GeneBe

CASQ1

protein-coding

calsequestrin 1, the group of Protein disulfide isomerases

Gene summary

This gene encodes the skeletal muscle specific member of the calsequestrin protein family. Calsequestrin functions as a luminal sarcoplasmic reticulum calcium sensor in both cardiac and skeletal muscle cells. This protein, also known as calmitine, functions as a calcium regulator in the mitochondria of skeletal muscle. This protein is absent in patients with Duchenne and Becker types of muscular dystrophy. [provided by RefSeq, Jun 2013]

Previous symbols:
  • CASQ

MANE transcript

NM_001231.5

Inheritance

AD

ClinVar variants

P:7U:216B:99

Top phenotype

Myopathy, vacuolar, with CASQ1 aggregates

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr1:160,190,575-160,201,886

External References & Databases

Ensembl (ENSG00000143318)NCBI Gene (844)OMIM (114250)HGNC:1512GenCCUniProt (P31415)AlphaFoldClinVar (CASQ1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy due to calsequestrin and SERCA1 protein overloadSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014546

Submitter: Labcorp Genetics (formerly Invitae)

tubular aggregate myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008051

Submitter: Orphanet

myopathy due to calsequestrin and SERCA1 protein overloadSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014546

Submitter: Orphanet

Clinical Genomic Database (CGD)

Myopathy, vacuolar, with CASQ1 aggregatesAD

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25116801Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CASQ1 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 356
Inborn genetic diseasesTotal: 98
not specifiedTotal: 43
Myopathy due to calsequestrin and SERCA1 protein overloadTotal: 34
CASQ1-related disorderTotal: 14
Myopathy with tubular aggregatesTotal: 2
MyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001231.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
81
clinvar
1
clinvar
 85
missense
2
clinvar
2
clinvar
180
clinvar
11
clinvar
3
clinvar
 198
nonsense
1
clinvar
11
clinvar
 12
start loss
1
clinvar
1
clinvar
 2
frameshift
1
clinvar
12
clinvar
 13
splice donor/acceptor (+/-2bp)
1
clinvar
9
clinvar
2
clinvar
 12
Total25216954322

Highest pathogenic variant AF is 0.0000371779

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001231.5RefSeqNP_001222.311MANE Select
ENST00000368078.8EnsemblENSP00000357057.311MANE Select
ENST00000467691.1EnsemblENSP00000418051.14Standard
ENST00000467691.2EnsemblENSP00000418051.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Antiarrhythmic Pathway, Pharmacodynamics
  • Calcium Regulation in the Cardiac Cell

Biological Process

  • endoplasmic reticulum organization
  • skeletal muscle tissue development
  • response to heat
  • response to organic substance
  • regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion

Molecular Function

  • calcium ion binding
  • protein binding
  • identical protein binding

Cellular Component

  • mitochondrion
  • mitochondrial matrix
  • endoplasmic reticulum
  • smooth endoplasmic reticulum
  • Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000368078
Coding exons
11
Length
11392
Individuals with no LoFs
125440
Homozygous LoFs
2
Heterozygous LoFs
306
Defined
125748
p
0.00123
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.01872262251.000.00001202640
Missense (PolyPhen)6471.7810.8916895
Synonymous0.9578394.90.8750.00000613710
Loss of Function-0.5702522.11.130.00000112258

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000550.00055rare
Latino/Admixed American0.000350.00035rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.00160.0016notable
Finnish0.000790.00079rare
European (Non-Finnish)0.00180.0018notable
South Asian0.000820.00078rare
Other0.00110.0011notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:28895244). Calcium ions are bound by clusters of acidic residues at the protein surface, often at the interface between subunits. Can bind around 80 Ca(2+) ions (PubMed:28895244). Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction. Negatively regulates store-operated Ca(2+) entry (SOCE) activity (PubMed:27185316). {ECO:0000269|PubMed:22337878, ECO:0000269|PubMed:27185316, ECO:0000269|PubMed:28895244, ECO:0000303|PubMed:22337878}.;
Disease
DISEASE: Myopathy, vacuolar, with CASQ1 aggregates (VMCQA) [MIM:616231]: An autosomal dominant mild muscle disorder characterized by adult onset of muscle cramping and weakness as well as increased levels of serum creatine kinase. The disorder is not progressive, and some patients may be asymptomatic. {ECO:0000269|PubMed:25116801, ECO:0000269|PubMed:26136523, ECO:0000269|PubMed:27196359, ECO:0000269|PubMed:28895244}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, tubular aggregate, 1 (TAM1) [MIM:160565]: A rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They may occur in a variety of circumstances, including inherited myopathies, alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness. {ECO:0000269|PubMed:28895244}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.201

Intolerance Scores

LoFtool
0.733
RVIS EVS
0.6
RVIS percentile EVS
82.74

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.598

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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