Hypertrophic Cardiomyopathy 18

Mendelian MONDO:0013475 Pathograph 22 Show in embeddings browser Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy 18 (CMH18) is the PLN-attributed member of the numbered familial hypertrophic cardiomyopathy series. PLN encodes phospholamban, a 52-amino-acid sarcoplasmic reticulum membrane protein that restrains the cardiac calcium pump SERCA2a until protein kinase A or CaMKII phosphorylation releases it. The lesion therefore sits in calcium reuptake, the relaxation arm of excitation-contraction coupling, rather than in the sarcomere, which makes CMH18 one of the rare non-sarcomeric, calcium-handling forms of HCM. The hypertrophic presentation rests on a small number of families. The truncating p.Leu39Ter (L39X, L39stop) allele is a functional null. Heterozygous carriers in North American and Australian HCM families and in two kindreds studied in Athens developed left ventricular hypertrophy, with preserved systolic function where it was measured, and in the one pedigree studied for it the allele cosegregated with HCM with incomplete penetrance. Seven further HCM probands carried rare promoter variants absent from controls; the two tested in reporter assays raise (-77A>G) or lower (-42C>G) PLN promoter activity. Across six screened HCM cohorts PLN accounts for roughly 0.65% of probands. The four reported probands were diagnosed between 51 and 67 years, all with atrial fibrillation, although one carrier child was affected at 3 years. The same L39X allele causes lethal dilated cardiomyopathy in homozygotes, and some heterozygotes also develop dilated cardiomyopathy, so CMH18 is allelic with dilated cardiomyopathy 1P (curated separately as Dilated_Cardiomyopathy_1P); ClinGen merges both into a single PLN-related intrinsic cardiomyopathy. Why loss of phospholamban, which leaves the mouse heart hypercontractile without heart failure into old age, produces hypertrophy in humans is not established.

Ask OpenScientist

Ask a research question about Hypertrophic Cardiomyopathy 18. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
5
Pathophys.
16
Phenotypes
1
Hypotheses
3
Gaps
22
Pathograph
1
Genes
3
Variants
5
Medical Actions
3
Models
4
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous PLN variants segregate with HCM as an autosomal dominant trait with incomplete penetrance: in the Mayo L39X pedigree an adult genotype-positive daughter was unaffected while her carrier child had HCM, in the two Athens L39stop kindreds only four of nine heterozygotes had left ventricular hypertrophy, and the -42C>G promoter family included a healthy adult carrier. Expressivity is variable, from isolated hypertrophy with normal function to dilated cardiomyopathy in some heterozygotes. Two L39X alleles produce a more severe, dilated phenotype, which ClinGen describes as a dosage effect or semidominance; that is a property of the allele rather than a separate recessive form of CMH18 and is recorded here rather than as autosomal recessive inheritance.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (5 references)
PMID:21167350 SUPPORT Human Clinical
"The PLN-L39X mutation cosegregates with incidence of HCM in this pedigree, and absence of an HCM phenotype in the proband's genotype-positive daughter at the present time indicates incomplete penetrance of the disease."
Dominant cosegregation of a heterozygous allele with HCM, with an unaffected adult carrier documenting incomplete penetrance.
PMID:12639993 SUPPORT Human Clinical
"their left ventricular systolic function (ejection fraction, 64.8% ± 2.8%) was normal, but four (I-3, II-1, II-3, III-7) exhibited left ventricular hypertrophy"
Only four of nine heterozygous L39stop carriers were hypertrophic, a second family-level observation of incomplete penetrance.
PMID:12639993 SUPPORT Human Clinical
"In this study, heterozygosity of PLN-L39stop was associated with hypertrophy in some members of both families and with overt dilated cardiomyopathy in other members."
The same heterozygous allele produced hypertrophy in some carriers and dilated cardiomyopathy in others, i.e. variable expressivity.
+ 2 more references
◈

Mechanistic Hypotheses

1
Chronic hypercontractility from phospholamban loss drives ventricular hypertrophy
pln_hypercontractility_to_hypertrophy EMERGING
Evidence balance 1 support 1 refute
Haghighi and colleagues proposed that partial loss of phospholamban imposes years of increased cardiac work, as in chronic catecholamine excess, and that this produces the hypertrophy seen in heterozygotes and the failure seen in homozygotes. It explains the L39X allele but not the -77A>G promoter variant, which should increase phospholamban, and it conflicts with the null mouse, which stays hypercontractile into old age without heart failure. No experiment has tested it in human cells or a heterozygous model.
Pathograph links
Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility -> Cardiomyocyte Hypertrophic Remodeling INDIRECT UNKNOWN INTERMEDIATES Proposed, not demonstrated: chronically increased cardiac work as the driver of hypertrophy in heterozygotes. The signalling steps between altered calcium cycling and the hypertrophic programme have not been studied in any PLN-HCM model.
Show evidence (2 references)
PMID:12639993 SUPPORT INDIRECT Human Clinical
"Increased cardiac work over a period of years could conceivably lead to ventricular hypertrophy, as seen in some of the heterozygous PLN-L39stop individuals, which may then progress to ventricular failure as observed in the homozygous mutants."
The original statement of the hypothesis.
PMID:12639993 REFUTE INDIRECT BACKGROUND Model Organism
"Whereas the PLN-null mouse displays chronically increased basal cardiac contractile function without developing heart failure, even in advanced age"
In the mouse, lifelong hypercontractility from total phospholamban loss does not lead to failure, which argues against hypercontractility alone being sufficient.
?

Discussions and Knowledge Gaps

3
Why does partial or complete loss of phospholamban produce hypertrophy and later dilatation in humans when total loss in the mouse produces a lifelong hypercontractile heart without heart failure?
HUMAN MODEL MISMATCH OPEN pln_null_mouse_human_hypertrophy
Attached to
pathophysiology#Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility pathophysiology#Cardiomyocyte Hypertrophic Remodeling animal_models#Mouse
The mouse evidence is abundant and points the other way: Pln-null mice are hypercontractile, tolerate it into old age, and were once taken as a model for phospholamban suppression as heart-failure therapy. The human L39X carriers instead develop hypertrophy (heterozygotes) or lethal dilated cardiomyopathy (homozygotes). The causal chain in this entry therefore passes through a hypercontractility node shown only in the mouse and a hypertrophy step shown only in humans. No heterozygous Pln model and no patient-derived or isogenic L39X iPSC cardiomyocyte has been studied for hypertrophic signalling.
Show evidence (2 references)
PMID:12639993 SUPPORT Human Clinical
"In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy."
Explicit statement of the species divergence.
PMID:8062415 SUPPORT Model Organism
"The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate."
The mouse side of the mismatch.
Do HCM-associated PLN alleles that should lower phospholamban (L39X, -42C>G) and one that should raise it (-77A>G) really converge on hypertrophy, and if so through what common step?
KNOWLEDGE GAP OPEN pln_dosage_direction_in_hcm
Attached to
pathophysiology#PLN L39X Truncating Variant pathophysiology#PLN Promoter Variant Altering Phospholamban Expression
The truncating allele and the -42C>G promoter variant reduce functional phospholamban, whereas the -77A>G promoter variant increases promoter activity, which would strengthen SERCA2a inhibition. Each promoter variant rests on one proband or family and reporter assays in non-human or non-cardiac cells, and none has been shown to change phospholamban protein in human heart. ClinGen states that the specific genetic mechanism of PLN cardiomyopathy is unclear. Either the promoter variants are not causal, or PLN-related hypertrophy is a response to disturbed calcium regulation in either direction; current data cannot separate these.
Show evidence (3 references)
PMID:12705874 SUPPORT In Vitro
"Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the phospholamban promoter activity."
The gain-of-expression direction.
PMID:16829191 SUPPORT In Vitro
"This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively."
The loss-of-expression direction.
CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"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."
ClinGen's own acknowledgement that the genetic mechanism is unresolved.
Is atrial fibrillation a specific feature of PLN-related HCM, and by what mechanism?
KNOWLEDGE GAP OPEN pln_hcm_atrial_fibrillation
Attached to
phenotypes#Atrial fibrillation
All four PLN-HCM probands reported by 2011 had atrial fibrillation, against 21% in the general Mayo HCM cohort, but four late-diagnosed cases are too few to separate a gene effect from age, left atrial enlargement or ascertainment. No study has examined atrial calcium handling in PLN variant carriers, so the phenotype is left unconnected to the mechanism chain.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"Again, further studies are required to elucidate any potential association between PLN function and atrial fibrillation."
The authors flag the association as unexplained.
⚙

Pathophysiology

5
PLN L39X Truncating Variant
Mechanism confidence: Established
The best-characterised CMH18 lesion is the heterozygous nonsense allele c.116T>G, p.Leu39Ter (L39X, L39stop), which truncates phospholamban within its second transmembrane segment. Expressed in cells, the truncated protein is barely detectable, does not inhibit SERCA2a, and is misrouted away from the sarcoplasmic reticulum when it is made; co-expression with wild-type phospholamban shows no dominant-negative effect. A heterozygote therefore carries roughly half the normal amount of functional phospholamban.
PLN hgnc:9080 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context PLN hgnc:9080 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Nonsense allele c.116T>G, p.Leu39Ter. Loss of function is shown biochemically and by absent protein in a homozygous explanted heart; haploinsufficiency in heterozygotes is inferred from the absence of a dominant-negative effect.
phospholamban inhibition of the SERCA2a calcium pump GO:0042030 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phospholamban inhibition of the SERCA2a calcium pump, annotated with ATPase inhibitor activity (GO:0042030). GO:0042030 is a molecular function from the Gene Ontology.
sarcoplasmic reticulum membrane GO:0033017 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcoplasmic reticulum membrane (GO:0033017). GO:0033017 is a cellular component from the Gene Ontology.
Experimental models
HEK-293 expression of PLN-L39stop OTHER Expresses the patient allele and measures SERCA2a inhibition and protein stability.
Adult rat ventricular myocyte expression of PLN-L39stop OTHER Expresses the patient allele in adult cardiomyocytes and measures its localisation and functional effect.
Downstream
Loss of Phospholamban Brake on SERCA2a Halving functional phospholamban removes part of the tonic inhibition of SERCA2a.
Show evidence (4 references)
PMID:21167350 SUPPORT Human Clinical
"one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family."
Identifies the L39X allele in a sarcomere-gene-negative HCM proband and shows it cosegregating with HCM in the family.
PMID:17655857 SUPPORT Human Clinical
"Two novel mutations in the CALR3 gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN gene (Leu39Ter)."
Independent identification of the same truncating allele in an Australian familial HCM cohort of 252 probands.
PMID:12639993 SUPPORT In Vitro
"showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
Shows that the truncated protein neither inhibits SERCA2a nor accumulates stably at the sarcoplasmic reticulum, i.e. loss of function.
+ 1 more reference
PLN Promoter Variant Altering Phospholamban Expression
Mechanism confidence: Hypothetical
Seven HCM probands in three cohorts carried rare single-nucleotide variants in the PLN promoter that were absent from controls. In reporter assays -77A>G raised promoter activity in neonatal rat cardiomyocytes, whereas -42C>G lowered it by 43-47% in C6 and C2C12 cells; five further promoter variants found in the Mayo cohort have no functional data. If the reporter results hold in the heart, these alleles would move phospholamban expression, and with it SERCA2a inhibition, in opposite directions. The node is HYPOTHETICAL: each variant rests on a single family or proband, none has been shown to alter phospholamban protein in human myocardium, and their causal role in HCM is not established.
PLN hgnc:9080 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context PLN hgnc:9080 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Promoter single-nucleotide variants -77A>G and -42C>G (relative to the transcription start site), plus unstudied -235C>T, -198A>C, -120A>G, -114T>C and -47G>T. Recorded as UNKNOWN because the two studied alleles change reporter activity in opposite directions.
phospholamban inhibition of the SERCA2a calcium pump GO:0042030 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal phospholamban inhibition of the SERCA2a calcium pump, annotated with ATPase inhibitor activity (GO:0042030). GO:0042030 is a molecular function from the Gene Ontology.
Downstream
Cardiomyocyte Hypertrophic Remodeling Proposed by the reporting authors from a single carrier or family each; the route from altered promoter activity to hypertrophy is not shown.
Show evidence (3 references)
PMID:12705874 SUPPORT In Vitro
"Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the phospholamban promoter activity."
Reporter evidence that -77A>G raises PLN promoter activity.
PMID:16829191 SUPPORT In Vitro
"This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively."
Reporter evidence that -42C>G lowers PLN promoter activity, the opposite direction.
PMID:21167350 SUPPORT Human Clinical
"In addition, promoter variants were identified in 5 out of 1064 probands which were not identified in 600 reference alleles."
Further rare promoter variants in HCM probands, without functional study.
Loss of Phospholamban Brake on SERCA2a
Mechanism confidence: Established
Dephosphorylated phospholamban lowers the calcium affinity of SERCA2a, and its phosphorylation by protein kinase A or CaMKII during beta-adrenergic stimulation lifts that brake. With less functional phospholamban the pump is partly disinhibited at rest and the beta-adrenergic release mechanism has less to act on. ClinGen frames the shared mechanism of all PLN-related cardiomyopathy as dysregulated SERCA2 function and calcium handling.
negative regulation of calcium ion import into sarcoplasmic reticulum GO:1902081 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of calcium ion import into sarcoplasmic reticulum (GO:1902081). GO:1902081 is a biological process from the Gene Ontology.
sarcoplasmic reticulum membrane GO:0033017 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcoplasmic reticulum membrane (GO:0033017). GO:0033017 is a cellular component from the Gene Ontology.
Downstream
Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility Removing phospholamban raises SERCA2a calcium affinity and accelerates relaxation and contraction; shown by complete ablation in the mouse.
Show evidence (2 references)
PMID:21167350 SUPPORT BACKGROUND Other
"PLN-encoded phospholamban (PLN, also known as PLB) is a small, 52 amino acid protein which negatively-regulates the Ca2+ uptake action of SERCA2."
Introduction statement of phospholamban's normal function, which the variant reduces.
CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"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."
ClinGen's synthesis of the shared PLN disease mechanism, which also states that the precise genetic mechanism is unclear.
Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
Mechanism confidence: Provisional
With the brake partly released, sarcoplasmic reticulum calcium reuptake is faster and basal contractility rises, as in a heart under continuous beta-adrenergic stimulation. This is directly demonstrated only in the phospholamban-null mouse. The human counterpart is indirect: L39X heterozygotes have normal or high ejection fractions (the Mayo proband reached 90% at peak exertion), and the original authors proposed that years of increased cardiac work lead to hypertrophy. Calcium transients in human heterozygous myocardium have not been measured.
Chronic hypercontractility from phospholamban loss drives ventricular hypertrophy
ventricular cardiomyocyte CL:2000046 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
calcium ion import into sarcoplasmic reticulum GO:1990036 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium ion import into sarcoplasmic reticulum (GO:1990036). GO:1990036 is a biological process from the Gene Ontology. cardiac muscle contraction GO:0060048 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology.
Animal models
Pln-null mouse Mouse recapitulates Complete phospholamban loss raises SERCA calcium affinity and basal contractility.
Downstream
Cardiomyocyte Hypertrophic Remodeling Proposed, not demonstrated: chronically increased cardiac work as the driver of hypertrophy in heterozygotes. The signalling steps between altered calcium cycling and the hypertrophic programme have not been studied in any PLN-HCM model. Chronic hypercontractility from phospholamban loss drives ventricular hypertrophy
Show evidence (2 references)
PMID:8062415 SUPPORT Model Organism
"These findings indicate that phospholamban acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein in mediating the heart's contractile responses to beta-adrenergic agonists."
Mouse knockout establishes phospholamban as the repressor of basal contractility.
PMID:21167350 SUPPORT INDIRECT Human Clinical
"He demonstrated a normal ejection fraction of 68% at rest increasing to 90% at peak physical exertion."
Preserved to high systolic function in a heterozygous L39X carrier, consistent with but not a measurement of enhanced cardiomyocyte contractility.
Cardiomyocyte Hypertrophic Remodeling
Mechanism confidence: Provisional
The left ventricle thickens, septal and apical in the Mayo L39X proband (MLVWT 24 mm), apical in the -42C>G family, and as an increase in left ventricular mass in four of nine L39X heterozygotes, with preserved systolic function. Onset in reported probands is in the sixth or seventh decade, although one carrier child was affected at 3 years. In a minority of heterozygotes the heart instead dilates and fails; both L39X homozygotes developed dilated cardiomyopathy, one of them after documented mild hypertrophy.
ventricular cardiomyocyte CL:2000046 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with ventricular cardiac muscle cell (CL:2000046). CL:2000046 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy GO:0003300 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology.
interventricular septum UBERON:0002094 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interventricular septum (UBERON:0002094). UBERON:0002094 is an anatomical location from the Uberon multi-species anatomy ontology. heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Pln-null mouse Mouse fails to recapitulate Lifelong hypercontractility in the null mouse is not followed by heart failure, the end stage of the human remodelling node; hypertrophy itself is not reported in the cited work.
Downstream
Hypertrophic cardiomyopathy The thickened, non-dilated ventricle is the clinical HCM.
Left ventricular hypertrophy Hypertrophic remodelling measured as increased left ventricular mass.
Apical hypertrophic cardiomyopathy Apical predominance of the hypertrophy in two of the reported families.
Dilated cardiomyopathy Progression from hypertrophy to dilatation has been documented in one L39X homozygote and is summarised by ClinGen as observed in a proband; its determinants are unknown. Some heterozygotes present with dilated rather than hypertrophic disease.
Congestive heart failure End-stage failure after dilatation, documented in homozygotes and in heterozygotes who dilate.
Show evidence (2 references)
PMID:21167350 SUPPORT Human Clinical
"The PLN-L39X-nonsense mutation was identified in a 58-year-old, Caucasian male with septal and apical HCM."
Distribution of hypertrophy in the L39X proband.
PMID:12639993 SUPPORT Human Clinical
"The heterozygous individuals exhibited hypertrophy without diminished contractile performance."
Hypertrophy with preserved contraction in heterozygous carriers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 18 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Cardiovascular 14
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21167350 SUPPORT Human Clinical
"Conversely, the younger daughter, who does not demonstrate features of HCM currently, has a 3 year-old, HCM phenotype-positive daughter. Both host the PLN-L39X mutation."
HCM in a young L39X carrier, alongside an unaffected adult carrier.
PMID:12705874 SUPPORT Human Clinical
"We found a heterozygous single nucleotide transition from A to G at -77-bp upstream of the transcription start site in the phospholamban promoter region of one patient with familial hypertrophic cardiomyopathy."
Familial HCM in a promoter-variant carrier.
Left ventricular hypertrophy HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"their left ventricular systolic function (ejection fraction, 64.8% ± 2.8%) was normal, but four (I-3, II-1, II-3, III-7) exhibited left ventricular hypertrophy"
Echocardiographic left ventricular hypertrophy in heterozygotes.
Apical hypertrophic cardiomyopathy HP:0031992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apical hypertrophic cardiomyopathy (HP:0031992). HP:0031992 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16829191 SUPPORT Human Clinical
"The PLN -42 C>G mutation was found in one patient with late onset familial apical hypertrophic cardiomyopathy."
Apical HCM in a promoter-variant proband.
PMID:21167350 SUPPORT Human Clinical
"The PLN-L39X-nonsense mutation was identified in a 58-year-old, Caucasian male with septal and apical HCM."
Septal and apical hypertrophy in the L39X proband.
Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"In addition, given that the frequency of atrial fibrillation in our cohort is 21%, the identification of this arrhythmia in all four PLN-HCM mutation cases described to date is notable."
Atrial fibrillation in every reported PLN-HCM proband.
Atrial flutter HP:0004749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial flutter (HP:0004749). HP:0004749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"At this time, ECG (Figure 2A) and echocardiographic (Figure 2B) analysis revealed sinus bradycardia with paroxysmal atrial fibrillation/flutter"
Paroxysmal atrial flutter alongside fibrillation in a single L39X proband.
Palpitations HP:0001962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palpitations (HP:0001962). HP:0001962 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21167350 SUPPORT REVIEW SYNTHESIS Human Clinical
"the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
Palpitations at presentation in the Australian L39X proband, as summarised by Landstrom et al.
PMID:21167350 SUPPORT Human Clinical
"He was diagnosed at 51 years of age presenting with palpitations and was maintained on atenolol and amiodarone for approximately two years"
Palpitations as the presenting symptom in the Mayo L39X proband.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT REVIEW SYNTHESIS Human Clinical
"the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
Syncope at presentation in a single L39X proband, as summarised by Landstrom et al.
Presyncope HP:0031972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Presyncope (HP:0031972). HP:0031972 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
Presyncope in a single L39X proband.
Ventricular tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-sustained ventricular tachycardia, annotated with Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"He was found to have conduction block as well as ventricular ectopy with symptomatic non-sustained ventricular tachycardia for which he received an automatic internal cardioverter defibrillator."
Non-sustained VT in a single L39X carrier.
Left atrial enlargement HP:0031295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left atrial enlargement (HP:0031295). HP:0031295 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"a MLVWT of 24 mm and left atrial enlargement with mild mitral valve regurgitation without resting or valsalva-induced left ventricular outflow tract obstruction"
Echocardiographic left atrial enlargement in a single L39X proband.
Mitral regurgitation HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral regurgitation (HP:0001653), qualified as severity mild. HP:0001653 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"a MLVWT of 24 mm and left atrial enlargement with mild mitral valve regurgitation without resting or valsalva-induced left ventricular outflow tract obstruction"
Mild mitral regurgitation in a single L39X proband.
Wolff-Parkinson-White syndrome HP:0001716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wolff-Parkinson-White syndrome (HP:0001716). HP:0001716 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21167350 SUPPORT Human Clinical
"At this time, he was diagnosed with Wolff-Parkinson-White (WPW) syndrome due to abnormalities on resting ECG."
WPW diagnosis in the L39X proband.
PMID:21167350 SUPPORT Human Clinical
"While, mutations in PRKAG2 have been associated with development of WPW, the proband was found to be PRKAG2 mutation negative"
The main phenocopy explanation for WPW with hypertrophy was excluded.
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"Likewise, there are undoubtedly as-yet-unidentified genetic influences that can modify the PLN-L39stop phenotype, as strongly suggested by the development of dilated cardiomyopathy in two heterozygous subjects from one of our kindreds but ventricular hypertrophy with normal cardiac function in..."
Dilated rather than hypertrophic disease in some heterozygous carriers.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
Heart failure in homozygous carriers of the CMH18 allele.
Respiratory 1
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21167350 SUPPORT Human Clinical
"Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
Dyspnea in the Mayo L39X proband.
PMID:21167350 SUPPORT REVIEW SYNTHESIS Human Clinical
"the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
Dyspnea at presentation in the Australian L39X proband, as summarised by Landstrom et al.
Constitutional 1
Chest pain HP:0100749 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chest pain (HP:0100749). HP:0100749 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
Chest discomfort in a single L39X proband.
🧬

Genetic Associations

1
PLN (Pathogenic Variants)
Gene: PLN hgnc:9080 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (8 references)
PMID:27532257 SUPPORT Human Clinical
"Rare variants were less numerous in other well-characterized HCM genes (TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC1, PLN) and phenocopy genes (GLA, LAMP2, PRKAG2)"
Names PLN among the established but low-yield HCM genes in a large case series.
PMID:27532257 SUPPORT Human Clinical
"For each of these genes there is a significant (P < 0.05 after Bonferroni correction) excess of variation in cases as compared with ExAC, thus confirming their association with disease"
HCM-specific case-excess evidence: PLN rare variation is significantly enriched in HCM cases over population reference samples.
PMID:21167350 SUPPORT Human Clinical
"This mutation cosegregated with incidence of HCM in a multigenerational family."
Segregation evidence in an HCM family.
+ 5 more references
Variants (3)
PLN p.Leu39Ter Pathogenic
nonsense
c.116T>G (T116G), p.Leu39Ter, also written L39X or L39stop. Nonsense allele truncating phospholamban in transmembrane domain II; a functional null with no dominant-negative effect. Reported heterozygous in HCM probands from North America (Mayo Clinic) and Australia and in two kindreds studied in Athens, where heterozygotes were hypertrophic or, in one kindred, dilated, and homozygotes had lethal dilated cardiomyopathy. Absent from 600 reference alleles in the Mayo study. Landstrom et al. describe position 39 as a possible relative mutational hot spot.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"This mutation was absent in 600 reference alleles (200 African American, 400 Caucasian American)."
Absence from controls in the Mayo study.
PLN promoter -77A>G
promoter
Heterozygous A-to-G change 77 bp upstream of the transcription start site, in one Japanese woman with familial HCM diagnosed at 56 with paroxysmal atrial fibrillation; absent from 296 controls and raised promoter activity in neonatal rat cardiomyocytes. Pathogenicity is not established.
Show evidence (1 reference)
PMID:12705874 SUPPORT Human Clinical
"This nucleotide change was not found in 296 control subjects."
Absence from controls.
PLN promoter -42C>G
promoter
Promoter variant in one Spanish family with late-onset benign apical HCM, including a healthy adult carrier; lowered promoter activity in reporter assays. Pathogenicity is not established.
Show evidence (1 reference)
PMID:16829191 SUPPORT Human Clinical
"The PLN -42 C>G mutation is associated with a benign form of apical hypertrophic cardiomyopathy in this family, though the presence of a healthy adult carrier suggests that other genetic and environmental factors could be involved."
Family-level association with incomplete penetrance.
💊

Medical Actions

5
Rate and Rhythm Control Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: atenolol CHEBI:2904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses atenolol (CHEBI:2904). CHEBI:2904 is a therapeutic agent from Chemical Entities of Biological Interest. sotalol CHEBI:63622 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sotalol (CHEBI:63622). CHEBI:63622 is a therapeutic agent from Chemical Entities of Biological Interest. amiodarone CHEBI:2663 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amiodarone (CHEBI:2663). CHEBI:2663 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
No PLN-specific therapy exists; management follows general HCM practice. The Mayo L39X proband was treated with atenolol, then sotalol (amiodarone was stopped after thyrotoxicosis) and candesartan for palpitations and paroxysmal atrial fibrillation.
Target Phenotypes: Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atrial fibrillation (HP:0005110). HP:0005110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"He was diagnosed at 51 years of age presenting with palpitations and was maintained on atenolol and amiodarone for approximately two years"
Single-patient treatment history; no outcome data.
Implantable Cardioverter-Defibrillator
Action: Implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
Placed in the Mayo L39X proband for symptomatic non-sustained ventricular tachycardia. Indications follow general HCM sudden-death risk criteria; no PLN-HCM-specific risk data exist.
Target Phenotypes: Non-sustained ventricular tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Non-sustained ventricular tachycardia, annotated with Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"He was found to have conduction block as well as ventricular ectopy with symptomatic non-sustained ventricular tachycardia for which he received an automatic internal cardioverter defibrillator."
ICD placement for NSVT in a CMH18 proband.
Cascade Screening and Cardiac Surveillance of At-Risk Relatives
Action: cascade genetic and cardiac screening of at-risk relativesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cascade genetic and cardiac screening of at-risk relatives, annotated with Cardiac Disease Screening (NCIT:C168126). NCIT:C168126 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Disease Screening NCIT:C168126
Platform: Other
Predictive testing of first- and second-degree relatives for the familial variant, with serial echocardiography and ECG in carriers. Incomplete penetrance means an unaffected adult carrier is not discharged.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"In an attempt to investigate whether this nonsense mutation might co-segregate with the proband's family history of HCM, we obtained genomic DNA from as many first and second degree relatives as possible"
Family genotyping that identified an affected child carrier and an unaffected adult carrier.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Counselling should cover autosomal dominant transmission with incomplete penetrance and variable expressivity, the possibility of later dilated cardiomyopathy, and the severe early dilated cardiomyopathy seen when a child inherits two L39X alleles (relevant to consanguineous or carrier-by-carrier couples).
Show evidence (1 reference)
CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"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"
Supplies the inheritance and dosage information counselling must convey.
Heart Transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Platform: Surgery
Required in adolescence or early adulthood by L39stop homozygotes with end-stage dilated cardiomyopathy; not reported for heterozygous HCM.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
Transplantation for the homozygous end of the allele's spectrum.
🔬

Diagnosis

3
Echocardiography
Documents unexplained left ventricular wall thickening (MLVWT above 13 mm in the Mayo study), its septal or apical distribution, left atrial size and systolic function, and screens genotype-positive relatives.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"Each of the subjects met the clinical diagnostic criteria for HCM (i.e. MLVWT greater than 13 mm in the absence of other confounding diagnoses)."
The echocardiographic diagnostic criterion applied to the PLN-screened cohort.
Electrocardiography and Rhythm Monitoring
Resting ECG and ambulatory monitoring for atrial fibrillation or flutter, pre-excitation, conduction block and non-sustained ventricular tachycardia, all reported in PLN-HCM carriers.
electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"At this time, ECG (Figure 2A) and echocardiographic (Figure 2B) analysis revealed sinus bradycardia with paroxysmal atrial fibrillation/flutter"
ECG detection of the atrial arrhythmia in the L39X proband.
PLN Genetic Testing Including the Promoter
Sequencing of PLN on a multigene cardiomyopathy panel. The coding region and promoter fit in two amplicons and background variation is very low, which favours inclusion; promoter coverage matters because several HCM-associated PLN variants are regulatory. A positive result should prompt phenocopy exclusion (PRKAG2, GLA, LAMP2) when pre-excitation is present, and cascade testing of relatives.
PLN sequencing including promoter, with cascade testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible."
Supports PLN testing on HCM panels.
📈

Progression

2
Genotype-positive relative
Penetrance is incomplete and onset in reported probands is in the sixth or seventh decade, but a 3-year-old carrier was affected, so carriers need longitudinal review from childhood.
Show evidence (1 reference)
PMID:21167350 SUPPORT Human Clinical
"Conversely, the younger daughter, who does not demonstrate features of HCM currently, has a 3 year-old, HCM phenotype-positive daughter. Both host the PLN-L39X mutation."
An unaffected adult carrier and an affected child carrier in one pedigree.
Established hypertrophic cardiomyopathy
Hypertrophy with preserved or high ejection fraction, frequently with atrial fibrillation. A minority of heterozygotes, and all reported homozygotes, progress to ventricular dilatation and heart failure.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"In this study, heterozygosity of PLN-L39stop was associated with hypertrophy in some members of both families and with overt dilated cardiomyopathy in other members."
The hypertrophic and dilated outcomes of the heterozygous state.
🧫

Experimental Models

2
HEK-293 expression of PLN-L39stop OTHER
Recombinant wild-type and L39stop phospholamban co-expressed with SERCA2a in HEK-293 cells (including a simulated heterozygous state), with calcium uptake, protein stability and localisation readouts.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:12639993
Pathograph links
PLN L39X Truncating Variant recapitulates fidelity: moderate observes: molecular Expresses the patient allele and measures SERCA2a inhibition and protein stability.
Limitations: Heterologous non-cardiac cells with overexpression; does not reproduce the human myocardial context or the hypertrophic outcome.
Show evidence (1 reference)
PMID:12639993 SUPPORT In Vitro
"showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
Reports the loss-of-function readouts.
Adult rat ventricular myocyte expression of PLN-L39stop OTHER
Wild-type and L39stop phospholamban adenovirally expressed in isolated adult rat ventricular myocytes, with localisation, cell shortening and calcium-transient readouts.
Organism
rat NCBITaxon:10116 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in rat, annotated with Rattus norvegicus (NCBITaxon:10116). NCBITaxon:10116 is an organism from the NCBI Taxonomy.
Publication
PMID:12639993
Pathograph links
PLN L39X Truncating Variant recapitulates fidelity: moderate observes: molecular Expresses the patient allele in adult cardiomyocytes and measures its localisation and functional effect.
Limitations: Rat myocytes with adenoviral overexpression on an endogenous rat Pln background; does not reproduce the human myocardial context or the hypertrophic outcome.
Show evidence (1 reference)
PMID:12639993 SUPPORT In Vitro
"showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
Reports the loss-of-function readouts.
🐁

Animal Models

1
Pln-null mouse
Phospholamban-deficient mice develop normally, with faster relaxation, higher +/-dP/dt and raised SERCA calcium affinity, reaching baseline values equal to those of maximally beta-stimulated wild-type hearts. They do not develop heart failure even in advanced age, unlike human L39X homozygotes; hypertrophy is not reported in the cited work.
Species
Mouse
Genotype
Pln-/- (targeted germline ablation)
Publication
PMID:8062415
Pathograph links
Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility recapitulates fidelity: moderate observes: organism Complete phospholamban loss raises SERCA calcium affinity and basal contractility.
Limitations: Homozygous null rather than the heterozygous human state; mouse calcium handling relies more on SERCA than the human heart does.
Readouts
Intraventricular pressure derivatives and SERCA calcium affinity
Direction: INCREASED
Interpretation: Contractility and pump calcium affinity rise without phospholamban.
Show evidence (1 reference)
PMID:8062415 SUPPORT Model Organism
"The first derivatives of intraventricular pressure (+/- dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca(2+)-ATPase for Ca2+ in the phospholamban-deficient hearts."
Reports the contractility and calcium-affinity readouts.
Show evidence (1 reference)
PMID:8062415 SUPPORT Model Organism
"The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate."
Supports the model as informative for the hypercontractility node.
Cardiomyocyte Hypertrophic Remodeling fails to recapitulate fidelity: low observes: organism Lifelong hypercontractility in the null mouse is not followed by heart failure, the end stage of the human remodelling node; hypertrophy itself is not reported in the cited work.
Limitations: Species difference in reliance on phospholamban regulation; a complete null, not a heterozygote; hypertrophy has not been specifically assessed in heterozygous Pln mice in the cited work.
Divergences from the human mechanism
boundary omission qualifying
The hypertrophy endpoint that defines this node was not assessed in the cited null-mouse work; the failure to recapitulate rests on the absent heart-failure course, not on a measured absence of hypertrophy.
Show evidence (1 reference)
PMID:12639993 SUPPORT BACKGROUND Model Organism
"Whereas the PLN-null mouse displays chronically increased basal cardiac contractile function without developing heart failure, even in advanced age"
The null mouse does not progress to the heart failure that ends the human remodelling course.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 18
creation_date: "2026-10-13T00:00:00Z"
category: Mendelian
synonyms:
- CMH18
- cardiomyopathy, hypertrophic, 18
- cardiomyopathy, familial hypertrophic, 18
- hypertrophic cardiomyopathy type 18
- PLN-related hypertrophic cardiomyopathy
description: >-
  Hypertrophic cardiomyopathy 18 (CMH18) is the PLN-attributed member of the
  numbered familial hypertrophic cardiomyopathy series. PLN encodes
  phospholamban, a 52-amino-acid sarcoplasmic reticulum membrane protein that
  restrains the cardiac calcium pump SERCA2a until protein kinase A or CaMKII
  phosphorylation releases it. The lesion therefore sits in calcium reuptake,
  the relaxation arm of excitation-contraction coupling, rather than in the
  sarcomere, which makes CMH18 one of the rare non-sarcomeric, calcium-handling
  forms of HCM.

  The hypertrophic presentation rests on a small number of families. The
  truncating p.Leu39Ter (L39X, L39stop) allele is a functional null.
  Heterozygous carriers in North American and Australian HCM families and in
  two kindreds studied in Athens developed left ventricular hypertrophy, with
  preserved systolic function where it was measured, and in the one pedigree
  studied for it the allele cosegregated with HCM with incomplete penetrance.
  Seven further HCM probands carried rare promoter variants absent from
  controls; the two tested in reporter assays raise (-77A>G) or lower
  (-42C>G) PLN promoter activity. Across six screened HCM cohorts PLN accounts
  for roughly 0.65% of probands. The four reported probands were diagnosed
  between 51 and 67 years, all with atrial fibrillation, although one carrier
  child was affected at 3 years. The same L39X allele causes
  lethal dilated cardiomyopathy in homozygotes, and some heterozygotes also
  develop dilated cardiomyopathy, so CMH18 is allelic with dilated
  cardiomyopathy 1P (curated separately as Dilated_Cardiomyopathy_1P); ClinGen
  merges both into a single PLN-related intrinsic cardiomyopathy. Why loss of
  phospholamban, which leaves the mouse heart hypercontractile without heart
  failure into old age, produces hypertrophy in humans is not established.
disease_term:
  preferred_term: hypertrophic cardiomyopathy 18
  term:
    id: MONDO:0013475
    label: hypertrophic cardiomyopathy 18
parents:
- Hypertrophic Cardiomyopathy
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: PMID:21167350
  title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
- reference: PMID:12639993
  title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
- reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
  title: "PLN / intrinsic cardiomyopathy (Definitive)"
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous PLN variants segregate with HCM as an autosomal dominant trait
    with incomplete penetrance: in the Mayo L39X pedigree an adult
    genotype-positive daughter was unaffected while her carrier child had HCM,
    in the two Athens L39stop kindreds only four of nine heterozygotes had left
    ventricular hypertrophy, and the -42C>G promoter family included a healthy
    adult carrier. Expressivity is variable, from isolated hypertrophy with
    normal function to dilated cardiomyopathy in some heterozygotes. Two
    L39X alleles produce a more severe, dilated phenotype, which ClinGen
    describes as a dosage effect or semidominance; that is a property of the
    allele rather than a separate recessive form of CMH18 and is recorded here
    rather than as autosomal recessive inheritance.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PLN-L39X mutation cosegregates with incidence of HCM in this pedigree, and absence of an HCM phenotype in the proband's genotype-positive daughter at the present time indicates incomplete penetrance of the disease."
    explanation: >-
      Dominant cosegregation of a heterozygous allele with HCM, with an
      unaffected adult carrier documenting incomplete penetrance.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their left ventricular systolic function (ejection fraction, 64.8% ± 2.8%) was normal, but four (I-3, II-1, II-3, III-7) exhibited left ventricular hypertrophy"
    explanation: >-
      Only four of nine heterozygous L39stop carriers were hypertrophic, a
      second family-level observation of incomplete penetrance.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, heterozygosity of PLN-L39stop was associated with hypertrophy in some members of both families and with overt dilated cardiomyopathy in other members."
    explanation: >-
      The same heterozygous allele produced hypertrophy in some carriers and
      dilated cardiomyopathy in others, i.e. variable expressivity.
  - reference: PMID:16829191
    reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PLN -42 C>G mutation is associated with a benign form of apical hypertrophic cardiomyopathy in this family, though the presence of a healthy adult carrier suggests that other genetic and environmental factors could be involved."
    explanation: >-
      A promoter-variant family with an affected son and a healthy adult
      carrier son, again showing incomplete penetrance.
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: >-
      ClinGen's summary of PLN inheritance across the allelic cardiomyopathies,
      including the dosage effect of biallelic loss.
pathophysiology:
- name: PLN L39X Truncating Variant
  description: >-
    The best-characterised CMH18 lesion is the heterozygous nonsense allele
    c.116T>G, p.Leu39Ter (L39X, L39stop), which truncates phospholamban within
    its second transmembrane segment. Expressed in cells, the truncated protein
    is barely detectable, does not inhibit SERCA2a, and is misrouted away from
    the sarcoplasmic reticulum when it is made; co-expression with wild-type
    phospholamban shows no dominant-negative effect. A heterozygote therefore
    carries roughly half the normal amount of functional phospholamban.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genetic_context:
    gene:
      preferred_term: PLN
      term:
        id: hgnc:9080
        label: PLN
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Nonsense allele c.116T>G, p.Leu39Ter. Loss of function is shown
      biochemically and by absent protein in a homozygous explanted heart;
      haploinsufficiency in heterozygotes is inferred from the absence of a
      dominant-negative effect.
  genes:
  - preferred_term: PLN
    term:
      id: hgnc:9080
      label: PLN
  molecular_functions:
  - preferred_term: phospholamban inhibition of the SERCA2a calcium pump
    term:
      id: GO:0042030
      label: ATPase inhibitor activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: sarcoplasmic reticulum membrane
    term:
      id: GO:0033017
      label: sarcoplasmic reticulum membrane
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family."
    explanation: >-
      Identifies the L39X allele in a sarcomere-gene-negative HCM proband and
      shows it cosegregating with HCM in the family.
  - reference: PMID:17655857
    reference_title: "Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two novel mutations in the CALR3 gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN gene (Leu39Ter)."
    explanation: >-
      Independent identification of the same truncating allele in an
      Australian familial HCM cohort of 252 probands.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
    explanation: >-
      Shows that the truncated protein neither inhibits SERCA2a nor
      accumulates stably at the sarcoplasmic reticulum, i.e. loss of function.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "does not exert a dominant-negative effect on PLN-WT"
    explanation: >-
      In simulated heterozygous cells the mutant does not interfere with the
      wild-type protein, so heterozygotes lose function by reduced dosage only.
  downstream:
  - target: Loss of Phospholamban Brake on SERCA2a
    causal_link_type: DIRECT
    description: >-
      Halving functional phospholamban removes part of the tonic inhibition of
      SERCA2a.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase"
      explanation: >-
        The truncated protein fails to inhibit the pump in cardiomyocytes,
        which is the step this edge asserts.
- name: PLN Promoter Variant Altering Phospholamban Expression
  description: >-
    Seven HCM probands in three cohorts carried rare single-nucleotide
    variants in the PLN promoter that were absent from controls. In reporter assays -77A>G raised
    promoter activity in neonatal rat cardiomyocytes, whereas -42C>G lowered it
    by 43-47% in C6 and C2C12 cells; five further promoter variants found in
    the Mayo cohort have no functional data. If the reporter results hold in
    the heart, these alleles would move phospholamban expression, and with it
    SERCA2a inhibition, in opposite directions. The node is HYPOTHETICAL: each
    variant rests on a single family or proband, none has been shown to alter
    phospholamban protein in human myocardium, and their causal role in HCM is
    not established.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  genetic_context:
    gene:
      preferred_term: PLN
      term:
        id: hgnc:9080
        label: PLN
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Promoter single-nucleotide variants -77A>G and -42C>G (relative to the
      transcription start site), plus unstudied -235C>T, -198A>C, -120A>G,
      -114T>C and -47G>T. Recorded as UNKNOWN because the two studied alleles
      change reporter activity in opposite directions.
  genes:
  - preferred_term: PLN
    term:
      id: hgnc:9080
      label: PLN
  molecular_functions:
  - preferred_term: phospholamban inhibition of the SERCA2a calcium pump
    term:
      id: GO:0042030
      label: ATPase inhibitor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12705874
    reference_title: "Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the phospholamban promoter activity."
    explanation: Reporter evidence that -77A>G raises PLN promoter activity.
  - reference: PMID:16829191
    reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively."
    explanation: Reporter evidence that -42C>G lowers PLN promoter activity, the opposite direction.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, promoter variants were identified in 5 out of 1064 probands which were not identified in 600 reference alleles."
    explanation: Further rare promoter variants in HCM probands, without functional study.
  downstream:
  - target: Cardiomyocyte Hypertrophic Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by the reporting authors from a single carrier or family each;
      the route from altered promoter activity to hypertrophy is not shown.
    evidence:
    - reference: PMID:12705874
      reference_title: "Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We suspect that the mutation plays an important role in the development of hypertrophic cardiomyopathy."
      explanation: >-
        The authors' own hedged inference from one familial HCM proband; no
        mechanism linking the variant to hypertrophy was tested.
    - reference: PMID:16829191
      reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PLN -42 C>G mutation was found in one patient with late onset familial apical hypertrophic cardiomyopathy."
      explanation: Association of a promoter variant with apical HCM in one family.
- name: Loss of Phospholamban Brake on SERCA2a
  description: >-
    Dephosphorylated phospholamban lowers the calcium affinity of SERCA2a, and
    its phosphorylation by protein kinase A or CaMKII during beta-adrenergic
    stimulation lifts that brake. With less functional phospholamban the pump
    is partly disinhibited at rest and the beta-adrenergic release mechanism
    has less to act on. ClinGen frames the shared mechanism of all PLN-related
    cardiomyopathy as dysregulated SERCA2 function and calcium handling.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: negative regulation of calcium ion import into sarcoplasmic reticulum
    term:
      id: GO:1902081
      label: negative regulation of calcium ion import into sarcoplasmic reticulum
    modifier: DECREASED
  cellular_components:
  - preferred_term: sarcoplasmic reticulum membrane
    term:
      id: GO:0033017
      label: sarcoplasmic reticulum membrane
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "PLN-encoded phospholamban (PLN, also known as PLB) is a small, 52 amino acid protein which negatively-regulates the Ca2+ uptake action of SERCA2."
    explanation: Introduction statement of phospholamban's normal function, which the variant reduces.
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: >-
      ClinGen's synthesis of the shared PLN disease mechanism, which also
      states that the precise genetic mechanism is unclear.
  downstream:
  - target: Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
    causal_link_type: DIRECT
    description: >-
      Removing phospholamban raises SERCA2a calcium affinity and accelerates
      relaxation and contraction; shown by complete ablation in the mouse.
    evidence:
    - reference: PMID:8062415
      reference_title: "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The first derivatives of intraventricular pressure (+/- dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca(2+)-ATPase for Ca2+ in the phospholamban-deficient hearts."
      explanation: >-
        Complete knockout in mouse, not human heterozygous loss; graded
        INDIRECT because the dose and species differ from CMH18.
- name: Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
  description: >-
    With the brake partly released, sarcoplasmic reticulum calcium reuptake is
    faster and basal contractility rises, as in a heart under continuous
    beta-adrenergic stimulation. This is directly demonstrated only in the
    phospholamban-null mouse. The human counterpart is indirect: L39X
    heterozygotes have normal or high ejection fractions (the Mayo proband
    reached 90% at peak exertion), and the original authors proposed that
    years of increased cardiac work lead to hypertrophy. Calcium transients in
    human heterozygous myocardium have not been measured.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: calcium ion import into sarcoplasmic reticulum
    term:
      id: GO:1990036
      label: calcium ion import into sarcoplasmic reticulum
    modifier: INCREASED
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: INCREASED
  evidence:
  - reference: PMID:8062415
    reference_title: "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings indicate that phospholamban acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein in mediating the heart's contractile responses to beta-adrenergic agonists."
    explanation: Mouse knockout establishes phospholamban as the repressor of basal contractility.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "He demonstrated a normal ejection fraction of 68% at rest increasing to 90% at peak physical exertion."
    explanation: >-
      Preserved to high systolic function in a heterozygous L39X carrier,
      consistent with but not a measurement of enhanced cardiomyocyte
      contractility.
  downstream:
  - target: Cardiomyocyte Hypertrophic Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - pln_hypercontractility_to_hypertrophy
    description: >-
      Proposed, not demonstrated: chronically increased cardiac work as the
      driver of hypertrophy in heterozygotes. The signalling steps between
      altered calcium cycling and the hypertrophic programme have not been
      studied in any PLN-HCM model.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Increased cardiac work over a period of years could conceivably lead to ventricular hypertrophy, as seen in some of the heterozygous PLN-L39stop individuals, which may then progress to ventricular failure as observed in the homozygous mutants."
      explanation: >-
        The discussing authors' hypothesis linking loss of phospholamban to
        hypertrophy; it is speculation framed around their clinical
        observations, hence INDIRECT.
- name: Cardiomyocyte Hypertrophic Remodeling
  description: >-
    The left ventricle thickens, septal and apical in the Mayo L39X proband
    (MLVWT 24 mm), apical in the -42C>G family, and as an increase in left
    ventricular mass in four of nine L39X heterozygotes, with preserved
    systolic function. Onset in reported probands is in the sixth or seventh
    decade, although one carrier child was affected at 3 years. In a minority
    of heterozygotes the heart instead dilates and fails; both L39X
    homozygotes developed dilated cardiomyopathy, one of them after
    documented mild hypertrophy.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:2000046
      label: ventricular cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PLN-L39X-nonsense mutation was identified in a 58-year-old, Caucasian male with septal and apical HCM."
    explanation: Distribution of hypertrophy in the L39X proband.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The heterozygous individuals exhibited hypertrophy without diminished contractile performance."
    explanation: Hypertrophy with preserved contraction in heterozygous carriers.
  downstream:
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: The thickened, non-dilated ventricle is the clinical HCM.
    evidence:
    - reference: PMID:21167350
      reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In agreement with previous findings, our PLN-L39X proband demonstrated cardiac hypertrophy with a family history suggestive of an autosomal dominant mode of inheritance as both his mother, sister, and granddaughter have HCM."
      explanation: Clinical HCM in the carrier and affected relatives.
  - target: Left ventricular hypertrophy
    causal_link_type: DIRECT
    description: Hypertrophic remodelling measured as increased left ventricular mass.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "their left ventricular systolic function (ejection fraction, 64.8% ± 2.8%) was normal, but four (I-3, II-1, II-3, III-7) exhibited left ventricular hypertrophy"
      explanation: Echocardiographic left ventricular hypertrophy in heterozygous carriers.
  - target: Apical hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: Apical predominance of the hypertrophy in two of the reported families.
    evidence:
    - reference: PMID:16829191
      reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One son had mild apical hypertrophic cardiomyopathy and carried the mutation, another son with normal ECG and echocardiogram also had the mutation."
      explanation: Apical HCM in a promoter-variant carrier.
  - target: Dilated cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progression from hypertrophy to dilatation has been documented in one
      L39X homozygote and is summarised by ClinGen as observed in a proband;
      its determinants are unknown. Some heterozygotes present with dilated
      rather than hypertrophic disease.
    evidence:
    - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
      reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Furthermore, a progressive cardiomyopathy beginning with hypertrophic and leading to dilated has been observed in a proband"
      explanation: ClinGen's summary of an observed hypertrophic-to-dilated course.
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "His homozygous sister exhibited only mild echocardiographic left ventricular hypertrophy at age 20 but developed progressive left ventricular dilation and cardiac failure, requiring cardiac transplantation at the age of 28."
      explanation: >-
        The observed transition, in a homozygous L39stop carrier; homozygosity
        is the more severe end of the same allele's dosage range.
  - target: Congestive heart failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: End-stage failure after dilatation, documented in homozygotes and in heterozygotes who dilate.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "His homozygous sister exhibited only mild echocardiographic left ventricular hypertrophy at age 20 but developed progressive left ventricular dilation and cardiac failure, requiring cardiac transplantation at the age of 28."
      explanation: Hypertrophy progressing to cardiac failure in a carrier of two L39stop alleles.
mechanistic_hypotheses:
- hypothesis_group_id: pln_hypercontractility_to_hypertrophy
  hypothesis_label: Chronic hypercontractility from phospholamban loss drives ventricular hypertrophy
  status: EMERGING
  description: >-
    Haghighi and colleagues proposed that partial loss of phospholamban
    imposes years of increased cardiac work, as in chronic catecholamine
    excess, and that this produces the hypertrophy seen in heterozygotes and
    the failure seen in homozygotes. It explains the L39X allele but not the
    -77A>G promoter variant, which should increase phospholamban, and it
    conflicts with the null mouse, which stays hypercontractile into old age
    without heart failure. No experiment has tested it in human cells or a
    heterozygous model.
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased cardiac work over a period of years could conceivably lead to ventricular hypertrophy, as seen in some of the heterozygous PLN-L39stop individuals, which may then progress to ventricular failure as observed in the homozygous mutants."
    explanation: The original statement of the hypothesis.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Whereas the PLN-null mouse displays chronically increased basal cardiac contractile function without developing heart failure, even in advanced age"
    explanation: >-
      In the mouse, lifelong hypercontractility from total phospholamban loss
      does not lead to failure, which argues against hypercontractility alone
      being sufficient.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic cardiomyopathy
  description: >-
    The defining diagnosis. Reported probands were diagnosed in later adult
    life (51, 56, 61 and 67 years in the four literature cases summarised by
    Landstrom et al.), although a 3-year-old carrier in the Mayo pedigree was
    affected.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, the younger daughter, who does not demonstrate features of HCM currently, has a 3 year-old, HCM phenotype-positive daughter. Both host the PLN-L39X mutation."
    explanation: HCM in a young L39X carrier, alongside an unaffected adult carrier.
  - reference: PMID:12705874
    reference_title: "Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a heterozygous single nucleotide transition from A to G at -77-bp upstream of the transcription start site in the phospholamban promoter region of one patient with familial hypertrophic cardiomyopathy."
    explanation: Familial HCM in a promoter-variant carrier.
- category: Cardiovascular
  name: Left ventricular hypertrophy
  description: >-
    Increased left ventricular mass with normal ejection fraction in four of
    nine heterozygous L39stop carriers in the two kindreds studied in Athens.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their left ventricular systolic function (ejection fraction, 64.8% ± 2.8%) was normal, but four (I-3, II-1, II-3, III-7) exhibited left ventricular hypertrophy"
    explanation: Echocardiographic left ventricular hypertrophy in heterozygotes.
- category: Cardiovascular
  name: Apical hypertrophic cardiomyopathy
  description: >-
    Apical involvement in the Mayo L39X proband (septal and apical) and in the
    -42C>G family, where it was late-onset and benign.
  phenotype_term:
    preferred_term: Apical hypertrophic cardiomyopathy
    term:
      id: HP:0031992
      label: Apical hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:16829191
    reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PLN -42 C>G mutation was found in one patient with late onset familial apical hypertrophic cardiomyopathy."
    explanation: Apical HCM in a promoter-variant proband.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PLN-L39X-nonsense mutation was identified in a 58-year-old, Caucasian male with septal and apical HCM."
    explanation: Septal and apical hypertrophy in the L39X proband.
- category: Cardiovascular
  name: Atrial fibrillation
  description: >-
    Atrial fibrillation (paroxysmal, with flutter in the Mayo proband) was
    present in all four PLN-HCM probands described up to 2011, against 21% in
    the 1,064-proband Mayo HCM cohort. Four cases cannot establish a frequency
    or a PLN-specific association, so no frequency band is assigned and no
    mechanism edge is drawn (see discussions).
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, given that the frequency of atrial fibrillation in our cohort is 21%, the identification of this arrhythmia in all four PLN-HCM mutation cases described to date is notable."
    explanation: Atrial fibrillation in every reported PLN-HCM proband.
- category: Cardiovascular
  name: Atrial flutter
  description: >-
    Paroxysmal atrial fibrillation/flutter in the Mayo L39X proband. A single
    case; no frequency is available for CMH18.
  phenotype_term:
    preferred_term: Atrial flutter
    term:
      id: HP:0004749
      label: Atrial flutter
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At this time, ECG (Figure 2A) and echocardiographic (Figure 2B) analysis revealed sinus bradycardia with paroxysmal atrial fibrillation/flutter"
    explanation: Paroxysmal atrial flutter alongside fibrillation in a single L39X proband.
- category: Cardiovascular
  name: Palpitations
  description: >-
    The presenting symptom in the Mayo L39X proband and in the Australian L39X
    proband. No cohort frequency exists.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
    explanation: Palpitations at presentation in the Australian L39X proband, as summarised by Landstrom et al.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was diagnosed at 51 years of age presenting with palpitations and was maintained on atenolol and amiodarone for approximately two years"
    explanation: Palpitations as the presenting symptom in the Mayo L39X proband.
- category: Cardiovascular
  name: Syncope
  description: Reported at presentation in the Australian L39X proband.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
    explanation: Syncope at presentation in a single L39X proband, as summarised by Landstrom et al.
- category: Cardiovascular
  name: Presyncope
  description: Episodic presyncope in the Mayo L39X proband before diagnosis.
  phenotype_term:
    preferred_term: Presyncope
    term:
      id: HP:0031972
      label: Presyncope
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
    explanation: Presyncope in a single L39X proband.
- category: Cardiovascular
  name: Dyspnea
  description: Reported in both L39X HCM probands; the Mayo proband also had presyncope.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
    explanation: Dyspnea in the Mayo L39X proband.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the L39X proband hosting this heterozygous mutation was a female and diagnosed late in life at 61 years of age with HCM upon development of palpitations, syncope and dyspnea, and demonstrated atrial fibrillation"
    explanation: Dyspnea at presentation in the Australian L39X proband, as summarised by Landstrom et al.
- category: Cardiovascular
  name: Chest pain
  description: Exertional and supine left-sided chest discomfort in the Mayo L39X proband.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over the next month he continued to develop episodic palpitations of increasing frequency, presyncope, dyspnea, and left-sided chest discomfort radiating to the left shoulder and arm"
    explanation: Chest discomfort in a single L39X proband.
- category: Cardiovascular
  name: Ventricular tachycardia
  description: >-
    Symptomatic non-sustained ventricular tachycardia with ventricular ectopy
    and conduction block in the Mayo L39X proband, who received an
    implantable cardioverter-defibrillator. No ventricular arrhythmia
    frequency is available for CMH18.
  phenotype_term:
    preferred_term: Non-sustained ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was found to have conduction block as well as ventricular ectopy with symptomatic non-sustained ventricular tachycardia for which he received an automatic internal cardioverter defibrillator."
    explanation: Non-sustained VT in a single L39X carrier.
- category: Cardiovascular
  name: Left atrial enlargement
  description: Left atrial enlargement with mild mitral regurgitation and no outflow obstruction in the Mayo L39X proband.
  phenotype_term:
    preferred_term: Left atrial enlargement
    term:
      id: HP:0031295
      label: Left atrial enlargement
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a MLVWT of 24 mm and left atrial enlargement with mild mitral valve regurgitation without resting or valsalva-induced left ventricular outflow tract obstruction"
    explanation: Echocardiographic left atrial enlargement in a single L39X proband.
- category: Cardiovascular
  name: Mitral regurgitation
  description: Mild mitral regurgitation in the Mayo L39X proband.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
    severity: MILD
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a MLVWT of 24 mm and left atrial enlargement with mild mitral valve regurgitation without resting or valsalva-induced left ventricular outflow tract obstruction"
    explanation: Mild mitral regurgitation in a single L39X proband.
- category: Cardiovascular
  name: Wolff-Parkinson-White syndrome
  description: >-
    The Mayo L39X proband was diagnosed with Wolff-Parkinson-White syndrome.
    Because ventricular pre-excitation with hypertrophy suggests the PRKAG2,
    Fabry and Danon phenocopies, those genes were tested and found negative.
    One case only; whether pre-excitation belongs to the PLN phenotype is
    unknown.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At this time, he was diagnosed with Wolff-Parkinson-White (WPW) syndrome due to abnormalities on resting ECG."
    explanation: WPW diagnosis in the L39X proband.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While, mutations in PRKAG2 have been associated with development of WPW, the proband was found to be PRKAG2 mutation negative"
    explanation: The main phenocopy explanation for WPW with hypertrophy was excluded.
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Not the CMH18 presentation itself but its documented end of the spectrum.
    Both L39stop homozygotes (in adolescence and early adulthood) and two
    heterozygous brothers from a second kindred (at 27 and 28 years)
    developed dilated cardiomyopathy. ClinGen lumps CMH18 with dilated
    cardiomyopathy 1P on a shared mechanism and cites this
    hypertrophic-to-dilated course in support.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Likewise, there are undoubtedly as-yet-unidentified genetic influences that can modify the PLN-L39stop phenotype, as strongly suggested by the development of dilated cardiomyopathy in two heterozygous subjects from one of our kindreds but ventricular hypertrophy with normal cardiac function in heterozygous individuals from the other kindred."
    explanation: Dilated rather than hypertrophic disease in some heterozygous carriers.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Heart failure requiring transplantation in adolescence or early adulthood
    in L39stop homozygotes. No heart failure or dilated cardiomyopathy was
    reported in the Mayo heterozygous pedigree.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
    explanation: Heart failure in homozygous carriers of the CMH18 allele.
genetic:
- name: PLN
  gene_term:
    preferred_term: PLN
    term:
      id: hgnc:9080
      label: PLN
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PLN (6q22.31) has a single coding exon encoding the 52-amino-acid
    phospholamban. relationship_type is CAUSATIVE on HCM-specific evidence:
    a heterozygous truncating allele cosegregates with HCM in a
    multigenerational family and was found independently in a second familial
    HCM cohort; heterozygotes in the original L39stop kindreds were
    hypertrophic; and in a large HCM case-series burden analysis PLN rare
    variation showed a Bonferroni-significant excess over ExAC reference
    samples. The
    attributable share is small (about 0.65% of probands). ClinGen has no
    PLN record filed against hypertrophic cardiomyopathy or against
    MONDO:0013475. Its Hypertrophic Cardiomyopathy Gene Curation Expert Panel
    lumped CMH18 (MIM 613874) with dilated cardiomyopathy 1P (MIM 609909) and
    classified PLN as Definitive (autosomal dominant) for intrinsic
    cardiomyopathy, MONDO:0000591. That is a broader disease concept than this
    entry, so it is cited as evidence and deliberately not recorded in
    gene_disease_validity. ClinGen's summary scores hypertrophic, dilated and
    arrhythmogenic PLN presentations together and does not grade the
    hypertrophic L39X and promoter alleles separately from p.Arg14del and
    p.Arg9Cys, whose mechanisms differ. Separately, ClinGen rates PLN
    Moderate for arrhythmogenic right ventricular cardiomyopathy, a different
    disease.
  variants:
  - name: PLN p.Leu39Ter
    description: >-
      c.116T>G (T116G), p.Leu39Ter, also written L39X or L39stop. Nonsense
      allele truncating phospholamban in transmembrane domain II; a functional
      null with no dominant-negative effect. Reported heterozygous in HCM
      probands from North America (Mayo Clinic) and Australia and in two
      kindreds studied in Athens, where heterozygotes were hypertrophic or, in one
      kindred, dilated, and homozygotes had lethal dilated cardiomyopathy.
      Absent from 600 reference alleles in the Mayo study. Landstrom et al.
      describe position 39 as a possible relative mutational hot spot.
    clinical_significance: PATHOGENIC
    type: nonsense
    evidence:
    - reference: PMID:21167350
      reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This mutation was absent in 600 reference alleles (200 African American, 400 Caucasian American)."
      explanation: Absence from controls in the Mayo study.
  - name: PLN promoter -77A>G
    description: >-
      Heterozygous A-to-G change 77 bp upstream of the transcription start
      site, in one Japanese woman with familial HCM diagnosed at 56 with
      paroxysmal atrial fibrillation; absent from 296 controls and raised
      promoter activity in neonatal rat cardiomyocytes. Pathogenicity is not
      established.
    type: promoter
    evidence:
    - reference: PMID:12705874
      reference_title: "Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This nucleotide change was not found in 296 control subjects."
      explanation: Absence from controls.
  - name: PLN promoter -42C>G
    description: >-
      Promoter variant in one Spanish family with late-onset benign apical
      HCM, including a healthy adult carrier; lowered promoter activity in
      reporter assays. Pathogenicity is not established.
    type: promoter
    evidence:
    - reference: PMID:16829191
      reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The PLN -42 C>G mutation is associated with a benign form of apical hypertrophic cardiomyopathy in this family, though the presence of a healthy adult carrier suggests that other genetic and environmental factors could be involved."
      explanation: Family-level association with incomplete penetrance.
  case_fractions:
  - population: Pooled hypertrophic cardiomyopathy proband cohorts (six cohorts, North American, Australian, Japanese, Spanish, Greek and European)
    case_fraction_percent: 0.65
    notes: >-
      Sum of coding-region L39X yield (2 of 1,595-1,605 probands, 0.13%) and
      control-absent promoter variants (7 of 1,343, 0.52%); the two
      denominators differ, and the promoter variants are not proven
      pathogenic, so this is an upper bound on the attributable share.
    evidence:
    - reference: PMID:21167350
      reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Incorporation of promoter variants identified which were not found in healthy control populations (7/1343, 0.52%) brings the overall yield of PLN genetic interrogation to 0.65% in HCM."
      explanation: Pooled PLN yield in HCM probands.
  - population: Unrelated hypertrophic cardiomyopathy index cases, Mayo Clinic
    case_fraction_percent: 0.094
    cohort_size: 1064
    notes: Coding-region (L39X) carriers only.
    evidence:
    - reference: PMID:21167350
      reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel."
      explanation: L39X frequency in the Mayo HCM cohort.
  evidence:
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare variants were less numerous in other well-characterized HCM genes (TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC1, PLN) and phenocopy genes (GLA, LAMP2, PRKAG2)"
    explanation: Names PLN among the established but low-yield HCM genes in a large case series.
  - reference: PMID:27532257
    reference_title: "Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For each of these genes there is a significant (P < 0.05 after Bonferroni correction) excess of variation in cases as compared with ExAC, thus confirming their association with disease"
    explanation: >-
      HCM-specific case-excess evidence: PLN rare variation is significantly
      enriched in HCM cases over population reference samples.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation cosegregated with incidence of HCM in a multigenerational family."
    explanation: Segregation evidence in an HCM family.
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While all HCM-positive members of this pedigree host the PLN-L39X mutation, the relatively small size of the reported family, and the number of individuals available for genotyping, prevents formal quantification of the strength of this cosegregation with a logarithm of the odds score."
    explanation: >-
      The authors' own limit on that segregation evidence: too few relatives
      for a LOD score.
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLN | HGNC:9080 | intrinsic cardiomyopathy | MONDO:0000591 | AD | Definitive"
    explanation: >-
      ClinGen Definitive for the broader lumped entity, not for MONDO:0013475;
      cited as evidence only (see notes).
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "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)"
    explanation: ClinGen's lumping of this entry's disease with the allelic dilated form.
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "PLN reached a definitive classification, with the phenotype spectrum including HCM, arrhythmogenic right ventricular cardiomyopathy, and dilated cardiomyopathy."
    explanation: >-
      The published ClinGen HCM gene curation, which placed PLN under intrinsic
      cardiomyopathy rather than HCM alone.
  - reference: PMID:34526680
    reference_title: "Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients."
    explanation: Places PLN among the minor, non-sarcomeric HCM genes.
diagnosis:
- name: Echocardiography
  description: >-
    Documents unexplained left ventricular wall thickening (MLVWT above 13 mm
    in the Mayo study), its septal or apical
    distribution, left atrial size and systolic function, and screens
    genotype-positive relatives.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each of the subjects met the clinical diagnostic criteria for HCM (i.e. MLVWT greater than 13 mm in the absence of other confounding diagnoses)."
    explanation: The echocardiographic diagnostic criterion applied to the PLN-screened cohort.
- name: Electrocardiography and Rhythm Monitoring
  description: >-
    Resting ECG and ambulatory monitoring for atrial fibrillation or flutter,
    pre-excitation, conduction block and non-sustained ventricular
    tachycardia, all reported in PLN-HCM carriers.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At this time, ECG (Figure 2A) and echocardiographic (Figure 2B) analysis revealed sinus bradycardia with paroxysmal atrial fibrillation/flutter"
    explanation: ECG detection of the atrial arrhythmia in the L39X proband.
- name: PLN Genetic Testing Including the Promoter
  description: >-
    Sequencing of PLN on a multigene cardiomyopathy panel. The coding region
    and promoter fit in two amplicons and background variation is very low,
    which favours inclusion; promoter coverage matters because several
    HCM-associated PLN variants are regulatory. A positive result should
    prompt phenocopy exclusion (PRKAG2, GLA, LAMP2) when pre-excitation is
    present, and cascade testing of relatives.
  diagnosis_term:
    preferred_term: PLN sequencing including promoter, with cascade testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible."
    explanation: Supports PLN testing on HCM panels.
progression:
- phase: Genotype-positive relative
  notes: >-
    Penetrance is incomplete and onset in reported probands is in the sixth or
    seventh decade, but a 3-year-old carrier was affected, so carriers need
    longitudinal review from childhood.
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, the younger daughter, who does not demonstrate features of HCM currently, has a 3 year-old, HCM phenotype-positive daughter. Both host the PLN-L39X mutation."
    explanation: An unaffected adult carrier and an affected child carrier in one pedigree.
- phase: Established hypertrophic cardiomyopathy
  notes: >-
    Hypertrophy with preserved or high ejection fraction, frequently with
    atrial fibrillation. A minority of heterozygotes, and all reported
    homozygotes, progress to ventricular dilatation and heart failure.
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, heterozygosity of PLN-L39stop was associated with hypertrophy in some members of both families and with overt dilated cardiomyopathy in other members."
    explanation: The hypertrophic and dilated outcomes of the heterozygous state.
treatments:
- name: Rate and Rhythm Control Pharmacotherapy
  description: >-
    No PLN-specific therapy exists; management follows general HCM practice.
    The Mayo L39X proband was treated with atenolol, then sotalol (amiodarone
    was stopped after thyrotoxicosis) and candesartan for palpitations and
    paroxysmal atrial fibrillation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atenolol
      term:
        id: CHEBI:2904
        label: atenolol
    - preferred_term: sotalol
      term:
        id: CHEBI:63622
        label: sotalol
    - preferred_term: amiodarone
      term:
        id: CHEBI:2663
        label: amiodarone
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was diagnosed at 51 years of age presenting with palpitations and was maintained on atenolol and amiodarone for approximately two years"
    explanation: Single-patient treatment history; no outcome data.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Placed in the Mayo L39X proband for symptomatic non-sustained ventricular
    tachycardia. Indications follow general HCM sudden-death risk criteria;
    no PLN-HCM-specific risk data exist.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Non-sustained ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was found to have conduction block as well as ventricular ectopy with symptomatic non-sustained ventricular tachycardia for which he received an automatic internal cardioverter defibrillator."
    explanation: ICD placement for NSVT in a CMH18 proband.
- name: Cascade Screening and Cardiac Surveillance of At-Risk Relatives
  description: >-
    Predictive testing of first- and second-degree relatives for the familial
    variant, with serial echocardiography and ECG in carriers. Incomplete
    penetrance means an unaffected adult carrier is not discharged.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cascade genetic and cardiac screening of at-risk relatives
    term:
      id: NCIT:C168126
      label: Cardiac Disease Screening
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an attempt to investigate whether this nonsense mutation might co-segregate with the proband's family history of HCM, we obtained genomic DNA from as many first and second degree relatives as possible"
    explanation: Family genotyping that identified an affected child carrier and an unaffected adult carrier.
- name: Genetic Counseling
  description: >-
    Counselling should cover autosomal dominant transmission with incomplete
    penetrance and variable expressivity, the possibility of later dilated
    cardiomyopathy, and the severe early dilated cardiomyopathy seen when a
    child inherits two L39X alleles (relevant to consanguineous or
    carrier-by-carrier couples).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "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"
    explanation: Supplies the inheritance and dosage information counselling must convey.
- name: Heart Transplantation
  description: >-
    Required in adolescence or early adulthood by L39stop homozygotes with
    end-stage dilated cardiomyopathy; not reported for heterozygous HCM.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
    explanation: Transplantation for the homozygous end of the allele's spectrum.
animal_models:
- name: Pln-null mouse
  species: Mouse
  genotype: Pln-/- (targeted germline ablation)
  publication: PMID:8062415
  description: >-
    Phospholamban-deficient mice develop normally, with faster relaxation,
    higher +/-dP/dt and raised SERCA calcium affinity, reaching baseline
    values equal to those of maximally beta-stimulated wild-type hearts. They
    do not develop heart failure even in advanced age, unlike human L39X
    homozygotes; hypertrophy is not reported in the cited work.
  modeled_mechanisms:
  - target: Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Complete phospholamban loss raises SERCA calcium affinity and basal contractility.
    limitations: >-
      Homozygous null rather than the heterozygous human state; mouse calcium
      handling relies more on SERCA than the human heart does.
    readouts:
    - name: Intraventricular pressure derivatives and SERCA calcium affinity
      target: Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
      direction: INCREASED
      interpretation: Contractility and pump calcium affinity rise without phospholamban.
      evidence:
      - reference: PMID:8062415
        reference_title: "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The first derivatives of intraventricular pressure (+/- dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca(2+)-ATPase for Ca2+ in the phospholamban-deficient hearts."
        explanation: Reports the contractility and calcium-affinity readouts.
    evidence:
    - reference: PMID:8062415
      reference_title: "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate."
      explanation: Supports the model as informative for the hypercontractility node.
  - target: Cardiomyocyte Hypertrophic Remodeling
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Lifelong hypercontractility in the null mouse is not followed by heart
      failure, the end stage of the human remodelling node; hypertrophy itself
      is not reported in the cited work.
    limitations: >-
      Species difference in reliance on phospholamban regulation; a complete
      null, not a heterozygote; hypertrophy has not been specifically assessed
      in heterozygous Pln mice in the cited work.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The hypertrophy endpoint that defines this node was not assessed in the
        cited null-mouse work; the failure to recapitulate rests on the absent
        heart-failure course, not on a measured absence of hypertrophy.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Whereas the PLN-null mouse displays chronically increased basal cardiac contractile function without developing heart failure, even in advanced age"
      explanation: The null mouse does not progress to the heart failure that ends the human remodelling course.
experimental_models:
- name: HEK-293 expression of PLN-L39stop
  description: >-
    Recombinant wild-type and L39stop phospholamban co-expressed with SERCA2a
    in HEK-293 cells (including a simulated heterozygous state), with calcium
    uptake, protein stability and localisation readouts.
  experimental_model_type: OTHER
  publication: PMID:12639993
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: PLN L39X Truncating Variant
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Expresses the patient allele and measures SERCA2a inhibition and protein stability.
    limitations: >-
      Heterologous non-cardiac cells with overexpression; does not reproduce
      the human myocardial context or the hypertrophic outcome.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
      explanation: Reports the loss-of-function readouts.
- name: Adult rat ventricular myocyte expression of PLN-L39stop
  description: >-
    Wild-type and L39stop phospholamban adenovirally expressed in
    isolated adult rat ventricular myocytes, with localisation, cell
    shortening and calcium-transient readouts.
  experimental_model_type: OTHER
  publication: PMID:12639993
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  modeled_mechanisms:
  - target: PLN L39X Truncating Variant
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Expresses the patient allele in adult cardiomyocytes and measures its localisation and functional effect.
    limitations: >-
      Rat myocytes with adenoviral overexpression on an endogenous rat Pln
      background; does not reproduce the human myocardial context or the
      hypertrophic outcome.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
      explanation: Reports the loss-of-function readouts.
discussions:
- discussion_id: pln_null_mouse_human_hypertrophy
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does partial or complete loss of phospholamban produce hypertrophy and
    later dilatation in humans when total loss in the mouse produces a
    lifelong hypercontractile heart without heart failure?
  attaches_to:
  - pathophysiology#Enhanced Sarcoplasmic Reticulum Calcium Uptake and Contractility
  - pathophysiology#Cardiomyocyte Hypertrophic Remodeling
  - animal_models#Mouse
  rationale: >-
    The mouse evidence is abundant and points the other way: Pln-null mice are
    hypercontractile, tolerate it into old age, and were once taken as a model
    for phospholamban suppression as heart-failure therapy. The human L39X
    carriers instead develop hypertrophy (heterozygotes) or lethal dilated
    cardiomyopathy (homozygotes). The causal chain in this entry therefore
    passes through a hypercontractility node shown only in the mouse and a
    hypertrophy step shown only in humans. No heterozygous Pln model and no
    patient-derived or isogenic L39X iPSC cardiomyocyte has been studied for
    hypertrophic signalling.
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy."
    explanation: Explicit statement of the species divergence.
  - reference: PMID:8062415
    reference_title: "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate."
    explanation: The mouse side of the mismatch.
- discussion_id: pln_dosage_direction_in_hcm
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do HCM-associated PLN alleles that should lower phospholamban (L39X,
    -42C>G) and one that should raise it (-77A>G) really converge on
    hypertrophy, and if so through what common step?
  attaches_to:
  - pathophysiology#PLN L39X Truncating Variant
  - pathophysiology#PLN Promoter Variant Altering Phospholamban Expression
  rationale: >-
    The truncating allele and the -42C>G promoter variant reduce functional
    phospholamban, whereas the -77A>G promoter variant increases promoter
    activity, which would strengthen SERCA2a inhibition. Each promoter
    variant rests on one proband or family and reporter assays in non-human
    or non-cardiac cells, and none has been shown to change phospholamban
    protein in human heart. ClinGen states that the specific genetic
    mechanism of PLN cardiomyopathy is unclear. Either the promoter variants
    are not causal, or PLN-related hypertrophy is a response to disturbed
    calcium regulation in either direction; current data cannot separate
    these.
  evidence:
  - reference: PMID:12705874
    reference_title: "Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the phospholamban promoter activity."
    explanation: The gain-of-expression direction.
  - reference: PMID:16829191
    reference_title: "Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN -42 C>G mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This mutation decreased phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines respectively."
    explanation: The loss-of-expression direction.
  - reference: CGGV:assertion_f49f65fb-a2df-4e86-9a89-da2325b207c8-2021-02-12T170000.000Z
    reference_title: "PLN / intrinsic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "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."
    explanation: ClinGen's own acknowledgement that the genetic mechanism is unresolved.
- discussion_id: pln_hcm_atrial_fibrillation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Is atrial fibrillation a specific feature of PLN-related HCM, and by what mechanism?
  attaches_to:
  - phenotypes#Atrial fibrillation
  rationale: >-
    All four PLN-HCM probands reported by 2011 had atrial fibrillation,
    against 21% in the general Mayo HCM cohort, but four late-diagnosed cases
    are too few to separate a gene effect from age, left atrial enlargement or
    ascertainment. No study has examined atrial calcium handling in PLN
    variant carriers, so the phenotype is left unconnected to the mechanism
    chain.
  evidence:
  - reference: PMID:21167350
    reference_title: "PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Again, further studies are required to elucidate any potential association between PLN function and atrial fibrillation."
    explanation: The authors flag the association as unexplained.
notes: >-
  GeneReviews: no PLN- or CMH18-specific chapter exists. The Nonsyndromic
  Hypertrophic Cardiomyopathy Overview (PMID:20301725) covers HCM generally
  and is tagged in references without evidence items. The clinical picture
  of CMH18 rests on four probands with HCM (two L39X, two promoter variants),
  the Mayo L39X pedigree and the two Athens L39stop kindreds, so
  symptoms and arrhythmias recorded here are single-case observations and no
  frequency bands are assigned. The p.Arg14del and p.Arg9Cys alleles cause
  dilated and arrhythmogenic cardiomyopathy through different mechanisms
  (SERCA2a superinhibition and protein kinase A trapping) and are curated in
  Dilated_Cardiomyopathy_1P, not here. No genotype-specific outcome data or
  trials exist for CMH18; management follows general HCM guidelines.
  Sudden cardiac death is not curated as a phenotype because no PLN-HCM
  carrier with sudden death is reported; the Mayo proband had no family
  history of it.
📚

References & Deep Research

References

4
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:21167350
PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing.
No top-level findings curated for this source.
PMID:12639993
Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.
No top-level findings curated for this source.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Hypertrophic Cardiomyopathy 18 (PLN, MONDO:0013475) · 2026-10-13T18:19:32Z · View source

New entry for CMH18 (PLN), replacing the stub. Deep research: research/Hypertrophic_Cardiomyopathy_18-deep-research-claude_code.md (claude_code provider; preflight-dr PASS, PLN mentioned 51 times); report treated as leads only, all claims re-sourced from cached references. Pathograph: L39X truncating variant (loss of SERCA2a inhibition, no dominant-negative effect) -> loss of phospholamban brake -> enhanced SR calcium uptake/contractility (mouse-null evidence, INDIRECT) -> hypertrophic remodelling (Haghighi 2003 hypothesis, INDIRECT_UNKNOWN_INTERMEDIATES) -> HCM, LVH, apical HCM, and (indirect) DCM and heart failure. A separate HYPOTHETICAL promoter-variant node records -77A>G (raises promoter activity) and -42C>G (lowers it). relationship_type CAUSATIVE on HCM-specific evidence (multigenerational L39X cosegregation, independent L39X in an Australian FHC cohort, hypertrophic heterozygotes in two kindreds, Bonferroni-significant HCM case excess in Walsh 2017). gene_disease_validity left empty: ClinGen's only PLN records are Definitive for intrinsic cardiomyopathy (MONDO:0000591, which explicitly lumps CMH18 with CMD1P) and Moderate for ARVC; neither is this entry's MONDO term, so the Definitive record is cited as evidence (list-gene-validity: other_disease). GeneReviews: only the HCM overview (PMID:20301725) applies; tagged. Discussions: mouse/human mismatch, opposing promoter-variant directions, unexplained atrial fibrillation association. Nine single-proband phenotypes (AF, symptoms, NSVT, LA enlargement, MR, WPW) are left without causal edges because no source links them to the mechanism. Validation: validate, validate-terms, count-verified-snippets 81/81, check-causal-targets, check-entity-refs, check-duplicate-keys, check-gene-validity, gene-activity grounding against origin/main, validate-disorders.

Claude Code ▸
Hypertrophic Cardiomyopathy 18 (CMH18; PLN-related HCM): Research Report
claude-haiku-5-5, claude-opus-5-5 8 citations 2026-10-13T13:40:26.926623

Hypertrophic Cardiomyopathy 18 (CMH18; PLN-related HCM): Research Report

Prepared 2026-10-13 for the dismech entry kb/disorders/Hypertrophic_Cardiomyopathy_18.yaml.

How the quotes were checked. Quotes marked [cache] were read word for word from files already in references_cache/: PMID:21167350, PMID:12610310, PMID:16432188, and the ClinGen CGGV: record. Quotes marked [web] came from PubMed abstracts through a summarising fetch tool. That tool limits quote length and is not guaranteed to be verbatim. Before using any [web] quote as a snippet, fetch the reference with just fetch-reference PMID:… and check it with just count-verified-snippets.

How the ontology IDs were checked. Only three identifiers were read from a source in this session: - MONDO:0013475, from the existing draft entry - HGNC:9080 and MONDO:0000591, from the cached ClinGen row

Every other CURIE below is a candidate written from memory. Look each one up before binding it, as the repo's term rule requires.

Executive summary

  • What it is. CMH18 is the OMIM-numbered form of familial hypertrophic cardiomyopathy caused by variants in PLN. PLN encodes phospholamban, a 52-amino-acid protein that inhibits the cardiac SR Ca²⁺ pump SERCA2a.
  • How much evidence there is. Very little. HCM-specific PLN evidence comes from a handful of probands:
  • the truncating variant p.Leu39Ter (L39X / L39stop), seen as a heterozygote in about three families;
  • two or three promoter variants: −77A>G, −42C>G, and further rare variants in the Mayo cohort.
  • How ClinGen handles it. ClinGen does not treat CMH18 as a separate disease. Its HCM Gene Curation Expert Panel merged CMH18 (MIM 613874) with dilated cardiomyopathy 1P (MIM 609909) into one entity, PLN / intrinsic cardiomyopathy (MONDO:0000591), autosomal dominant, rated Definitive (curated 2017, recurated 2021-02-12).
  • Mechanism. The disease follows from abnormal SERCA2a regulation and abnormal Ca²⁺ cycling in cardiomyocytes. L39X behaves as a dose-dependent null allele:
  • heterozygotes develop hypertrophy with preserved systolic function;
  • homozygotes develop lethal dilated cardiomyopathy (DCM).
  • A naming trap to avoid. The well-known PLN p.Arg14del founder variant (Netherlands, Greece) and p.Arg9Cys cause mainly DCM and arrhythmogenic cardiomyopathy, not CMH18. Cite them only as context for the shared mechanism. Do not use them as evidence for HCM phenotypes.

1. Disease information

Overview. Landstrom et al. (2011) frame HCM as "unexplained cardiac hypertrophy" affecting ~1 in 500 people [cache, PMID:21167350]. CMH18 is the subset attributed to PLN, usually found in families whose sarcomere-gene panel came back negative.

Identifiers

System ID Status
MONDO MONDO:0013475 "hypertrophic cardiomyopathy 18" from draft entry; confirm label with just validate-terms
OMIM (phenotype) 613874 stated in ClinGen record [cache]
OMIM (gene PLN) 172405 web search (OMIM mirror)
HGNC PLN, HGNC:9080 (write as hgnc:9080) ClinGen row [cache]
ClinGen lumped entity MONDO:0000591 intrinsic cardiomyopathy [cache]
Orphanet No CMH18-specific ORPHA code found. Orphanet's familial isolated HCM entry is a candidate parent; check references_cache/ORPHA_* not verified
ICD-10-CM I42.1 / I42.2 (obstructive / other HCM) standard; not specific to CMH18

Synonyms. CMH18; cardiomyopathy, hypertrophic, 18; PLN-related HCM; familial hypertrophic cardiomyopathy 18.

Data provenance. Everything here comes from aggregated, disease-level resources (OMIM, ClinGen) and from family and case reports. There is no EHR or registry dataset specific to CMH18.

2. Etiology

Primary cause. Germline heterozygous PLN variants: truncating (L39X) and promoter (regulatory).

Key evidence

  • Chiu et al. 2007 (PMID:17655857) screened 252 unrelated Australian familial HCM probands across 7 Ca²⁺-handling genes. They found a novel PLN Leu39Ter and concluded that "mutations in Ca(2+) handling genes are an infrequent but important cause of FHC" [web].
  • Landstrom et al. 2011 (PMID:21167350) [cache]:
  • "one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel."
  • "This mutation cosegregated with incidence of HCM in a multigenerational family."
  • "we identified an overall yield of PLN-HCM mutations of 0.65%"
  • Minamisawa et al. 2003 (PMID:12705874) found a heterozygous promoter variant −77A>G in 1 of 87 HCM patients. It was absent from 296 controls, and "the mutation, -77A-->G, increased the phospholamban promoter activity" in neonatal rat cardiomyocytes [web].
  • Medin et al. 2007 (PMID:16829191) found a −42C>G promoter variant in a Spanish HCM patient with reduced penetrance. This is summarised in Landstrom 2011 [cache]; the Medin abstract itself was not read.

Risk factors. - Genetic: carrying a PLN variant; L39X dosage, since homozygosity shifts the phenotype to DCM. - Environmental: none documented for CMH18. - Protective factors and gene–environment interactions: none reported. - Common PLN promoter variant −36A>C: Landstrom saw no excess in HCM probands (8.3% vs 7.5% in Caucasian controls) [cache]. It should not be recorded as an HCM risk factor.

3. Phenotypes

Data are sparse. Each item below rests on single probands or small pedigrees. HPO IDs are candidates to verify.

Phenotype Evidence Onset Candidate HPO
Left ventricular / septal hypertrophy (the defining feature), septal and apical Landstrom proband: MLVWT 24 mm, "septal and apical HCM" [cache]; Haghighi 2003 heterozygotes "exhibited hypertrophy without diminished contractile performance" [web] Adult (diagnosed at 51, 56, 61 and 67 in the reported probands); one 3-year-old carrier was affected HP:0001639 Hypertrophic cardiomyopathy; HP:0001712 Left ventricular hypertrophy
Preserved ejection fraction / no LVOT obstruction (in the Landstrom proband) "normal ejection fraction of 68%… without resting or valsalva-induced left ventricular outflow tract obstruction" [cache] — — (a negative finding; use as a note)
Atrial fibrillation / flutter Landstrom: "the identification of this arrhythmia in all four PLN-HCM mutation cases described to date is notable" (vs 21% in the whole cohort) [cache] Adult HP:0005110 Atrial fibrillation; HP:0004749 Atrial flutter
Palpitations, presyncope, dyspnea, chest pain Landstrom proband [cache] Adult HP:0001962; HP:0100660 (dyskinesia? — verify; presyncope term to look up); HP:0002094 Dyspnea; HP:0100749 Chest pain
Non-sustained ventricular tachycardia, conduction block; ICD implanted Landstrom proband [cache] Adult HP:0004756 Ventricular tachycardia (verify the NSVT term); HP:0011675 Arrhythmia
Left atrial enlargement, mild mitral regurgitation Landstrom proband [cache] Adult HP:0031295 Left atrial enlargement (verify); HP:0001653 Mitral regurgitation
Ventricular pre-excitation (WPW) Landstrom proband; PRKAG2, GLA and LAMP2 all negative [cache] Adult HP:0001715? (verify; Wolff-Parkinson-White term)
Progression to DCM / heart failure (homozygotes; possibly some heterozygotes) Homozygous L39X: DCM, transplant "at ages 16 and 27" [web, PMID:12639993]; ClinGen: "a progressive cardiomyopathy beginning with hypertrophic and leading to dilated has been observed in a proband" [cache] Adolescent to young adult (homozygotes) HP:0001644 Dilated cardiomyopathy; HP:0001635 Congestive heart failure

No quality-of-life data exist for CMH18. General HCM instruments (KCCQ, NYHA class) apply.

4. Genetic and molecular information

Gene. PLN (6q22.31) has a single coding exon and encodes a 52-amino-acid SR transmembrane protein. ClinGen [cache]: - "PLN is encoded by one exon … many of the mutations (even LOF) result in a protein product." - "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."

Variants attributed to HCM

Variant Type Functional effect Source
c.116T>G p.Leu39Ter (L39X) Nonsense Null: no SERCA inhibition; protein unstable or mislocalised; "no detectable PLN protein" in a homozygous explanted heart [web] PMID:12639993, PMID:17655857, PMID:21167350
−77A>G (promoter) Regulatory Higher promoter activity, i.e. more PLN, i.e. more SERCA inhibition (inferred) PMID:12705874
−42C>G (promoter) Regulatory Reduced penetrance; function not established here PMID:16829191
C>T −235, A>C −198, A>G −120, T>C −114, G>T −47 (promoter) Regulatory, rare Unknown; absent from 600 control alleles PMID:21167350 [cache]

Landstrom also reports that "We did not observe any PLN coding sequence genetic variation in 600 reference alleles" [cache]. Check gnomAD for L39X before writing any allele frequency.

Mechanism by variant. L39X is a loss-of-function allele with a dosage effect (ClinGen calls it "semidominance") [cache]. The promoter variants plausibly cause gain of expression, but this is shown in vitro only.

Other points - Germline origin. - No modifier genes, epigenetic data or chromosomal abnormalities have been reported for CMH18. - ClinGen validity: Definitive, AD, for intrinsic cardiomyopathy (MONDO:0000591). That record's MONDO is not CMH18's disease_term. Under the repo's rules it is a "broader ClinGen lumping": cite it as evidence, but do not record it as a gene_disease_validity assertion for MONDO:0013475 unless an exactMatch mapping justifies it. The ARVC/Moderate record is a separate disease.

5. Environmental information

None documented. No infectious agent is involved.

6. Mechanism / pathophysiology

Causal chain (L39X arm; steps marked inferred are not directly shown in CMH18 patients)

  1. Heterozygous PLN L39X produces truncated phospholamban that is unstable or mislocalised. Cell work shows "no PLN inhibition of SR Ca(2+)-ATPase" [web, PMID:12639993]. The result is reduced functional PLN dosage.
  2. Less PLN means SERCA2a is released from inhibition: faster SR Ca²⁺ reuptake and altered Ca²⁺ transients. The mouse evidence is Luo 1994: PLN-null mice "exhibited enhanced myocardial performance" and PLN "acts as a critical repressor of basal myocardial contractility" [web, PMID:8062415].
  3. Chronically altered Ca²⁺ cycling then leads to Ca²⁺-dependent hypertrophic signalling in cardiomyocytes, with left ventricular hypertrophy and preserved contractility in heterozygotes. Inferred: no study of a CMH18 patient has shown the specific signalling pathway (calcineurin–NFAT or CaMKII).
  4. Branch A (heterozygote). HCM with atrial fibrillation and ventricular ectopy or NSVT. The association with AF is notable but unexplained: "further studies are required to elucidate any potential association between PLN function and atrial fibrillation" [cache].
  5. Branch B (homozygote, total loss). Lethal DCM and heart failure, needing transplant in adolescence or young adulthood. Human PLN loss is therefore harmful, unlike in mice. This is a HUMAN_MODEL_MISMATCH candidate.
  6. ClinGen synthesis [cache]: "the overall disease mechanism for PLN associated cardiomyopathy is dysregulation of SERCA2 function, Ca2+ handling, and disrupted relaxation and contraction of the heart."

Promoter arm. The −77A>G variant increases promoter activity, which should mean more PLN and more SERCA2a inhibition. That is the opposite direction to L39X. Why both directions would end in HCM is unresolved; record it as a knowledge gap.

Contrast, for context only. R9C traps PKA and blocks PLN phosphorylation [cache, PMID:12610310]. R14del "superinhibits" SERCA [cache, PMID:16432188]. Both cause DCM.

Ontology suggestions (verify)

Kind Candidates
GO regulation of calcium ion transport into the sarcoplasmic reticulum; negative regulation of calcium ion-transporting ATPase activity (PLN's normal function); cardiac muscle hypertrophy (GO:0003300); regulation of cardiac muscle contraction by calcium ion signaling; release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
GO cellular component sarcoplasmic reticulum membrane (GO:0033017)
CL cardiac muscle cell (CL:0000746); ventricular cardiac muscle cell; atrial cardiac muscle cell (for AF)
CHEBI calcium(2+) (CHEBI:29108)

There are no omics, single-cell or CRISPR-screen data specific to CMH18.

7. Anatomical structures

  • Organ and system: heart; cardiovascular system.
  • Sites: interventricular septum, LV apex, left atrium.
  • Tissue and cell: myocardium; ventricular and atrial cardiomyocytes.
  • Subcellular: sarcoplasmic reticulum membrane.
  • Laterality: left-sided predominance.
  • Candidate UBERON terms: heart (UBERON:0000948), interventricular septum (UBERON:0002094), left cardiac atrium (UBERON:0002079), myocardium (UBERON:0002349).

8. Temporal development

  • Onset: typically adult, diagnosed at 51–67 in the reported probands. One heterozygous child was phenotype-positive at 3 years [cache]. Onset is insidious.
  • Course: chronic and lifelong. Progression to DCM has been seen in homozygotes, and ClinGen notes a hypertrophic-to-dilated course [cache].
  • Penetrance: incomplete. A 38-year-old carrier daughter was unaffected [cache].
  • Staging: no CMH18-specific staging exists.

9. Inheritance and population

  • Inheritance: autosomal dominant with incomplete penetrance. Recessive or semidominant dosage applies for L39X homozygotes [cache: "autosomal recessive inheritance has been noted and appears to follow a dosage effect or semidominance"]. Candidate HPO terms: HP:0000006 Autosomal dominant inheritance; HP:0003829 Typified by incomplete penetrance.
  • Frequency: PLN accounts for ~0.65% of panel-negative HCM probands, counting promoter variants, and 0.13% for coding L39X alone [cache].
  • Prevalence: no population figure exists for CMH18. Background HCM prevalence is about 1/500.
  • Populations: probands have been reported as Caucasian North American, Australian, Japanese, Spanish and Greek (the L39X families in Haghighi 2003).
  • Not reported: founder effect, sex ratio, anticipation, mosaicism.

10. Diagnostics

  • Imaging: echocardiography and CMR showing maximal LV wall thickness of at least 13–15 mm without another cause.
  • ECG: AF, pre-excitation, conduction block.
  • Monitoring: ambulatory ECG for NSVT.
  • Genetic testing: a multigene cardiomyopathy panel that includes PLN. Landstrom argues PLN's small size (two amplicons) and very low background variation make it easy to add to panels [cache]. Promoter coverage matters, because several HCM-linked variants are regulatory.
  • Differential diagnosis: sarcomeric HCM; phenocopies such as PRKAG2 (which causes WPW), Fabry (GLA), Danon (LAMP2), and amyloid; athlete's heart; hypertensive LVH.
  • Cascade screening: first-degree relatives, following the 2024 AHA/ACC HCM guideline (PMID:38718139 / 38727647).
  • Candidate NCIT diagnostic actions: echocardiography, electrocardiography, genetic testing.

11. Outcome and prognosis

There are no survival data specific to CMH18. - Heterozygotes: HCM with arrhythmia burden; ICD implanted in the Mayo proband. - Homozygotes: end-stage DCM requiring transplant at 16 and 27.

General HCM prognosis and sudden-death risk models apply (PMID:40088231 validates the guideline's SCD risk recommendations).

12. Treatment

There is no PLN-specific therapy. Treatment follows general HCM management (2024 AHA/ACC guideline, PMID:38718139).

Treatment Notes Candidate NCIT
β-blockers, non-dihydropyridine CCB, sotalol/amiodarone The proband was treated with atenolol, amiodarone, sotalol and candesartan [cache] NCIT:C15986 Pharmacotherapy + therapeutic_agent
Mavacamten (cardiac myosin inhibitor) For obstructive HCM (EXPLORER-HCM, PMID:32871100). Its relevance to PLN-HCM without obstruction is unproven Pharmacotherapy
ICD implantation For NSVT/SCD risk; implanted in the Mayo proband Surgical Procedure + device qualifier
AF anticoagulation / ablation AF is common in PLN-HCM —
Heart transplantation Homozygous L39X DCM NCIT:C15289 Organ Transplantation

Experimental. PLN-targeted approaches have been explored mainly for R14del DCM: antisense oligonucleotides, AAV-delivered inhibitory PLN, and gene editing. No trials target CMH18.

13. Prevention

  • No primary prevention.
  • Secondary: cascade genetic and clinical screening of relatives, with periodic echo and ECG for carriers given incomplete and variable-age penetrance.
  • Genetic counselling covering homozygosity risk (DCM) in consanguineous or carrier-by-carrier unions.
  • Tertiary: SCD risk stratification and AF management.

14. Other species

No naturally occurring PLN-HCM in animals was found (OMIA not searched in depth). PLN is highly conserved across vertebrates.

15. Model organisms

Model Relevance Fidelity / limitations
Pln-knockout mouse (Luo 1994, PMID:8062415) Hypercontractile, faster relaxation, no lethal DCM Fails to recapitulate the human null phenotype (human homozygous L39X causes DCM). This is the explicit "critical difference between mouse and human" (PMID:12639993 title)
Transgenic PLN-R9C mouse (PMID:12610310) DCM with premature death Different variant and phenotype (DCM)
Transgenic PLN-R14del mouse (PMID:16432188) DCM with premature death Different variant and phenotype
HEK-293 co-expression (L39X; R14del) In vitro SERCA inhibition assays No cardiomyocyte context
Neonatal rat cardiomyocyte promoter-reporter (−77A>G; PMID:12705874) Promoter activity Reporter assay only

There is no L39X-heterozygous animal or iPSC-cardiomyocyte HCM model. That is an open knowledge gap.

Curation notes for the dismech entry

  1. Lump/split. ClinGen merged CMH18 into PLN intrinsic cardiomyopathy. Keep CMH18 as a DISEASE entry, since the MONDO term exists, but quote the ClinGen lumping paragraph and note the overlap with DCM1P.
  2. Evidence already cached: PMID:21167350 (full text), PMID:12610310, PMID:16432188, and the CGGV PLN records. To fetch: PMID:12639993, 17655857, 12705874, 16829191, 8062415.
  3. Suggested discussion items:
  4. a HUMAN_MODEL_MISMATCH for the mouse vs human PLN null;
  5. a KNOWLEDGE_GAP on why opposite directions of PLN dosage (L39X null vs promoter up-regulation) would both cause HCM;
  6. a KNOWLEDGE_GAP on the AF association.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 2
Quoted claims not found in source 1
References weighed for topical relevance 12
On topic 4
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:12639993: "critical difference between mouse and human"
  • closest text in source: "In this study, the surprising difference between human and mouse PLN-null cardiac phenotypes emphasizes the need to better understand inherent differences in cardiac physiology and Ca2+-cycling mechanisms between mice and humans (31)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 28
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 1
Terms whose name was checked 4
Terms named correctly 2
Terms named as a different term 0
Terms whose name is worth a second look 2

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0001715 (1 mention) - HP does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • MONDO:0000591 (4 mentions) - the report calls it "intrinsic cardiomyopathy", "ClinGen validity: Definitive, AD, for *intrinsic cardiomyopathy"; MONDO calls it intrinsic cardiomyopathy**
  • UBERON:0000948 (1 mention) - the report calls it "Candidate UBERON terms: heart"; UBERON calls it heart**, and lists "chambered heart" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0000591 - called "intrinsic cardiomyopathy", "ClinGen validity:* Definitive, AD, for intrinsic cardiomyopathy"