, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, 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 2Q, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 23, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 27, muscular dystrophy, limb-girdle, autosomal recessive 29

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

11 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 2 likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1803007	NM_000859.3(HMGCR):c.2465G>A (p.Gly822Asp)	HMGCR	Pathogenic	criteria provided, single submitter
2506432	NM_000859.3(HMGCR):c.365+4A>G	HMGCR	Pathogenic	no assertion criteria provided
2506433	NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys)	HMGCR	Pathogenic	no assertion criteria provided
2506430	NM_000859.3(HMGCR):c.1328G>A (p.Arg443Gln)	HMGCR	Likely pathogenic	criteria provided, single submitter
2506431	NM_000859.3(HMGCR):c.1867G>A (p.Asp623Asn)	HMGCR	Likely pathogenic	criteria provided, single submitter
2506435	NM_000859.3(HMGCR):c.1519TCT[1] (p.Ser508del)	HMGCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2620865	NM_000859.3(HMGCR):c.1799G>A (p.Cys600Tyr)	HMGCR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2506434	NM_000859.3(HMGCR):c.1327C>T (p.Arg443Trp)	HMGCR	Uncertain significance	criteria provided, single submitter
3383321	NM_000859.3(HMGCR):c.1401C>G (p.Ile467Met)	HMGCR	Uncertain significance	criteria provided, single submitter
4532000	NM_000859.3(HMGCR):c.1789C>T (p.Pro597Ser)	HMGCR	Uncertain significance	criteria provided, single submitter
4532001	NM_000859.3(HMGCR):c.2425A>C (p.Thr809Pro)	HMGCR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
HMGCR	Strong	Autosomal recessive	muscular dystrophy, limb-girdle, autosomal recessive 28	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HMGCR	Orphanet:653725	Autosomal recessive limb-girdle muscular dystrophy, type 28

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HMGCR	HGNC:5006	ENSG00000113161	P04035	3-hydroxy-3-methylglutaryl-coenzyme A reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HMGCR	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HMGCR	Enzyme (other)	yes	1.1.1.34	SSD, HMG_CoA_Rdtase, HMG_CoA_Rdtase_eu_arc

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
cortical plate	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HMGCR	286	ubiquitous	marker	adrenal tissue, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HMGCR	5,062

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMGCR	P04035	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Lanosterol biosynthesis	1	761.3×	0.005	HMGCR
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.005	HMGCR
Activation of gene expression by SREBF (SREBP)	1	259.6×	0.005	HMGCR
PPARA activates gene expression	1	94.4×	0.011	HMGCR

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
coenzyme A metabolic process	1	3370.4×	0.001	HMGCR
isoprenoid biosynthetic process	1	1685.2×	0.001	HMGCR
sterol biosynthetic process	1	1685.2×	0.001	HMGCR
negative regulation of amyloid-beta clearance	1	1685.2×	0.001	HMGCR
negative regulation of protein secretion	1	887.0×	0.002	HMGCR
regulation of ERK1 and ERK2 cascade	1	581.1×	0.003	HMGCR
cholesterol biosynthetic process	1	421.3×	0.003	HMGCR
negative regulation of protein catabolic process	1	366.4×	0.003	HMGCR
visual learning	1	306.4×	0.004	HMGCR
long-term synaptic potentiation	1	280.9×	0.004	HMGCR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HMGCR	SIMVASTATIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HMGCR	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR
LOVASTATIN	4	HMGCR
TANNIC ACID	4	HMGCR
PRAVASTATIN SODIUM	4	HMGCR
GLENVASTATIN	2	HMGCR
MEGLUTOL	2	HMGCR
MEVASTATIN	2	HMGCR
APOMINE	1	HMGCR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HMGCR	153	Binding:148, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HMGCR	1.1.1.34	hydroxymethylglutaryl-CoA reductase (NADPH)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
HMGCR	153

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
HMGCR	1

Chemical tractability of cohort targets

15 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.

Compound	Max phase	Cohort target (bioactivity)
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR
LOVASTATIN	4	HMGCR
TANNIC ACID	4	HMGCR
PRAVASTATIN SODIUM	4	HMGCR
GLENVASTATIN	2	HMGCR
MEGLUTOL	2	HMGCR
MEVASTATIN	2	HMGCR
APOMINE	1	HMGCR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HMGCR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.