TCAP
protein-codingtitin-cap
Gene summary
Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]
- LGMD2G
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011170
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0015152
Submitter: ClinGen
The relationship between *TCAP* and autosomal recessive limb girdle muscular dystrophy (type 2G included), has been evaluated using the ClinGen Clinical Validity Framework as of August, 2021. This association was made using case-level, segregation, and experimental data. The *TCAP* gene is located on chromosome 17q12. The transcript referred to in the literature (NM_003673.3) is 960 bp long with 2 exons encoding a 167-amino acid protein. More than 20 pathogenic and likely pathogenic variants reported in humans with autosomal recessive limb girdle muscular dystrophy (AR-LGMD) are recorded in ClinVar, most of them being predicted loss of function variants such as nonsense, frameshift, deletion/duplication and splicing variants. Since the gene has only 2 exons, most predicted loss of function variants do not cause nonsense-mediated mRNA decay. Patients with AR-LGMD due to *TCAP* variants show progressive proximal muscle weakness (along with distal weakness in some) with an average age at onset in the second decade, difficulty in walking and running with loss of ambulation in some, foot drop, increased serum creatine kinase levels, and a muscle biopsy showing dystrophic changes. *TCAP* has been reported in association with AR-LGMD as early as 2000 by Moreira et al (PMID: 10655062). Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 10655062, 28666572, 27618135, 25055047). Variants in the gene segregated with disease in 11 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models, expression studies, and protein interaction assays. *TCAP* encodes the telethonin protein that localizes to the Z-disk in the sarcomere and interacts with titin to form the titin cap, which is essential for sarcomere formation and integrity (PMID: 9645487). Telethonin is expressed in the striated muscles, including the heart and skeletal muscles (PMID: 9817758). The effects of *TCAP* knockdown are studied in zebrafish models (PMID: 19679566), and the effects of *TCAP* knockout are studied in mouse models (PMIDs: 20233748, 21799151). Studies show loss of swimming ability in fish and balancing ability on rotating road in mice, as well as muscle histological changes similar to human patients with AR-LGMD due to *TCAP* variants. In summary, this gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. OMIM entities: Hypertrophic cardiomyopathy 25; autosomal recessive limb girdle muscular dystrophy 7. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found significant difference in phenotype AND inheritance pattern AND in the absence of a well-defined molecular mechanism in the above-mentioned disease entities. Therefore, the two disease entities may be split and curated separately.
Inheritance Pattern: AR
Disease ID:MONDO:0011170
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
TCAP was originally evaluated for DCM by the ClinGen DCM GCEP on 08/12/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 4/18/2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. At least 12 variants, including 11 heterozygous missense and 1 homozygous intron, have been reported in humans with DCM. These variants were identified in case-level and case-control data sets (Hayashi et al., 2004, PMID: 15582318; Hershberger et al., 2008, PMID: 19412328; Hirtle-Lewis et al., 2013, PMID: 24037902; Akinrinade et al, 2015, PMID: 26084686; Walsh et al, 2017, PMID: 27532257; Nguyen et al., 2021, PMID: 34011823; Alaei et al., 2023, PMID: 37752589). However, due to high minimal allele frequency and limited number of screened genes, three missense variants were scored. One case control study was scored. In addition, this gene-disease association is supported by expression data and shared biochemical function and protein interaction with other genes known to be associated with DCM (i.e., TTN) (Valle et al, 1997, PMID: 9350988; Gregorio et al, 1998, PMID: 9817758). Though mouse models failed to recapitulate exact human DCM phenotypes, a zebra fish model partially recapitulate human DCM phenotypes (Knöll et al., 2011, PMID: 21799151; Ibrahim et al, 2013, PMID: 23100327; Zhao et al., 2024, PMID: 39226992). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of TCAP with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on April 18th, 2025 (SOP Version 10)
Inheritance Pattern: AD
Disease ID:MONDO:0024573
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011843
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011843
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011170
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011170
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
The *TCAP* gene was first associated with hypertrophic cardiomyopathy (HCM) in 2004 with missense variants found in 2 probands (Hayashi et al, PMID 15582318). Three subsequent studies have identified missense variants in 6 probands (Bos et al, 2006, PMID 16352453; Andersen et al, 2009, PMID 19035361; Toste et al. 2020, PMID 32565061). None of these variants have functional evidence in support of pathogenicity. Furthermore, 1 variant (2 probands) is common in the population (Bos et al, 2006, PMID 16352453), and 2 co-occurred with other variants (pathogenic *TNNI3* variant, Andersen et al, 2009, PMID 19035361; VUS in *MYBPC3*, Bos et al. 2006, PMID 16352453). The mechanism for disease is unknown. The gene-disease association is supported by expression data (Valle et al. 1997, PMID 9350988; Fagerberg et al. 2014, PMID 24309898, Uhlen et al. 2015, PMID:25613900) and an interaction with CSRP3 (Knoll et al. 2002, PMID 12507422; Vafiadaki et al. 2014, PMID 24860983) which has moderate evidence for HCM. In summary, the evidence supporting the relationship between *TCAP *and HCM has been DISPUTED. More evidence is needed to either support or entirely refute the role *TCAP *plays in this disease. This gene-disease relationship was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2016. This gene-disease relationship was reevaluated on September 14, 2022 by the Hereditary Cardiovascular Disorders GCEP. As a result of this reevaluation, the classification changed from LIMITED to DISPUTED.
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Surveillance (eg, with echocardiography/electrocardiography) and preventive management may ameliorate/prevent severe sequelae
Comments: The reported onset of heart failure has been in the adult period (including in young adults), but surveillance and early treatment may be indicated prior to adulthood; A variant has been described in an individual with intestinal pseudo-obstruction, but it is not clear if early (genetic) diagnosis would be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TCAP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003673.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 91 | 2 | 95 | ||
| missense | 1 | 2 | 176 | 12 | 191 | |
| nonsense | 4 | 6 | 7 | 17 | ||
| start loss | 2 | 2 | ||||
| frameshift | 10 | 9 | 14 | 33 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 16 | 21 | 199 | 103 | 2 | 341 |
Highest pathogenic variant AF is 0.00001363389
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003664.1 | 2 | MANE Select | |
| Ensembl | ENSP00000312624.2 | 2 | MANE Select | |
| Ensembl | ENSP00000462787.1 | 3 | Standard | |
| Ensembl | ENSP00000462787.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tcap | Danio rerio | Structure: skeletal muscle cell Quality: increased variability of size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Striated Muscle Contraction
- Striated Muscle Contraction
- Muscle contraction
Biological Process
- somitogenesis
- skeletal muscle contraction
- cardiac muscle hypertrophy
- adult heart development
- cardiac muscle hypertrophy in response to stress
Molecular Function
- protein binding
- structural constituent of muscle
- protein binding, bridging
- titin binding
- BMP binding
Cellular Component
- cytosol
- Z disc
- I band
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000309889
- Coding exons
- 2
- Length
- 2369
- Individuals with no LoFs
- 125617
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 37
- Defined
- 125654
- p
- 0.000147
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0856 | 102 | 104 | 0.976 | 0.00000664 | 1054 |
| Missense (PolyPhen) | 40 | 48.055 | 0.83237 | 486 | ||
| Synonymous | -0.182 | 45 | 43.5 | 1.04 | 0.00000246 | 354 |
| Loss of Function | 1.67 | 2 | 6.63 | 0.302 | 2.86e-7 | 71 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0012 | 0.0012 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000072 | 0.000062 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.;
- Disease
- DISEASE: Limb-girdle muscular dystrophy 2G (LGMD2G) [MIM:601954]: An autosomal recessive degenerative myopathy characterized by proximal and distal muscle weakness and atrophy in the limbs, dystrophic changes on muscle biopsy, and absence of telethonin. Cardiac muscle is involved in a subset of patients. {ECO:0000269|PubMed:10655062}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.273
Intolerance Scores
- LoFtool
- 0.340
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.664
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |