CSRP3
protein-codingcysteine and glycine rich protein 3, the group of LIM domain containing
Gene summary
This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012804
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011840
Submitter: ClinGen
CSRP3 was originally evaluated for DCM by the ClinGen DCM GCEP on 11/06/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 05/30/2025. As a result, the overall genetic evidence points increased and experimental evidence points decreased. With these updates at the time of recuration, the clinical validity classification did not change and remains Limited. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. CSRP3 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2002 (Knoll et al. 2002, PMID: 12507422). Human genetic evidence supporting this gene-disease relationship includes case-level and case-control data. At least four missense variants have been reported in humans with DCM (Mohapatra et al. 2003, PMID 14567970; Hershberger et al. 2008, PMID 19412328; Shakeel M et al. 2018, PMID 29776034; and Zimmerman et al. 2010, PMID 20474083). Two case-control studies did not find evidence of enrichment of the missense variant in cases, however, the confidence intervals were wide due to limited sample size (Mazzarotto et al. 2020, PMID 31983221; Walsh et al. 2017, PMID 27532257). In 2022, Trachoo et al. PMID 36166435 identified a missense variant in a cohort of DCM patients from Thailand. This gene-disease assertion is supported by experimental data from expression studies and animal, ex-vivo, and cell culture models. Arber et al. (1997, PMID 9039266) reported the phenotype of a transgenic homozygous CSRP3-null mouse, demonstrating defects of the cardiomyocyte cytoskeletal architecture with Z-disc misalignment and myofibrillar disarray. Knoll et al. (2002, PMID 12507422) demonstrated a defect in cardiomyocyte stretch-induced response. No further scorable variants were identified in the re-curation process. Although this gene-disease assertion is supported by experimental evidence, there is limited convincing genetic evidence that has directly implicated this gene in human disease. More evidence is needed to support the relationship of CSRP3 and AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/30/2025 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0012804
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011840
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012804
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012804
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0005045
Submitter: ClinGen
The CSRP3 gene has been associated with semidominant hypertrophic cardiomyopathy in 73 probands across 17 publications. Semidominance includes both dominant and recessive inheritance patterns where individuals with heterozygous variants have an intermediate phenotype and individuals with homozygous variants have a more severe phenotype and/or earlier onset. Twenty-five unique variants (16 missense, 4 frameshift, 2 nonsense, 2 canonical splice site, and 1 indel) that have been reported in humans (PMIDs: 16352453, 18505755, 15781201, 23396983, 26656175, 21425739, 12642359, 19035361, 25351510, 23861362, 20087448, 30012424, 34558151, 33035702, 31919335, 33012304, 37431535) are included in this curation. CSRP3 was first associated with this disease in humans in 2003 (Geier et al., PMID 12642359). This gene-disease relationship has been studied in at least 5 case-control studies (PMIDs: 23396983, 28082330, 27532257, 37431535) at the aggregate variant level and showed nominally significant case excess. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is loss of function. The gene-disease relationship is also supported by expression studies (Uhlén M, et al., 2015, PMID: 25613900), protein interaction with alpha-actinin (Knöll R, et al., 2002, PMID: 12507422), biochemical function (Hoffmann C, et al., 2014, PMID: 24934443), mouse models (Ehsan M, et al., 2018, PMID: 30048712, Arber S, et al., 1997, PMID: 9039266), a cell culture model (Li X, et al., 2019, PMID: 31406109), and a rescue model (Arber S, et al., 1997, PMID: 9039266). In summary, there is definitive evidence supporting the relationship between CSRP3 and semidominant hypertrophic cardiomyopathy. 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 evaluated by the Hypertrophic Cardiomyopathy GCEP on December 19, 2017. It was re-evaluated on August 9, 2023 by the ClinGen Hereditary Cardiovascular Disease GCEP (SOP Version 9). As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case-level and experimental data and the inclusion of recessive data given the change to a semidominant mode of inheritance.
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011840
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal
Intervention: Cardiovascular
Rationale: Surveillance for manifestations (including with electrocardiogram and echocardiogram), including in asymptomatic individuals, is recommended; For individuals with cardiomyopathy, treatment such as medical therapy, pacemakers, and ICD can decrease morbidity and mortality, and early recognition and treatment can improve outcomes, though some individuals with progressive/refractory disease may require cardiac transplantation
Comments: There is a wide range of age at presentation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSRP3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003476.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 4 | 84 | 1 | 91 | |
| missense | 4 | 4 | 218 | 7 | 2 | 235 |
| nonsense | 5 | 5 | 3 | 13 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 14 | 8 | 9 | 31 | ||
| splice donor/acceptor (+/-2bp) | 10 | 3 | 1 | 14 | ||
| Total | 23 | 30 | 239 | 92 | 3 | 387 |
Highest pathogenic variant AF is 0.000040310726
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003467.1 | 5 | MANE Select | |
| Ensembl | ENSP00000265968.3 | 5 | MANE Select | |
| RefSeq | NP_001356333.1 | 4 | Standard | |
| Ensembl | ENSP00000431813.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| csrp3 | Danio rerio | Structure: cardiac muscle cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of the force of heart contraction
- cardiac muscle hypertrophy
- cellular calcium ion homeostasis
- skeletal muscle tissue development
- protein localization to organelle
Molecular Function
- actin binding
- protein binding
- structural constituent of muscle
- telethonin binding
- identical protein binding
Cellular Component
- nucleus
- cytoskeleton
- Z disc
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000533783
- Coding exons
- 5
- Length
- 28543
- Individuals with no LoFs
- 125715
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 33
- Defined
- 125748
- p
- 0.000131
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.139 | 115 | 111 | 1.04 | 0.00000705 | 1263 |
| Missense (PolyPhen) | 49 | 52.914 | 0.92603 | 620 | ||
| Synonymous | -1.66 | 58 | 44.0 | 1.32 | 0.00000324 | 361 |
| Loss of Function | 0.881 | 7 | 10.0 | 0.699 | 5.04e-7 | 131 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Positive regulator of myogenesis. Acts as cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis (By similarity). Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein that promotes the assembly of interacting proteins at Z-line structures. It is essential for calcineurin anchorage to the Z line. Required for stress-induced calcineurin-NFAT activation (By similarity). The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly: Shown to enhance CFL2-mediated F-actin depolymerization dependent on the CSRP3:CFL2 molecular ratio, and also shown to reduce the ability of CLF1 and CFL2 to enhance actin depolymerization (PubMed:19752190, PubMed:24934443). Proposed to contribute to the maintenance of muscle cell integerity through an actin-based mechanism. Can directly bind to actin filaments, cross-link actin filaments into bundles without polarity selectivity and protect them from dilution- and cofilin-mediated depolymerization; the function seems to involve its self-association (PubMed:24934443). In vitro can inhibit PKC/PRKCA activity (PubMed:27353086). Proposed to be involved in cardiac stress signaling by down-regulating excessive PKC/PRKCA signaling (By similarity). {ECO:0000250|UniProtKB:P50462, ECO:0000250|UniProtKB:P50463, ECO:0000269|PubMed:19752190, ECO:0000269|PubMed:24934443, ECO:0000269|PubMed:27353086}.;
- Disease
- DISEASE: Cardiomyopathy, dilated 1M (CMD1M) [MIM:607482]: 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:12507422, ECO:0000269|PubMed:18505755, ECO:0000269|PubMed:19412328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 12 (CMH12) [MIM:612124]: 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:12642359, ECO:0000269|PubMed:15205937, ECO:0000269|PubMed:18505755, ECO:0000269|PubMed:27353086}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.217
Intolerance Scores
- LoFtool
- 0.339
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 28.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.687
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |