myopathy due to calsequestrin and SERCA1 protein overload

Summary

myopathy due to calsequestrin and SERCA1 protein overload (MONDO:0014546) is a disease caused by CASQ1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CASQ1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 32
• Phenotypes (HPO): 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

2 HPO clinical features (Orphanet curated; top 2 by frequency):

HPO ID	Term	Frequency
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy due to calsequestrin and SERCA1 protein overload
Mondo ID	MONDO:0014546
OMIM	616231
Orphanet	88635
SNOMED CT	724095006
UMLS	C4015624
MedGen	864061
GARD	0016770
Is cancer (heuristic)	no

Also known as: myopathy, vacuolar, with CASQ1 aggregates · VMCQA

Data availability: 32 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of protein SERCA1 › myopathy due to calsequestrin and SERCA1 protein overload

Related subtypes (1): Brody myopathy

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

32 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 4 conflicting classifications of pathogenicity, 1 pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
183021	NM_001231.5(CASQ1):c.731A>G (p.Asp244Gly)	CASQ1	Pathogenic	criteria provided, single submitter
2687779	NM_001231.5(CASQ1):c.984+1G>A	CASQ1	Likely pathogenic	criteria provided, single submitter
1510878	NM_001231.5(CASQ1):c.1061C>T (p.Ala354Val)	CASQ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1560538	NM_001231.5(CASQ1):c.134G>T (p.Gly45Val)	CASQ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522913	NM_001231.5(CASQ1):c.1018G>A (p.Asp340Asn)	CASQ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732718	NM_001231.5(CASQ1):c.280-1G>C	CASQ1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1302432	NM_001231.5(CASQ1):c.165G>T (p.Lys55Asn)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330246	NM_001231.5(CASQ1):c.298G>A (p.Glu100Lys)	CASQ1	Uncertain significance	criteria provided, single submitter
1365538	NM_001231.5(CASQ1):c.748GAG[1] (p.Glu251del)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371281	NM_001231.5(CASQ1):c.143G>A (p.Arg48His)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1389336	NM_001231.5(CASQ1):c.574G>C (p.Glu192Gln)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1750554	NM_001231.5(CASQ1):c.592G>A (p.Glu198Lys)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1801697	NM_001231.5(CASQ1):c.1148del (p.Gly383fs)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1930774	NM_001231.5(CASQ1):c.707T>A (p.Met236Lys)	CASQ1	Uncertain significance	criteria provided, single submitter
2002076	NM_001231.5(CASQ1):c.87G>C (p.Lys29Asn)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2061962	NM_001231.5(CASQ1):c.715C>G (p.Pro239Ala)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2162707	NM_001231.5(CASQ1):c.515C>T (p.Ala172Val)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2397771	NM_001231.5(CASQ1):c.476A>G (p.Asp159Gly)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439763	NM_001231.5(CASQ1):c.429G>C (p.Glu143Asp)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439764	NM_001231.5(CASQ1):c.46del (p.Arg16fs)	CASQ1	Uncertain significance	criteria provided, single submitter
2439765	NM_001231.5(CASQ1):c.984+2T>G	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439766	NM_001231.5(CASQ1):c.142C>T (p.Arg48Cys)	CASQ1	Uncertain significance	criteria provided, single submitter
2987690	NM_001231.5(CASQ1):c.865G>A (p.Ala289Thr)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3137670	NM_001231.5(CASQ1):c.808G>A (p.Glu270Lys)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4078192	NM_001231.5(CASQ1):c.884-31C>G	CASQ1	Uncertain significance	criteria provided, single submitter
4078193	NM_001231.5(CASQ1):c.604G>C (p.Glu202Gln)	CASQ1	Uncertain significance	criteria provided, single submitter
422913	NM_001231.5(CASQ1):c.1176TGA[2] (p.Asp395_Asp396del)	CASQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4532052	NM_001231.5(CASQ1):c.1118T>C (p.Leu373Pro)	CASQ1	Uncertain significance	criteria provided, single submitter
4846981	NM_001231.5(CASQ1):c.41del (p.Gly14fs)	CASQ1	Uncertain significance	criteria provided, single submitter
547945	NM_001231.5(CASQ1):c.837T>G (p.Asp279Glu)	CASQ1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
CASQ1	Strong	Autosomal dominant	myopathy due to calsequestrin and SERCA1 protein overload	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASQ1	Orphanet:2593	Tubular aggregate myopathy
CASQ1	Orphanet:88635	Vacuolar myopathy with sarcoplasmic reticulum protein aggregates

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
CASQ1	HGNC:1512	ENSG00000143318	P31415	Calsequestrin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASQ1	Calsequestrin-1	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASQ1	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASQ1	195	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASQ1	1,601

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASQ1	P31415	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Ion homeostasis	1	203.9×	0.016	CASQ1
Stimuli-sensing channels	1	135.9×	0.016	CASQ1
Cardiac conduction	1	108.8×	0.016	CASQ1
Ion channel transport	1	96.0×	0.016	CASQ1
Muscle contraction	1	77.2×	0.016	CASQ1
Transport of small molecules	1	25.1×	0.040	CASQ1

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
positive regulation of store-operated calcium channel activity	1	16852.0×	6e-04	CASQ1
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	4213.0×	0.001	CASQ1
response to denervation involved in regulation of muscle adaptation	1	2407.4×	0.001	CASQ1
regulation of store-operated calcium entry	1	1053.2×	0.002	CASQ1
protein polymerization	1	991.3×	0.002	CASQ1
positive regulation of release of sequestered calcium ion into cytosol	1	495.6×	0.003	CASQ1
endoplasmic reticulum organization	1	421.3×	0.003	CASQ1
response to heat	1	421.3×	0.003	CASQ1
sarcomere organization	1	383.0×	0.003	CASQ1
skeletal muscle tissue development	1	290.6×	0.003	CASQ1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
CASQ1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	CASQ1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CASQ1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.