PLN
protein-codingphospholamban
Gene summary
The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]
- PLB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013475
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0000591
Submitter: ClinGen
PLN : Intrinsic Cardiomyopathy. The PLN gene is associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (van der Zwaag, 2012 PMID: 22820313) and heart failure of unknown etiology. The typical inheritance for PLN related cardiomyopathy is autosomal dominant, albeit autosomal recessive inheritance has been noted and appears to follow a dosage effect or semidominance, as loss of both alleles results in an earlier and more severe phenotypic presentation (Haghighi, 2003 PMID: 12639993). PLN is encoded by one exon, and missense, nonsense, and frameshift mutations in the coding exon and the promoter region have been reported. Given that PLN only has one exon, many of the mutations (even LOF) result in a protein product. PLN encodes the 52 amino acid protein, phospholamban, that functions to regulate SERCA2 function in the sarcoplasmic reticulum. Phospholamban exists in both monomeric and homopentameric forms. The monomeric form is thought to inhibit SERCA2 activity. PLN-mediated SERCA2 inhibition is released upon phosphorylation of monomeric PLN by either PKA or CAMKII, and thus stabilization of the pentameric form (reviewed in Haghighi, 2014 PMID: 25451386, Young, 2015 PMID: 25563649). While the distinct genetic mechanism of PLN-mediated cardiomyopathy is unclear, the overall disease mechanism for PLN associated cardiomyopathy is dysregulation of SERCA2 function, Ca2+ handling, and disrupted relaxation and contraction of the heart. Multiple cases of PLN-mediated cardiomyopathy are reported in the literature, allowing and extending beyond the maximum score for genetic evidence (12 pts). This gene-disease association is supported by the function of the gene product, alteration of normal function in non-patient cells expressing patient-derived mutant PLN, and animal models. In summary, PLN is definitively associated with intrinsic cardiomyopathy. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Hypertrophic Cardiomyopathy Gene Curation committee on September 19, 2017 using SOP version 4. This gene-disease relationship was updated and recurated on February 12, 2021. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: (1) Cardiomyopathy, dilated, 1P (MIM: 609909) and (2) Cardiomyopathy, hypertrophic, 18 (MIM:613874). Evidence suggests that the mechanism of the disease is impaired SERCA2 regulation of Ca2+ handling for all conditions associated with PLN. Furthermore, a progressive cardiomyopathy beginning with hypertrophic and leading to dilated has been observed in a proband (Haghighi, 2003 PMID: 12639993). Both interfamilial and intrafamilial variability were observed between PLN variants (Haghighi, 2003 PMID: 12639993; van der Zwaag, 2012 PMID: 22820313). For clinical management, no striking differences should occur, as all of the phenotypes and conditions associated with PLN are of cardiovascular nature, and individuals should be monitored appropriately. Therefore, all of the disease entities have been lumped into one disease entity, Intrinsic cardiomyopathy. Data on the occurrence of cardiomyopathy in individuals with PLN associated intrinsic cardiomyopathy was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Mutation of PLN results in the development of an intrinsic cardiomyopathy that can present with left ventricular hypertrophy. The mechanism for PLN induced intrinsic cardiomyopathy is attributed to SERCA2 dysfunction and improper Ca2+- handling, which significantly alters contraction and relaxation of the heart, resulting in heart failure (reviewed in Haghighi, 2014 PMID: 25451386, Young, 2015 PMID: 25563649).
Inheritance Pattern: AD
Disease ID:MONDO:0012362
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013475
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0015470
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012362
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000591
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012362
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: The conditions can involve cardiomyopathy, and surveillance and preventive measures, including medical management, may reduce morbidity and mortality
Comments: The severity may depend on inheritance (ie, heterozygosity vs. homozygosity/compound heterozygosity)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PLN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002667.5. 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 | 16 | 1 | 17 | |||
| missense | 1 | 4 | 47 | 1 | 53 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 1 | 1 | 2 | |||
| frameshift | 2 | 4 | 9 | 15 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 5 | 11 | 56 | 17 | 1 | 90 |
Highest pathogenic variant AF is 0.000019242801
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002658.1 | 1 | MANE Select | |
| Ensembl | ENSP00000350132.5 | 1 | MANE Select | |
| Ensembl | ENSP00000545783.1 | 1 | Standard | |
| Ensembl | ENSP00000545783.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dilated cardiomyopathy (DCM) - Homo sapiens (human)
- Thyroid hormone signaling pathway - Homo sapiens (human)
- Adrenergic signaling in cardiomyocytes - Homo sapiens (human)
- Calcium signaling pathway - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
Biological Process
- regulation of the force of heart contraction
- calcium ion transport
- Notch signaling pathway
- blood circulation
- regulation of heart contraction
Molecular Function
- enzyme inhibitor activity
- calcium channel regulator activity
- protein binding
- ATPase inhibitor activity
- identical protein binding
Cellular Component
- mitochondrion
- endoplasmic reticulum
- membrane
- mitochondrial membrane
- vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000357525
- Coding exons
- 1
- Length
- 12433
- Individuals with no LoFs
- 125630
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125633
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.624 | 19 | 28.4 | 0.670 | 0.00000172 | 332 |
| Missense (PolyPhen) | 1 | 1.574 | 0.63532 | 30 | ||
| Synonymous | 1.14 | 5 | 9.46 | 0.529 | 4.80e-7 | 104 |
| Loss of Function | 1.13 | 0 | 1.49 | 0.00 | 6.47e-8 | 18 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Reversibly inhibits the activity of ATP2A2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Modulates the contractility of the heart muscle in response to physiological stimuli via its effects on ATP2A2. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in the heart muscle. The degree of ATP2A2 inhibition depends on the oligomeric state of PLN. ATP2A2 inhibition is alleviated by PLN phosphorylation. {ECO:0000269|PubMed:22427649, ECO:0000269|PubMed:22707725}.;
- Disease
- DISEASE: Cardiomyopathy, dilated 1P (CMD1P) [MIM:609909]: 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:12610310, ECO:0000269|PubMed:16432188, ECO:0000269|PubMed:22137083, ECO:0000269|PubMed:22427649, ECO:0000269|PubMed:22707725}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, familial hypertrophic 18 (CMH18) [MIM:613874]: 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:12705874}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.676
- RVIS EVS
- 0.12
- RVIS percentile EVS
- 62.38
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |