TTN
protein-codingtitin, the group of Fibronectin type III domain containing|I-set domain containing|Myosin light chain kinase family
Gene summary
This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
- CMD1G
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~304.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0024573
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011362
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011362
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:1060225
Submitter: ClinGen
The relationship between *TTN* and autosomal dominant *TTN*-related myopathy, dominant-negative TTNsv was first reported in 2024 (PMID: 37935568). It is due specifically to monoallelic, multi‑exon in‑frame deletions/CNVs that escape NMD and produce an expressed, internally deleted titin and is supported by multiple independent probands with consistent phenotypes as well as by experimental data from patient muscle. Nine probands were curated from Perrin et al., 2024 (PMID: 37935568) and Gohlke et al., 2024 (PMID: 39277846). In five Perrin families (A, B, F, G, H), affected individuals carry large in‑frame A‑, I‑, or A/M‑band deletions with muscle RNA‑seq demonstrating 50% mutant allele expression and in‑frame exon–exon junctions, confirming NMD escape and supporting expression of a shortened titin isoform. Clinical features across these families include congenital, childhood‑onset, or adult‑onset proximal and/or distal muscle weakness, contractures, variable respiratory involvement, and in some cases cardiomyopathy. Families with out‑of‑frame deletions (D, E) or in‑frame deletions without RNA confirmation (C) were not included as evidence for this mechanism. Gohlke et al. Case 5 (same pedigree originally described in Roggenbuck 2019) provides mechanistic confirmation of the exons 346–362 deletion as in‑frame, with allelic balance ~0.46, co‑expression of full‑length and shortened titin (loss of M‑band domains M8–M9), Z‑disk and M‑line disruption on electron microscopy, and increased titin‑dependent passive tension in slow fibers with preserved active contractility. Together, these patient‑derived data demonstrate a dominant‑negative structural mechanism caused by incorporation of an internally deleted titin molecule into sarcomeres. Experimental evidence (2.5 points) includes *TTN* expression in striated muscle (PMID: 16949617), relevant biochemical function (PMID: 20551232), muscle RNA‑seq demonstrating mutant transcript stability (PMID: 37935568), and patient‑tissue functional alteration including altered force mechanics and structural disruption (PMID: 39277846). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of note, across the Congenital Myopathies GCEP’s *TTN* curations, disorders were separated based on distinct molecular mechanisms, variant classes, inheritance patterns, and phenotype clusters. Autosomal dominant Tibial muscular dystrophy (TMD), caused by last‑exon variants producing a late‑onset distal myopathy, and HMERF, caused by exon 344 missense variants, are mechanistically and clinically distinct from both recessive congenital titinopathies (biallelic LOF; lumped all recessive presentations—including LGMD2J, centronuclear‑like myopathy, Salih myopathy, Emery‑Dreifuss‑like myopathy, titinopathy with congenital contractures, minicore myopathy, and distal titinopathy) and the present entity involving multi‑exon in‑frame CNVs that escape NMD and produce an internally deleted titin. Therefore, each disorder is curated separately.
Inheritance Pattern: AD
Disease ID:MONDO:0010870
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012127
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018759
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012714
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011362
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012127
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
*TTN* was first reported in association with autosomal dominant hypertrophic cardiomyopathy (HCM) in humans in 2009 (Arimura et al. 2009, PMID 19608031). *TTN* gene encodes titin protein which is a large protein in the sarcomere. There are multiple transcripts with N2BA and N2B as the primary cardiac transcripts. Many variants in *TTN* have been reported in individuals with HCM but the majority are missense without functional data or located in an exon with low percent spliced in (PSI) for cardiac tissue. There is one report of a frameshift located in the A-band (PSI 100%) (Sepp et al. 2022, PMID 35626289), and one termination in the I-band (PSI 100%) (Micheu et al. 2020, PMID 33297573) in individuals with HCM. Also of note, Higashikuse et al. (2019, PMID 31628103) provide strong functional data for two missense variants in the MURF1 binding region. Case-control data is contradictory towards an association with HCM. No excess *TTN* variants were noted in cases compared to controls in two studies (Herman et al. 2012, PMID 22335739, Zhang et al. 2017, 28822653). An additional study reported a higher proportion of controls with *TTN* truncations and missense variants compared to cases (Mademont-Soler et al. 2017, PMID: 28771489). The gene-disease association is supported by expression studies in the human heart and animal models (Collins et al. 1996, PMID 8841931, Wang et al. 1999, PMID 10093045, Ponten et al. 2008, PMID 18853439, GTEX Consortium 2013, PMID 23715323). Protein interactions and biochemical function studies show Titin interacts with other sarcomere proteins associated with HCM (Freiburg et al. 2009, PMID 8631348, Frazier et al. 2011, PMID 21297871, Satoh et al, 1999, PMID 10462489). Previous mouse models showed homozygous individuals developed signs of HCM (Peng et al. 2007, PMID 17261657, Granzier et al. 2009, PMID 19679835). Most notably, a medaka fish model created through ENU mutagenesis developed features of HCM, and positional cloning led to a *TTN* missense variant in the MURF1 binding region (Higashikuse et al. 2019, PMID 31628103). This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on December 12, 2016. This gene-disease relationship was re-evaluated on July 27, 2023 by the Hereditary Cardiovascular Disorders GCEP. While more points were initially scored for the gene-disease relationship, the classification was downgraded to Limited due to the contradictory case-control data and limited case-level evidence. As a result of this re-evaluation, the classification did not change. This classification pair was last evaluated by the Hereditary Cardiovascular disease GCEP on July 27, 2023. It was reevaluated on October 28, 2025 (SOP v11). Scoring for two cases (PMIDs 28822653, 33297573) carrying truncating variants in *TTN* (TTNtv) was reduced from 0.1 to 0 to reflect the frequency of TTNtv in the population. Additionally, two missense and a TTNtv were added to the curation (PMIDs 39895828, 38880420) but were all scored 0 due to variant type, population frequency or lack of functional evidence of variant impact. The score modifications and additional cases do not change the classification.
Inheritance Pattern: AR
Disease ID:MONDO:0015705
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010870
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012127
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0010870
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011400
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: ClinGen
*TTN*: Arrythmogenic Right Ventricular Cardiomyopathy Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) HGNC:12403 MONDO:0016587 Expert Panel: Arrythmogenic Right Ventricular Cardiomyopathy Nine papers were reviewed related to *TTN* and ARVD (23297410, 23299917, 25157032, 29750433, 24055113, 24082139, 25445213, 29221435, 21810661). In a paper the authors found in 11 of 35 ARVD patients missense variants in *TTN*. After evaluation of the family members they conclude that *TTN* missense variants had either a very low penetrance or negligible pathogenicity on the disease (29750433). Gonzalez-Garay et al found a missense variant in an ARVD patient that was also found 19 times in gnomAD (25157032). Only in two papers from the same group potentially relevant information was found. 38 ARVD families were analyzed for the *TTN* gene because previously analyzed ARVD linked genes (DSC2, DSG2, DSP, and PKP2) were negative. Eight unique *TTN* nonsynonymous variants were identified in seven unrelated ARVC probands with one proband that was a compound heterozygote having two *TTN* variants. This is not strange to find because the gene is huge and in reference alleles in gnomAD missense variants are very common. Five of these variants occur relatively often in gnomAD (between 18 and 1134 times) making them less likely as a disease causing variant. One of these variants could be of interest. The variant NM_133378.4 (TTN): c.8687C>T; p.T2896I showed co-segregation (published lod score of 2.41) in 9 (probably) affected with the genotype of whom six of them had ARVD (21810661, 25157032). The variant, present in an Ig10 domain, was further tested in an in vitro functional assay by two independent groups (21810661, 23297410). Both found that the variant introduced an aberrant function. Unfortunately only a very small part of the protein was tested and the TTN protein contains many of these domains therefore making it difficult to judge if the variant will alter the mutant protein in the patient. Total awarded points = 1.00; Final classification = limited. This gene-disease pair was originally evaluated by the Arrhythmogenic Right Ventricular Cardiomyopathy GCEP on August 6, 2019. It was re-evaluated on October 15, 2025 by the Hereditary Cardiovascular GCEP. As a result of this reevaluation, the classification was changed from Limited to Disputed given the lack of evidence in the originally curated cases and the lack of any new cases since the original curation that have convincing evidence of isolated arrhythmogenic right ventricular cardiomyopathy due to monogenic variation in *TTN*.
Inheritance Pattern: AR
Disease ID:MONDO:0100175
Submitter: ClinGen
Autosomal recessive TTN-related myopathy first reported in 2002 (Hackman et al., PMID: 12145747). Over 40 unique TTN variants (including missense, nonsense, frameshift, and splicing variants) associated with a TTN-related myopathy phenotype and autosomal recessive inheritance pattern have been reported in humans. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found insufficient evidence of a distinct molecular mechanism and wide phenotypic variability between the recessive forms of titinopathies and, therefore, the following disease entities asserted in the literature have been lumped into one disease entity termed "TTN-related myopathy": limb-girdle muscular dystrophy, (MIM #608807) centronuclear myopathy (not an OMIM entity, note that the histopathological findings observed in affected individuals may not always include internal nuclei and the term congenital myopathy with multiple internal nuclei may be more appropriate to represent this heterogeneity), Salih myopathy (MIM #611705), Emery-Dreifuss-like muscular dystrophy (not an OMIM entity), titinopathy with congenital contractures (not an OMIM entity), minicore myopathy (not an OMIM entity), and distal titinopathy (not an OMIM entity). Evidence supporting this gene-disease relationship includes case-level data and familial segregation data from 30 probands in 13 publications (PMID: 12145747, PMID: 17444505, PMID: 23975875, PMID: 24105469, PMID: 24395473, PMID: 25772186, PMID: 26392295, PMID: 26581302, PMID: 27796757, PMID: 28040389, PMID: 29575618, PMID: 29691892, PMID: 31660661, ), extending beyond the maximum score for genetic evidence (totaling 12 points). Additional case-level evidence is available in the literature. Of note, multiple reported individuals asserted to have a limb girdle muscular dystrophy presentation were evaluated and determined to meet the Limb Girdle Muscular Dystrophy GCEP-specified criteria for a limb girdle muscular dystrophy phenotype (progressive weakness in limb musculature (pelvic and shoulder girdle), independent ambulation by the age 2 years, elevated creatine kinase of >2X the upper limit of normal, muscle biopsy with dystrophic and myopathic features): PMID: 12145747; Proband V-3, PMID: 26392295. This gene-disease association is also supported by experimental evidence, including expression (PMID: 16949617, PMID: 29598826), biochemical function (PMID: 20551232), protein interactions (PMID: 8537379) and multiple animal models (mouse and zebrafish; PMID: 12464612, PMID: 27836965, PMID: 30700140) supporting the role of TTN in the assembly and function of the sarcomere (totaling 6 points). In summary, TTN is definitively associated with autosomal recessive TTN-related myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on 8/23/2021 and by the ClinGen Limb Girdle Muscular Dystrophy Gene Curation Expert Panel (secondary contributor to this curation) on 1/11/2022 (SOP Version 7). Prenatal GCEP Secondary Analysis, 4/22/2025 Prenatal phenotypes described in the literature in association with autosomal recessive TTN-related myopathy include reduced fetal movements, hydrops, poly/oligohydramnios, limb contractures, pleural effusion, pericardial effusion, thickened nuchal translucency, and cystic hygroma (PMIDs: 29575618, 36495114, 36761691, 38937733, and 38148006). Stillbirth has been reported with bi-allelic TTN variants in one family in the literature (PMID: 36495114). Additional clinical reports and genetic studies are needed to confirm an association between bi-allelic TTN variants and stillbirths. Recent RNA-seq studies have allowed inferring disease course based on the splicing patterns of the exons involving TTN truncating variants (TTNtv). TTNtv located in exons with a high percentage splice in (PSI) in fetal muscles, typically result in genotypes causing severe prenatal phenotypes (PMID: 39198997).
Inheritance Pattern: AD
Disease ID:MONDO:0010870
Submitter: ClinGen
*TTN* was first reported in relation to autosomal dominant tibial muscular dystrophy in 2002 (Hackman et al., PMID: 12145747). At least 6 unique missense, nonsense, and frameshift variants affecting the titin M line have been reported in 6 families. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined the inheritance pattern, unique genetic basis (missense and truncating variants in the M line), and distinct clinical presentation of autosomal dominant tibial muscular dystrophy warranted a split curation from autosomal recessive titinopathies and from autosomal dominant hereditary myopathy with prominent resipiratory failure. Evidence supporting this gene-disease relationship includes case-level data from 6 probands in 4 publications (PMID: 12145747, PMID: 12891679, PMID: 18948003, PMID: 19911250) as well as familial segregation data (4.1 points). This gene-disease association is also supported by biochemical and expression evidence supporting the role of *TTN* in affected tissues (PMID: 20551232, PMID: 16949617) and a mouse model of the recurrent Finnish variant (NM_003319.4:c.80585_80595delinsTGAAAGAAAAA (p.Glu26862_Trp26865delinsValLysGluLys), often referred to as FINmaj) (PMID: 20855473). In summary, there is moderate evidence to support the relationship between *TTN* and autosomal dominant tibial muscular dystrophy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally approved by the CM GCEP on 03/24/2022. It was reevaluated on 06/23/2025. As a result of this reevaluation no new evidnece was identified and the classification remained Moderate.
Inheritance Pattern: AD
Disease ID:MONDO:0700223
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012714
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019952
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011400
Submitter: ClinGen
TTN was originally evaluated for DCM by ClinGen DCM GCEP on September 29, 2020. Evidence of the association of this gene with DCM was re-evaluated on 3/19/2025. As a result, the classification did not change. A summary of the information contributing to the classification of t/he gene at the time of re-evaluation is summarized herein. Titin (TTN) was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2002 (Gerull et al, 2002, PMID: 22335739). Human genetic evidence supporting this gene-disease relationship includes case-level data, case-control data and segregation data. Over 100 truncating TTN variants (TTNtv) have been reported in humans with DCM (Gerull et al, 2006, PMID: 16733766; Herman et al, 2012 PMID: 22335739; Norton et al, 2013, PMID: 23418287; Akinrinade et al, 2015, PMID: 26084686; Franaszczyk et al, 2017, PMID: 28045875; Akinrinade et al, 2019, PMID: 30858397; Cannatà et al, 2022, PMID: 35138330; Massier, 2025, PMID: 39844436). Strong case-control data has been reported in a study comparing the frequency of TTNtv in large populations of healthy volunteers and DCM patients (Roberts et al, 2015, PMID: 25589632; Haggerty et al, 2019, PMID: 31216868). In addition, this gene-disease association is supported by experimental data including animal models (zebrafish – Xu et al, 2002, PMID: 11788825; mouse – Gramlich et al, 2009, PMID: 19406126 and rat – Schafer et al, 2017, PMID: 27869827); human induced pluripotent stem cell studies (Hinson et al, 2015, PMID: 26315439) and phenotype rescue experiments in animal models and human induced pluripotent stem cells from DCM patients (Gramlich et al, 2015, PMID: 25759365). Ghahremani et al (2024, PMID: 38235591) showed that in human iPSC models TTN CRISPR activation rescued TTN truncating variants-related functional deficits (normalized sarcomere content and contractile function). Additional evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence has been reached. TTN has also been curated by the Congenital Myopathies gene curation expert group for TTN-related myopathy (Definitive, 01/11/2022), the Congenital Myopathies gene curation expert group for tibial muscular dystrophy (Moderate, 03/14/2022), the Congenital Myopathies gene curation expert group for myopathy, myofibrillar, 9, with early respiratory failure (Moderate, 03/14/2022), the Hereditary Cardiovascular Disease gene curation expert group for HCM (Limited, 07/27/2023), and the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert group for ARVC (Limited, 08/06/2019). In summary, truncating variants TTN are definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on September 29, 2020 (SOP Version 7). This written summary was updated on 3/19/2025 and approved by the DCM GCEP on 05/30/2025.
Inheritance Pattern: AD
Disease ID:MONDO:0011400
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011362
Submitter: ClinGen
*TTN* was first reported in relation to autosomal dominant hereditary proximal myopathy with prominent respiratory failure in 2012 (Pfeffer et al., 2012, PMID: 22577215). At least 17 unique missense variants affecting exon 344 of the titin A band have been reported in over 50 affected individuals. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined the unique genetic basis (missense variants in exon 344 of the titin A band) and clinical presentation of autosomal dominant hereditary proximal myopathy with prominent respiratory failure warranted a split curation from autosomal recessive titinopathies and from autosomal dominant tibial muscular dystrophy. Evidence supporting this gene-disease relationship includes case-level data from 40 probands in 15 publications (PMID: 22577215, PMID: 23446887, PMID: 23514108, PMID: 23606733, PMID: 25253871, PMID: 30666435, PMID: 34108290, PMID: 34839411, PMID: 25500009, PMID: 22577218, PMID: 24231549, PMID: 24384345, PMID: 33041974, PMID: 34670883, PMID: 32307395, PMID: 38655354) as well as familial segregation data (11.9 points). This gene-disease association is also supported by biochemical and expression evidence supporting the role of *TTN* in affected tissues (PMID: 20551232, PMID: 16949617, 1 point). As well, as functional alteration in muscle fiber studies (PMID: 39277846, 1 point). In summary, *TTN* is definitively associated with autosomal dominant hereditary proximal myopathy with early respiratory failure. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally approved by the CM GCEP on 8/23/2021. It was reevaluated on 06/23/2025. As a result of this reevaluation new genetic (PMIDs: 34108290, 34839411, 34670883, 38655354) and experimental evidence (PMID: 39277846) was identified and the classification increased from Moderate to Definitive.
Inheritance Pattern: AD
Disease ID:MONDO:0011400
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013412
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012714
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Surveillance (including with echocardiography) may allow early detection and treatment, (including with interventions such as left ventricular assist device), and preventive measures may be additionally beneficial; Heart transplantation has been described for some conditions related to variants in TTN
Comments: Some allelic conditions have been reported as potentially including cardiovascular anomalies, but it is unclear if molecular diagnosis was uniformly verified
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TTN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001267550.2. 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 | 3 | 14 | 270 | 12612 | 88 | 12987 |
| missense | 14 | 129 | 11093 | 2911 | 115 | 14262 |
| nonsense | 102 | 1967 | 104 | 1 | 2174 | |
| start loss | 1 | 1 | ||||
| frameshift | 152 | 3406 | 152 | 1 | 3711 | |
| splice donor/acceptor (+/-2bp) | 39 | 650 | 127 | 3 | 3 | 822 |
| Total | 310 | 6166 | 11747 | 15527 | 207 | 33957 |
Highest pathogenic variant AF is 0.00016106728
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001254479.2 | 362 | MANE Select | |
| Ensembl | ENSP00000467141.1 | 362 | MANE Select | |
| RefSeq | NP_001243779.1 | 312 | Standard | |
| RefSeq | NP_003310.4 | 190 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ttn.1 | Danio rerio | Structure: skeletal muscle cell Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dilated cardiomyopathy (DCM) - Homo sapiens (human)
- Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
- Striated Muscle Contraction
- Striated Muscle Contraction
- Muscle contraction
Biological Process
- platelet degranulation
- cardiac muscle hypertrophy
- muscle contraction
- striated muscle contraction
- mitotic chromosome condensation
Molecular Function
- protease binding
- protein serine/threonine kinase activity
- protein tyrosine kinase activity
- calcium ion binding
- protein binding
Cellular Component
- condensed nuclear chromosome
- extracellular region
- cytosol
- striated muscle thin filament
- sarcomere
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000589042
- Coding exons
- 362
- Length
- 304814
- Individuals with no LoFs
- 124166
- Homozygous LoFs
- 4
- Heterozygous LoFs
- 1578
- Defined
- 125748
- p
- 0.00631
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.10 | 18060 | 1.76e+4 | 1.02 | 0.000987 | 233777 |
| Missense (PolyPhen) | ||||||
| Synonymous | -0.166 | 6427 | 6.41e+3 | 1.00 | 0.000367 | 72068 |
| Loss of Function | 22.8 | 435 | 1.33e+3 | 0.327 | 0.0000763 | 18944 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.021 | 0.019 | notable |
| Latino/Admixed American | 0.0063 | 0.0061 | notable |
| Ashkenazi Jewish | 0.0043 | 0.0043 | notable |
| East Asian | 0.0054 | 0.0053 | notable |
| Finnish | 0.0031 | 0.0030 | notable |
| European (Non-Finnish) | 0.0060 | 0.0058 | notable |
| South Asian | 0.0061 | 0.0057 | notable |
| Other | 0.0059 | 0.0057 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase. {ECO:0000269|PubMed:9804419}.;
- Disease
- DISEASE: Hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]: Autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. {ECO:0000269|PubMed:15802564}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 9 (CMH9) [MIM:613765]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:10462489}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1G (CMD1G) [MIM:604145]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:11788824, ECO:0000269|PubMed:11846417, ECO:0000269|PubMed:16465475}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tardive tibial muscular dystrophy (TMD) [MIM:600334]: Autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later. {ECO:0000269|PubMed:12145747, ECO:0000269|PubMed:12891679}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-girdle muscular dystrophy 2J (LGMD2J) [MIM:608807]: An autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. {ECO:0000269|PubMed:12145747}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Salih myopathy (SALMY) [MIM:611705]: An autosomal recessive, early-onset muscular disorder characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Skeletal muscle biopsies show minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes become apparent in the second decade. Cardiac muscle biopsies show disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. Sudden death may occurr due to cardiomyopathy. {ECO:0000269|PubMed:17444505}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.384
Intolerance Scores
- LoFtool
- 0.971
- RVIS EVS
- 2.17
- RVIS percentile EVS
- 98.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.949
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |