PDLIM3
protein-codingPDZ and LIM domain 3, the group of LIM domain containing|PDZ domain containing
Gene summary
The protein encoded by this gene contains a PDZ domain and a LIM domain, indicating that it may be involved in cytoskeletal assembly. In support of this, the encoded protein has been shown to bind the spectrin-like repeats of alpha-actinin-2 and to colocalize with alpha-actinin-2 at the Z lines of skeletal muscle. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Aberrant alternative splicing of this gene may play a role in myotonic dystrophy. [provided by RefSeq, Apr 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~34.8 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:0005045
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
PDLIM3 was originally evaluated for DCM by the ClinGen DCM GCEP on October 4th, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 29th, 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. PDLIM3 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). There is no supporting human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation. Wang and colleagues (2019, PMID: 31424159) designed a case‐control study in 111 idiopathic DCM patients and 137 healthy controls. PDLIM3 and PDLIM5 exons were amplified by polymerase chain reactions. Authors identified five synonymous polymorphisms showing statistical distribution differences between DCM patients and controls. In addition, Arola and colleagues (2007, PMID: 17254821) investigated 185 unrelated DCM patients by polymerase chain reaction and identified a truncating variant (c.178insCA) in PDLIM3. However, lack of segregation data and additional info related to other genes, the DCM GCEP excluded this variant as supporting evidence. There is no experimental evidence supporting this gene-disease relationship. In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of PDLIM3 and autosomal dominant DCM. The relationship of PDLIM3 with DCM is unclear and therefore classified as disputed. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 29th, 2025 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
*PDLIM3* was first associated with hypertrophic cardiomyopathy (HCM) in humans in 2010 (Bagnall et al, 2010, PMID: 20801532) although no mechanistic data was provided to allow the missense variant to be scored. The *PDLIM3* gene has been associated with HCM in 2 probands in 2 publications. One variant of unknown significance and 1 multi-exon deletion have been reported. The multi-exon deletion was given 1.0 point for genetic evidence although it could not be officially scored as breakpoints were not provided, inhibiting the ability to enter the deletion into the ClinGen Allele Registry, at the time. *PDLIM3* is expressed in heart and interacts with *ACTN2*. However, there is no known mechanism through which *PDLIM3* causes HCM. In summary, there is limited evidence to support this gene-disease relationship with HCM. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2016.This gene-disease relationship was reevaluated on February 23, 2023 by the Hereditary Cardiovascular Disorders GCEP. As a result of this reevaluation, the classification did not change.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PDLIM3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014476.6. 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 | 113 | 115 | |||
| missense | 251 | 13 | 264 | |||
| nonsense | 6 | 6 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 1 | 12 | 13 | |||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 0 | 1 | 280 | 126 | 0 | 407 |
Highest pathogenic variant AF is 0.0000034203797
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055291.2 | 8 | MANE Select | |
| Ensembl | ENSP00000284767.8 | 8 | MANE Select | |
| RefSeq | NP_001107579.1 | 7 | Standard | |
| RefSeq | NP_001244891.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fibroblast growth factor-1
Biological Process
- actin filament organization
- heart development
Molecular Function
- protein binding
- cytoskeletal protein binding
- structural constituent of muscle
- metal ion binding
Cellular Component
- actin cytoskeleton
- Z disc
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000284770
- Coding exons
- 8
- Length
- 33916
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 40
- Defined
- 125748
- p
- 0.000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0223 | 224 | 223 | 1.00 | 0.0000139 | 2374 |
| Missense (PolyPhen) | 95 | 84.968 | 1.1181 | 858 | ||
| Synonymous | -0.492 | 92 | 86.2 | 1.07 | 0.00000587 | 732 |
| Loss of Function | 0.922 | 12 | 16.0 | 0.751 | 7.72e-7 | 189 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00019 | 0.00019 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play a role in the organization of actin filament arrays within muscle cells. {ECO:0000250}.;
Recessive Scores
- pRec
- 0.111
Intolerance Scores
- LoFtool
- 0.556
- RVIS EVS
- -0.53
- RVIS percentile EVS
- 20.7
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.347
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |