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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous ACTC1 missense variants transmitted as an autosomal dominant trait. The founding evidence is cosegregation in two unrelated kindreds with hereditary idiopathic dilated cardiomyopathy. A de novo heterozygous allele has also been reported in a sporadic infant case, so absence of family history does not exclude the diagnosis.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:9563954 SUPPORT DIRECT Human Clinical

"Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families."

The founding cosegregation evidence in two independent families, which is what established ACTC1 as a DCM gene.

PMID:39759977 SUPPORT DIRECT Human Clinical

"For this reason, it was very interesting to find that the ACTC1 mutation in the subject of study was not segregated by either of the parents, denoting its de novo origin"

A de novo heterozygous allele in a sporadic case, which is why a negative family history does not exclude an ACTC1 aetiology.

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z SUPPORT DIRECT Other

ClinGen records the mode of inheritance as autosomal dominant - and, in the same row, grades the strength of the ACTC1-DCM relationship as Moderate.

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Mechanistic Hypotheses

3

Thin-filament calcium-desensitization model

actc1_calcium_desensitization_model CANONICAL

Evidence balance 2 support 2 refute

The field's default account of sarcomeric cardiomyopathy: hypertrophic alleles increase the calcium sensitivity of the myofilament and dilated alleles decrease it, so at a given systolic calcium transient the mutant sarcomere generates less force, the ventricle is hypocontractile, and it dilates. Applied to ACTC1 this is the model that predicts the R312C/R312H split at a single codon. It is recorded as CANONICAL because it is the frame the whole literature is written against, not because ACTC1 confirms it - the direct measurements on the ACTC1 DCM alleles are inconsistent with it as often as not, which is the substance of the other two hypothesis groups.

The two REFUTE items disagree with each other as well as with the model - one laboratory reports R312H as calcium-sensitising and the other as desensitising. That disagreement is itself curated, in the knowledge-gap discussion, rather than resolved by picking a side.

Pathograph links

Altered Thin Filament Regulation of Actomyosin -> Left Ventricular Dilation and Systolic Dysfunction INDIRECT UNKNOWN INTERMEDIATES The direct route from a mis-regulated filament to a dilated ventricle, which the desensitisation and residual-activity models both assert and neither has demonstrated in an intact ACTC1 heart. Marked INDIRECT_UNKNOWN_INTERMEDIATES for that reason: the steps between an in vitro motility measurement and chamber remodelling are not filled in.

Show evidence (4 references)

PMID:39802493 SUPPORT DIRECT In Vitro

"HCM results from increases in calcium sensitivity and/or force production, while DCM results from reductions in these activities."

The model stated in its own terms by a group that then goes on to test it on ACTC1.

PMID:39802493 SUPPORT DIRECT In Vitro

"Characterization of variants of cardiac actin (ACTC) found in patients with HCM or DCM has generally supported the calcium sensitivity hypothesis."

The general-case support, quoted with its hedge intact. The same paper reports the specific failure below.

PMID:19799913 REFUTE DIRECT In Vitro

"In contrast when compared to WT actin, the R312H mutation increased Ca++-sensitivity for velocity in the motility assay without effecting myosin strong-binding activation at pCa 10."

A direct contradiction of the model for the principal ACTC1 DCM allele: the model requires R312H to be calcium-desensitising and this measurement makes it sensitising. Recorded as REFUTE rather than hidden in a note.

+ 1 more reference

Troponin-I phosphorylation uncoupling and loss of cardiac reserve

actc1_tni_phosphorylation_uncoupling_model ALTERNATIVE

Evidence balance 3 support

The model with the best in vivo support in ACTC1. Normally, PKA phosphorylation of troponin I during beta-adrenergic stimulation desensitises the myofilament to calcium, which speeds relaxation and supplies inotropic and lusitropic reserve. The ACTC1 E361G allele abolishes that phosphorylation-dependent shift: calcium sensitivity becomes fixed rather than modulable. The predicted consequence is a heart that is normal at rest and fails under demand, and that is exactly what the E361G mouse shows - unremarkable baseline contractility and cardiac dimensions out to eighteen months, a blunted response to dobutamine, and overt systolic dysfunction only after four weeks of angiotensin II stress. Under this model the primary lesion is a regulatory one, and dilation is the consequence of chronic inability to meet load rather than of weak sarcomeres.

Sourced entirely from one allele (E361G) in one transgenic line from one group. It is the most complete mechanistic account in ACTC1-DCM and also the narrowest, and no equivalent in vivo work exists for R312H.

Pathograph links

Altered Thin Filament Regulation of Actomyosin -> Loss of Adrenergic Contractile and Lusitropic Reserve DIRECT Under the uncoupling model, fixing calcium sensitivity so that troponin I phosphorylation no longer shifts it is precisely what removes the reserve.

Loss of Adrenergic Contractile and Lusitropic Reserve -> Left Ventricular Dilation and Systolic Dysfunction INDIRECT KNOWN INTERMEDIATES In the mouse this step required an experimental stress to appear: four weeks of angiotensin II infusion converted a normal-looking heart into a dilated, dysfunctional one, while wild-type animals were unaffected. Intermediates: Chronic haemodynamic or neurohormonal stress that a reserve-less ventricle cannot meet.

Show evidence (3 references)

PMID:20600154 SUPPORT DIRECT Model Organism

"We propose that the ACTC E361G mutation uncouples myofilament Ca(2+)-sensitivity from Troponin I phosphorylation and blunts the response to adrenergic stimulation, leading to a reduced cardiac reserve with consequent contractile dysfunction under stress, leading to dilated cardiomyopathy."

The model stated in full by the group that generated the mouse.

PMID:20600154 SUPPORT DIRECT Model Organism

"For NTG actin-containing thin filaments EC(50) native/dPTn=3.0+/-0.3 but for E361G-containing thin filaments EC(50) native/dPTn=1.04+/-0.07."

The measurement the model rests on: wild-type thin filaments shift threefold on troponin dephosphorylation, E361G filaments do not shift at all.

PMID:26432839 SUPPORT DIRECT Model Organism

"Thus as predicted, the uncoupling of the relationship between Ca2+ sensitivity and TnI phosphorylation by theACTCE361G DCM-causing mutation results in reduced physiological cardiac reserve."

The prediction tested in intact heart muscle five years later, closing the loop from the reconstituted-filament measurement to whole-organ physiology.

Residual myosin activity under relaxing conditions

actc1_residual_activity_relaxation_model EMERGING

Evidence balance 4 support

The newest proposal, and the one that most directly displaces calcium sensitivity as the discriminator. Characterising R312C and R312H side by side, both variants shifted calcium sensitivity in the same direction, but they differed in how much actomyosin activity persisted at pCa 10, where tropomyosin should be blocking myosin entirely. R312H filaments were the most active of the three under those relaxing conditions - every filament moved, where some wild-type filaments did not - while producing lower force under load. The proposal is that a sarcomere which never fully switches off cannot relax properly, and that chronic failure of relaxation, not weak contraction, is what dilates the ventricle.

The same 2024 paper notes that this has a therapeutic consequence which cuts against standard reasoning: a myosin activator, the intuitive drug for a hypocontractile DCM, would amplify the lesion if the lesion is excess resting activity.

Pathograph links

Altered Thin Filament Regulation of Actomyosin -> Left Ventricular Dilation and Systolic Dysfunction INDIRECT UNKNOWN INTERMEDIATES The direct route from a mis-regulated filament to a dilated ventricle, which the desensitisation and residual-activity models both assert and neither has demonstrated in an intact ACTC1 heart. Marked INDIRECT_UNKNOWN_INTERMEDIATES for that reason: the steps between an in vitro motility measurement and chamber remodelling are not filled in.

Show evidence (4 references)

PMID:39802493 SUPPORT DIRECT In Vitro

"We observed a gradient of increased residual myosin activity with R312-ACTC variant proteins under relaxing conditions which may trigger different disease development."

The proposal, stated with the authors' own hedge.

PMID:39802493 SUPPORT DIRECT In Vitro

"As opposed to WT-ACTC and R312C-ACTC where some filaments showed no movement, all R312H-ACTC filaments exhibited a velocity greater than zero."

The concrete observation behind it, at the level of individual filaments under conditions where none should be moving.

PMID:39802493 SUPPORT DIRECT In Vitro

"R312H-ACTC had the significantly lower displacement force while R312C-ACTC displacement force was significantly higher (Table 2)."

The force half of the same result, and the part that does fit the DCM direction: the DCM allele generates less force than wild type, the HCM allele more.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Does the ACTC1 R312H variant increase or decrease myofilament calcium sensitivity, and is the DCM allele hypocontractile at all?

KNOWLEDGE GAP OPEN cmd1r_r312h_biophysics_disagreement

Attached to

pathophysiology#Altered Thin Filament Regulation of Actomyosin mechanistic_hypotheses#actc1_calcium_desensitization_model

Three laboratories have measured R312H and reached incompatible answers. In 2010 it increased calcium sensitivity of velocity in the motility assay. In 2012 it had reduced thermal stability, a raised polymerisation critical concentration and markedly faster nucleotide release. In 2022 its melting temperature and polymerisation kinetics were indistinguishable from wild type, its calcium sensitivity was reduced rather than raised, and it was the most active of the three proteins under relaxing conditions. These are not small quantitative differences; they point in opposite directions on the axis the canonical model uses to separate DCM from HCM. Until they are reconciled, the mechanistic account of the principal ACTC1 DCM allele is unsettled, and this matters therapeutically: a myosin activator is the obvious drug for a hypocontractile sarcomere and would worsen one whose problem is that it never switches off.

Proposed experiments

Knock-in mouse or human iPSC-cardiomyocyte carrying ACTC1 R312H

cmd1r_exp_r312h_knockin_mouse

Generate a heterozygous R312H knock-in - in mouse, and independently in isogenic human iPSC-derived cardiomyocytes - and measure myofilament calcium sensitivity, resting tension, relaxation kinetics and contractile reserve in the same preparation, avoiding the recombinant-protein purification differences the authors themselves blame for the disagreement.

Would support

mechanistic_hypotheses#actc1_residual_activity_relaxation_model

Would refute

mechanistic_hypotheses#actc1_residual_activity_relaxation_model

Supporting outcome

Elevated resting tension and impaired relaxation with normal or near-normal peak systolic force, matching the residual-activity model rather than simple hypocontractility.

Refuting outcome

Reduced calcium sensitivity and reduced peak force with normal resting tension and normal relaxation, which would return the canonical desensitisation model to the field.

The 2022 authors propose a zebrafish knock-in as their own next step. A mammalian knock-in or an isogenic human iPSC pair is proposed here instead because the open question is calcium handling and adrenergic reserve, where zebrafish physiology diverges most.

Do human ACTC1 carriers actually have reduced contractile reserve before their ventricles dilate?

HUMAN MODEL MISMATCH OPEN cmd1r_no_human_reserve_measurement

Attached to

pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve

The most complete mechanistic account in this entry - troponin-I phosphorylation uncoupling producing a heart that is normal at rest and fails under stress - rests entirely on one transgenic mouse line carrying one allele, studied by one group. It is coherent and it is corroborated across reconstituted filaments, papillary muscle and intact animals, but every step of it is murine. No human CMD1R carrier has had contractile reserve measured. If the model is right it has an immediate clinical consequence: a genotype-positive relative with a normal resting echocardiogram might still be abnormal on stress testing, which would make stress echocardiography or cardiopulmonary exercise testing the right surveillance tool rather than serial resting imaging. If it is wrong, the mouse is describing a transgene artefact.

Proposed experiments

Stress echocardiography and cardiopulmonary exercise testing in genotype-positive ACTC1 carriers

cmd1r_exp_human_stress_echo

Recruit ACTC1 variant carriers identified by cascade screening, including those with normal resting ventricular dimensions and ejection fraction, and measure contractile and lusitropic reserve by dobutamine or exercise stress echocardiography alongside peak oxygen uptake, against genotype-negative relatives as controls.

Would support

pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve

Would refute

pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve

Supporting outcome

Blunted augmentation of ejection fraction and of relaxation indices on stress in carriers with normal resting studies, mirroring the dobutamine response of the E361G mouse.

Refuting outcome

Normal contractile and lusitropic reserve in phenotype-negative carriers, which would confine the uncoupling mechanism to the transgenic mouse and leave human dilation unexplained by it.

Is the sex difference in the zebrafish ACTC1 model - earlier diastolic dysfunction and worse survival in females - present in human ACTC1 carriers?

HUMAN MODEL MISMATCH OPEN cmd1r_zebrafish_sex_dimorphism

Attached to

animal_models#Zebrafish

The zebrafish acta1b p.T126I model reports pronounced sexual dimorphism as its central finding, with female mutants showing earlier and sustained diastolic dysfunction, greater remodelling and significantly lower survival. Human dilated cardiomyopathy in general does show sex differences, but in the opposite direction from what is usually assumed for sarcomeric disease, and no sex-stratified analysis of ACTC1 carriers exists. Two features make the translation genuinely uncertain rather than merely untested: the mutation is in a skeletal actin paralogue rather than a cardiac one, and zebrafish sex determination and cardiac physiology differ substantially from human. Recorded as a mismatch rather than a plain knowledge gap because the model evidence is strong and specific while its human validity is what is open.

Proposed experiments

Sex-stratified natural-history analysis of ACTC1 dilated-cardiomyopathy carriers

cmd1r_exp_sex_stratified_carriers

Pool ACTC1 DCM carriers across cardiomyopathy registries and analyse age at diagnosis, diastolic indices, remodelling and event-free survival stratified by sex, with non-ACTC1 sarcomeric DCM carriers as the comparison group so that any effect can be attributed to the gene rather than to DCM in general.

Would support

animal_models#Zebrafish

Would refute

animal_models#Zebrafish

Supporting outcome

Earlier onset and worse outcomes in female ACTC1 carriers relative to male carriers, and relative to the sex difference seen in non-ACTC1 sarcomeric DCM.

Refuting outcome

No sex difference in ACTC1 carriers beyond that seen in sarcomeric DCM generally, which would make the zebrafish dimorphism a property of the model rather than of the gene.

The anchor is `animal_models#Zebrafish` rather than the model's `name`, because the schema resolves `animal_models#` against the `species` slot. It reads oddly beside the model's own name and is nonetheless the correct reference.

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Pathophysiology

4

ACTC1 Missense Variant in Cardiac Alpha-Actin

Mechanism confidence: Established

A heterozygous missense substitution in cardiac alpha-actin, the monomer that polymerises into the thin filament. The DCM-associated alleles are single amino-acid changes at conserved residues; the two founding ones, R312H and E361G, lie in the parts of actin that engage the Z band and the intercalated disc rather than in the myosin-binding surface, which is why the original interpretation was a force-transmission defect. Notably, the intrinsic properties of the mutant protein are barely changed - polymerisation kinetics, melting temperature and DNase-I inhibition are close to wild type - so the lesion is in how the filament is regulated, not in whether it forms.

cardiac muscle cell CL:0000746

ACTC1 hgnc:143

actin filament binding within the cardiac thin filament GO:0051015 ⚠ ABNORMAL

Downstream

Altered Thin Filament Regulation of Actomyosin A substitution in the actin monomer changes the regulated filament it builds, which is the immediate molecular consequence.

Show evidence (5 references)

PMID:9563954 SUPPORT DIRECT Human Clinical

"Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs."

The structural localisation of the two founding alleles, and the basis for the original force-transmission interpretation.

PMID:9563954 SUPPORT INDIRECT Human Clinical

"these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure"

The authors' own inference, quoted with its hedge. Indirect: the sentence proposes a mechanism from variant position rather than reporting one measured.

PMID:39802493 SUPPORT DIRECT In Vitro

"Our results here, however, do not reflect major changes in overall actin structure for either the R312C- or R312H-ACTC proteins compared to WT-ACTC, with similar polymerization rates, melting temperatures and DNase-I inhibition IC50 values."

The negative result that localises the defect away from actin folding and polymerisation and toward filament regulation.

+ 2 more references

Altered Thin Filament Regulation of Actomyosin

Mechanism confidence: Provisional

The regulated thin filament - actin plus tropomyosin plus troponin - no longer switches between its blocked, closed and open states normally. What exactly goes wrong is where the three hypothesis groups diverge, and the downstream edges are tagged accordingly rather than being collapsed into one claim. Measurements that are agreed across laboratories: maximal calcium-activated filament velocity is reduced, and myosin's ADP release is slowed so it detaches more slowly. Measurements that are not agreed: the direction of the shift in calcium sensitivity, and whether the filament is fully inhibited in the absence of calcium.

Residual myosin activity under relaxing conditions Thin-filament calcium-desensitization model Troponin-I phosphorylation uncoupling and loss of cardiac reserve

cardiac muscle cell CL:0000746

regulation of cardiac muscle contraction by the thin filament GO:0055117 ↕ DYSREGULATED actin-myosin filament sliding GO:0033275 ↓ DECREASED

myofibril GO:0030016

Downstream

Loss of Adrenergic Contractile and Lusitropic Reserve Under the uncoupling model, fixing calcium sensitivity so that troponin I phosphorylation no longer shifts it is precisely what removes the reserve.

Left Ventricular Dilation and Systolic Dysfunction The direct route from a mis-regulated filament to a dilated ventricle, which the desensitisation and residual-activity models both assert and neither has demonstrated in an intact ACTC1 heart. Marked INDIRECT_UNKNOWN_INTERMEDIATES for that reason: the steps between an in vitro motility measurement and chamber remodelling are not filled in.

Show evidence (4 references)

PMID:19799913 SUPPORT DIRECT In Vitro

"Both the HCM (E99K) and DCM (R312H) human actin mutations resulted in significant reductions in maximal Ca++-regulated thin filament velocity."

One of the two findings that laboratories agree on, and notably one that does not separate the HCM allele from the DCM allele.

PMID:19799913 SUPPORT DIRECT In Vitro

"Without any demonstrable effect on k+ATP, these data suggest that both the E99K and the R312H mutation result in a decrease in ADP release kinetics"

The kinetic step behind the velocity reduction: slower ADP release keeps myosin bound to actin for longer.

PMID:22590617 SUPPORT DIRECT In Vitro

"The R312H variant exhibited reduced stability, with a T(m) of 53.6 °C compared to 56.8 °C for WT actin, accompanied with increased polymerization critical concentration and Pi release rate, and a marked increase in nucleotide release rates."

A third laboratory's measurements on R312H, which disagree with the 2022 report of near-normal melting temperature and polymerisation quoted on the node above. Both are recorded; the disagreement is the point.

+ 1 more reference

Loss of Adrenergic Contractile and Lusitropic Reserve

Mechanism confidence: Provisional

A ventricle that performs acceptably at rest but cannot increase its output or speed its relaxation when driven. In the E361G mouse, dobutamine raised cardiac output by 2,100 microlitres per minute in wild-type animals and only 900 in mutants, and the relaxation indices moved by a quarter to a third of the wild-type amount. Baseline cardiac dimensions and systolic function were essentially normal over four to eighteen months. The clinical reading is that CMD1R may be a disease of failed reserve, which would explain why human onset can be late and why an intercurrent stress can precipitate presentation.

Troponin-I phosphorylation uncoupling and loss of cardiac reserve

cardiac muscle cell CL:0000746

regulation of the force of heart contraction GO:0002026 ↓ DECREASED

myocardium UBERON:0002349

Animal models

ACTC E361G transgenic mouse Mouse recapitulates This node is defined by the mouse rather than merely supported by it. Blunted inotropic and lusitropic responses to dobutamine, measured by papillary muscle mechanics, conductance catheter and echocardiography, are the primary observations.

Downstream

Left Ventricular Dilation and Systolic Dysfunction In the mouse this step required an experimental stress to appear: four weeks of angiotensin II infusion converted a normal-looking heart into a dilated, dysfunctional one, while wild-type animals were unaffected.

Show evidence (3 references)

PMID:26432839 SUPPORT DIRECT Model Organism

"The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min."

The quantified loss of inotropic reserve.

PMID:26432839 SUPPORT DIRECT Model Organism

"Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response."

The lusitropic half, measured by conductance catheter in the intact animal.

PMID:20600154 SUPPORT DIRECT Model Organism

"We measured cardiac performance by cine-MRI, echocardiography and with a conductance catheter over a period of 4 to 18 months and found minimal systematic differences between NTG and ACTC E361G mice under basal conditions."

The baseline-normal half of the phenotype, which is what makes this a reserve defect rather than a resting contractile defect.

Left Ventricular Dilation and Systolic Dysfunction

Mechanism confidence: Established

The organ-level phenotype that defines the disease: a dilated left ventricle with impaired systolic contraction, in the absence of loading conditions or coronary disease sufficient to explain it. Severity spans the range - from an adult diagnosed at 36 to a one-year-old with severe dilation and dysfunction who died suddenly.

cardiac muscle cell CL:0000746

cardiac muscle contraction GO:0060048 ↓ DECREASED

heart left ventricle UBERON:0002084

Animal models

ACTC E361G transgenic mouse Mouse partially recapitulates The mouse reaches a dilated, dysfunctional ventricle, but only after four weeks of angiotensin II infusion, and it passes through a hypertrophic stage on the way.

Acta1b p.T126I zebrafish Zebrafish recapitulates Progressive dilation and pump failure arising without experimental provocation, which is the part of the human phenotype the mouse model does not reproduce unaided.

Downstream

Dilated Cardiomyopathy

Reduced Left Ventricular Ejection Fraction

Congestive Heart Failure

Show evidence (2 references)

PMID:39759977 SUPPORT DIRECT Human Clinical

"The present study details the clinical and genetic characterization of a malignant dilated cardiomyopathy (DCM) case in a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD."

The severe end of the reported range, with the chamber phenotype and the outcome in one sentence.

PMID:39802493 SUPPORT INDIRECT Human Clinical

"The R312H ACTC variant found in patients ranging in age from 2 years to 36 years of age was amongst the first linked to DCM"

The age range across reported R312H carriers. Indirect: this is a 2022 in vitro paper's summary of the clinical literature it builds on, not its own patient series.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Cardiovascular 3

Dilated Cardiomyopathy OBLIGATE HP:0001644

Show evidence (2 references)

PMID:9563954 SUPPORT DIRECT Human Clinical

"To test the hypothesis that actin dysfunction leads to heart failure, patients with hereditary idiopathic dilated cardiomyopathy (IDC) were examined for mutations in the cardiac actin gene (ACTC)."

The ascertainment: these families were collected as hereditary idiopathic DCM, which is the phenotype the gene was found in.

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z SUPPORT DIRECT Other

ClinGen's expert-panel assertion that this gene-disease pair exists, at Moderate strength.

Reduced Left Ventricular Ejection Fraction HP:0012664

No `frequency` is asserted. Impaired systolic contraction is definitional for DCM so the phenotype is certainly present, but no CMD1R series reports ejection fractions across a cohort, and FrequencyEnum has no value for "present but unquantified". A band here would have been a number invented from the disease definition rather than counted in ACTC1 carriers.

Show evidence (1 reference)

PMID:39759977 SUPPORT DIRECT Human Clinical

"a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD"

Severe systolic dysfunction in the one CMD1R case with detailed reporting.

Congestive Heart Failure HP:0001635

No `frequency` is asserted. No CMD1R report gives a proportion of carriers reaching symptomatic heart failure, and a grade derived from the disease definition rather than from a counted series would be a fabricated denominator.

Show evidence (1 reference)

PMID:9563954 SUPPORT INDIRECT Human Clinical

"Coupled with previous data showing that dystrophin mutations also cause dilated cardiomyopathy, these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure."

Indirect: the sentence frames DCM as a heritable form of heart failure rather than reporting heart-failure events in the ACTC families, whose clinical detail is not in the cached abstract.

Constitutional 1

Sudden Death HP:0001699

No `frequency` is asserted, and this is the case where a band would have been most misleading. The evidence is a single infant who also carried a TTN variant. No arrhythmic risk estimate exists for CMD1R, and none should be inferred from this entry.

Show evidence (2 references)

PMID:39759977 SUPPORT DIRECT Human Clinical

"a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD"

The sudden-death outcome in the reported infant case.

PMID:39759977 NO_EVIDENCE DIRECT Human Clinical

"it is also suggestive that the cause of the malignant condition reported here may be derived from a polygenic synergistic effect of both ACTC1 and TTN variants, where this double hit is necessary to impair the phenotypic manifestation of an early and severe DCM"

Recorded as NO_EVIDENCE because the authors themselves raise the possibility that the severity required both variants, which means this case does not establish that an ACTC1 allele alone confers this outcome. It bears on interpretation without supporting or refuting the phenotype claim.

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Genetic Associations

1

ACTC1

Gene: ACTC1 hgnc:143 relationship_type: CAUSATIVE

Show evidence (4 references)

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z SUPPORT DIRECT Other

The ClinGen DCM expert panel assertion, at Moderate strength, dated 2026-03-04, and keyed directly to MONDO:0013261 rather than to the generic dilated-cardiomyopathy term.

CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z SUPPORT INDIRECT Other

The comparison that makes the Moderate grade above meaningful: the same gene is Definitive for the other cardiomyopathy. Indirect for a DCM entry, and included solely to fix the evidential asymmetry in place.

PMID:37457373 SUPPORT INDIRECT Human Clinical

"Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction."

The allelic spectrum of the gene stated in one sentence. Cited only for that scoping purpose - the study itself is about distal arthrogryposis and contributes nothing to the DCM mechanism.

+ 1 more reference

Variants (4)

p.Arg312His (R312H) Pathogenic

Gene: ACTC1 hgnc:143 missense variant

The principal DCM allele and one of the two identified in 1998. Its interest is that the same codon carries an HCM allele: R312C is found in hypertrophic cardiomyopathy patients and R312H in dilated cardiomyopathy patients, which makes this pair the cleanest available demonstration that in ACTC1 the allele determines the phenotype. The biophysical characterisation of R312H is inconsistent across laboratories and is the basis for the three hypothesis groups in this entry. One source notes it has also been seen in HCM patients, so even this allele is not phenotypically exclusive.

Show evidence (3 references)

PMID:39802493 SUPPORT DIRECT In Vitro

"Of interest are two different substitution mutations at R312 on ACTC: R312H leads to DCM, while R312C was found in patients with HCM."

The allele-determines-phenotype statement at a single codon.

PMID:39510186 SUPPORT INDIRECT Human Clinical

"Though the pathogenicity is difficult to determine, R312C was found in patients clinically presenting with HCM (4), while R312H has been found in both HCM and DCM patients (3)"

The important qualifier, and the reason this entry does not claim a clean one-allele one-disease rule: R312H itself has been reported in both phenotypes. Indirect because it is this paper's summary of the clinical literature rather than its own cohort.

PMID:22590617 SUPPORT DIRECT In Vitro

"The two ACTC mutants associated with DCM are R312H and E361G."

Names this allele as one of the two ACTC1 variants associated with dilated cardiomyopathy, which is the attribution the 1998 abstract leaves implicit.

p.Glu361Gly (E361G) Pathogenic

Gene: ACTC1 hgnc:143 missense variant

The second 1998 allele, and the only ACTC1 DCM variant modelled in a transgenic animal. All of the in vivo mechanistic evidence in this entry comes from that mouse.

Show evidence (2 references)

PMID:20600154 SUPPORT INDIRECT Model Organism

"We have investigated a transgenic mouse model of inherited dilated cardiomyopathy that stably expresses the ACTC E361G mutation at around 50% of total actin in the heart."

Names the allele and its identity as an inherited DCM mutation. Indirect for the human variant claim because this is the mouse paper; the human ascertainment is in the 1998 report.

PMID:22590617 SUPPORT DIRECT In Vitro

"The two ACTC mutants associated with DCM are R312H and E361G."

Names this allele as one of the two ACTC1 variants associated with dilated cardiomyopathy, which is the attribution the 1998 abstract leaves implicit.

p.Thr126Ile (T126I)

Gene: ACTC1 hgnc:143 missense variant

A DCM-associated ACTC1 allele modelled in zebrafish through the orthologous Acta1b substitution. No human clinical report of this allele is cited here; it enters the entry through the animal model, which is why no clinical_significance is asserted for it.

Show evidence (1 reference)

PMID:42563511 SUPPORT INDIRECT Model Organism

"Although sarcomere mutations such as cardiac actin ACTC1 p.T126I contribute to familial DCM, the in vivo effects and sex-specific consequences remain unclear."

Names the allele and assigns it to familial DCM. Indirect for a human-variant claim: this is the introductory framing of a zebrafish paper, not a clinical report, which is why the entry does not grade the allele's pathogenicity.

p.Ala222Thr (c.664G>A) Likely Pathogenic

Gene: ACTC1 hgnc:143 missense variant

A de novo allele in a one-year-old with severe DCM and sudden cardiac death. Absent from gnomAD and the other control databases, and reported in ClinVar by other submitters, including two likely-pathogenic de novo DCM classifications. The case also carried a paternally inherited TTN variant classified as uncertain, and the authors do not attribute the phenotype to ACTC1 alone.

Show evidence (2 references)

PMID:39759977 SUPPORT DIRECT Human Clinical

"Notwithstanding, it is of important notice that there are five previous reports of this variant from different submitters in ClinVar database, two of them being classified as likely pathogenic in DCM cases also with a de novo origin."

Independent ClinVar submissions of the same allele in DCM, which is the basis for the LIKELY_PATHOGENIC grade rather than the single case alone.

PMID:39759977 SUPPORT DIRECT Human Clinical

"Ala222Thr variant in the available literature or in databases such as PubMed, and it is absent in control cohorts as 1000 genomes, exome sequencing project, the exome aggregation consortium (ExAC), or the genome aggregation database (gnomAD)."

Absence from population databases, the rarity criterion.

💊

Medical Actions

4

Guideline-Directed Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin receptor-neprilysin inhibitor NCIT:C190796 ACE inhibitor NCIT:C247 evidence-based beta blocker NCIT:C29576 mineralocorticoid receptor antagonist NCIT:C101255 SGLT2 inhibitor NCIT:C98083

Platform: Small molecule

Standard medical therapy for heart failure with reduced ejection fraction: the four contemporary pillars - an angiotensin receptor-neprilysin inhibitor or ACE inhibitor or ARB, an evidence-based beta blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor - with diuresis for congestion as required. It is not directed at the actin lesion, and no CMD1R outcome data exist. Recorded because it is what these patients actually receive, and without an efficacy claim.

Implantable Cardioverter Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

Device therapy for prevention of sudden cardiac death, indicated by general cardiomyopathy and arrhythmia criteria. There is no ACTC1-specific arrhythmic risk stratification, and the single reported sudden death in a CMD1R patient occurred in an infant who also carried a TTN variant, which is not a basis for a genotype-specific rule.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Platform: Surgery

The endpoint for refractory advanced heart failure, on the same criteria as any other dilated cardiomyopathy. No CMD1R-specific transplant series exists.

Cascade Screening of At-Risk Relatives

Action: genetic screening of at-risk relatives Ontology label: Genetic Screening NCIT:C92803

Platform: Other

Cardiac surveillance of first-degree relatives with genetic testing where the familial variant is known. The rationale in CMD1R is the disease's own history: the gene was found by cosegregation in families, and the E361G mouse suggests carriers may look normal at rest until stressed, which is an argument for imaging relatives rather than waiting for symptoms. Contemporary implementation guidance for genotype-positive relatives of any cardiomyopathy gene suggests ECG plus echocardiography every one to three years before age sixty and every three to five years thereafter, individualised by variant, family history and phenotype. That interval is general cardiomyopathy practice, not an ACTC1 finding, and no CMD1R-specific surveillance schedule has been validated.

Show evidence (1 reference)

PMID:20301486 SUPPORT INDIRECT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic"

GeneReviews names risk assessment of asymptomatic relatives as one of the overview's purposes. Quoted short because the cached record for this chapter holds only the front matter, and indirect because it is generic to DCM rather than to ACTC1.

🔬

Diagnosis

1

Genetic testing on a dilated cardiomyopathy panel

CMD1R has no distinguishing clinical or imaging feature. It is diagnosed by finding a pathogenic ACTC1 variant in a patient whose ventricle is dilated and hypocontractile without an adequate acquired explanation, usually on a multigene cardiomyopathy panel or exome sequencing. Two interpretation problems are specific to this gene. First, the ACTC1 result must be read against the phenotype: the same gene yields HCM, LVNC, atrial septal defect and a skeletal-muscle syndrome, so the variant, not the gene, carries the diagnosis. Second, ClinGen grades the gene-disease relationship for DCM as Moderate, which is the tier at which a variant of uncertain significance should not be over-read.

Show evidence (2 references)

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z SUPPORT DIRECT Other

The validity grade that should temper interpretation of an ACTC1 finding in a DCM patient.

PMID:37457373 SUPPORT INDIRECT Human Clinical

"Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction."

Why an ACTC1 hit does not by itself make a CMD1R diagnosis: four other phenotypes share the gene.

📈

Progression

2

Infantile severe presentation

The severe extreme of the reported range. A one-year-old with severe left ventricular dilation and dysfunction, carrying a de novo ACTC1 p.Ala222Thr allele together with a paternally inherited TTN variant, died suddenly. The fatal outcome is recorded here rather than as a phenotype because HPO files death in infancy under clinical course. The double genotype means this case cannot be used to characterise the ACTC1 allele on its own.

Show evidence (1 reference)

PMID:39759977 SUPPORT DIRECT Human Clinical

"In conclusion, our findings suggest a likely pathogenic de novo mutation in ACTC1 in coexpression of a TTN variant as possible causes of an early onset of a severe DCM and premature death."

The authors' conclusion, quoted with both variants named, because the attribution to ACTC1 alone is exactly what they decline to make.

Adult-onset dilated cardiomyopathy

The typical presentation, and the one the founding families represent: hereditary idiopathic dilated cardiomyopathy diagnosed in adulthood. Across reported R312H carriers the age range runs from two to thirty-six years, so childhood presentation is possible but the mode is adult. The E361G mouse suggests a mechanism for late onset - the heart is normal until it is stressed - but that link has not been tested in patients.

Show evidence (1 reference)

PMID:39802493 SUPPORT INDIRECT Human Clinical

"The R312H ACTC variant found in patients ranging in age from 2 years to 36 years of age was amongst the first linked to DCM [15]"

The reported age range for the principal DCM allele. Indirect because it is a citing summary rather than a primary clinical series.

📊

Prevalence

1

Reported literature

Cases In Literature Unknown

No population prevalence has been published for ACTC1-related dilated cardiomyopathy, and none is asserted here. What exists is a small set of reported families and cases beginning with the two 1998 kindreds. ACTC1 is not among the genes that account for most familial DCM; the strongest quantitative statement available about it is ClinGen's Moderate gene-disease validity grade, which is a statement about evidence rather than about frequency.

Show evidence (2 references)

PMID:9563954 SUPPORT DIRECT Human Clinical

"Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families."

The founding case count.

CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z SUPPORT INDIRECT Other

Indirect for a prevalence record: a Moderate rather than Definitive validity grade reflects a limited accumulated case count, which is why it is quoted here, but it is not a frequency measurement.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1R:

TTN-truncating and other higher-evidence genetic dilated cardiomyopathy

Overlapping Features TTN truncating variants are the commonest identifiable genetic cause of DCM, and LMNA, BAG3, FLNC, RBM20, DES and PLN account for much of the rest. All are clinically indistinguishable from CMD1R; the separation is molecular. This differential is not academic for ACTC1 - the one detailed CMD1R case in the literature also carried a TTN variant, and its authors could not assign causality to either gene alone.

Distinguishing Features

Only sequencing separates the genotypes; imaging and clinical course overlap.
A second variant in a higher-evidence DCM gene in the same patient weakens attribution to ACTC1, as in the reported infant case.

Show evidence (1 reference)

PMID:39759977 SUPPORT DIRECT Human Clinical

"For a matter of fact, its crucial role and its nucleotide length make TTN the major affected gene in DCM cases [38, 39]."

TTN as the dominant genetic cause of DCM, stated in the very paper where a TTN variant complicated an ACTC1 attribution.

Acquired dilated cardiomyopathy

Overlapping Features Coronary disease, hypertension, valvular disease, sustained tachyarrhythmia, alcohol and other cardiotoxins, myocarditis and the peripartum state all produce a dilated, hypocontractile ventricle and must be excluded before a genetic diagnosis is made.

Distinguishing Features

A coronary-territory wall-motion abnormality or an ischaemic pattern of late gadolinium enhancement favours ischaemic cardiomyopathy.
An identified exposure or loading condition with recovery after its removal, and no family history, favours an acquired cause.

🐁

Animal Models

2

ACTC E361G transgenic mouse

The only animal model of an ACTC1 dilated-cardiomyopathy allele. It expresses the human E361G actin at about half of total cardiac actin, which approximates the heterozygous human state better than most sarcomeric transgenics do. Its scientific value is that it is almost normal: baseline contractility, cardiac dimensions and myocyte function are unremarkable, and the phenotype only appears when the animal is challenged with dobutamine or with four weeks of angiotensin II.

Species

Mouse

Genotype

Transgenic expressing human ACTC E361G at approximately 50% of total cardiac actin

Publication

PMID:20600154

Pathograph links

Loss of Adrenergic Contractile and Lusitropic Reserve recapitulates fidelity: high This node is defined by the mouse rather than merely supported by it. Blunted inotropic and lusitropic responses to dobutamine, measured by papillary muscle mechanics, conductance catheter and echocardiography, are the primary observations.

Limitations: A transgenic overexpression model rather than a knock-in, so the mutant protein competes with endogenous mouse actin at a ratio set by the transgene rather than by allelic balance. Mouse and human cardiac beta-adrenergic signalling and heart rates differ substantially, and the corresponding measurement - contractile reserve on stress testing - has never been made in a human ACTC1 carrier.

Readouts

Dobutamine-stimulated increase in cardiac output

Direction: DECREASED

Interpretation: The standard measure of inotropic reserve, and the one that falls furthest - from 2,100 to 900 microlitres per minute.

Show evidence (1 reference)

PMID:26432839 SUPPORT DIRECT Model Organism

"The combination of these effects is to reduce the dobutamine-stimulated increase in CO (a measure of cardiac reserve) from 2,100 to 900 μl/min."

The measurement, with both values.

Peak rate of force decline normalised to force in papillary muscle under dobutamine

Direction: DECREASED

Interpretation: The lusitropic readout. DECREASED refers to the dobutamine-induced *increment*: wild type gains about 50% and the mutant only 20 to 30%, so the drug-stimulated relaxation response is smaller, not that relaxation is slower at baseline.

Show evidence (1 reference)

PMID:26432839 SUPPORT DIRECT Model Organism

"In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was..."

The wild-type and mutant increments side by side, which is what makes this a blunted response rather than an absolute deficit.

Show evidence (1 reference)

PMID:20600154 SUPPORT DIRECT Model Organism

"However, the increase in septal thickening, ejection fraction, heart rate and cardiac output following dobutamine treatment was significantly less in ACTC E361G mice compared with NTG."

Establishes the model as informative for this node: the reserve deficit is the phenotype it has.

Left Ventricular Dilation and Systolic Dysfunction partially recapitulates fidelity: moderate The mouse reaches a dilated, dysfunctional ventricle, but only after four weeks of angiotensin II infusion, and it passes through a hypertrophic stage on the way.

Limitations: PARTIALLY_RECAPITULATES because the model does not develop spontaneous dilated cardiomyopathy: over 4 to 18 months unstressed it is indistinguishable from wild type, and the DCM phenotype requires an experimental pressor stress that has no counterpart in the human disease. The authors also note that the response to chronic angiotensin II is strongly mouse-strain dependent, and that C57BL/6 animals are particularly resistant, which limits how far the stress protocol generalises.

Readouts

Left ventricular ejection fraction after chronic angiotensin II

Direction: DECREASED

Interpretation: The endpoint the authors interpret as dilated cardiomyopathy in this model.

Show evidence (1 reference)

PMID:26432839 SUPPORT DIRECT Model Organism

"Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM."

The measured drop and the authors' reading of it.

Show evidence (2 references)

PMID:26432839 SUPPORT DIRECT Model Organism

"Altogether, these data suggest that under chronic angiotensin-induced stress,ACTCE361G mouse hearts develop hypertrophy initially and later dilation."

Supports the model as informative for the dilation node, and states the hypertrophic intermediate stage that makes the recapitulation partial rather than complete.

+ 1 more reference

Acta1b p.T126I zebrafish

A zebrafish knock-in carrying the fish orthologue of a human ACTC1 DCM allele, followed longitudinally and analysed separately by sex. Unlike the E361G mouse it develops spontaneous progressive dilated cardiomyopathy with ventricular dilation, pericardial effusion and reduced survival, without an imposed stress. Its most striking result is a sex effect: female mutants had earlier and sustained diastolic dysfunction, more remodelling and significantly worse survival.

Species

Zebrafish

Genotype

Acta1b p.T126I, orthologous to human ACTC1 p.T126I

Publication

PMID:42563511

Pathograph links

Left Ventricular Dilation and Systolic Dysfunction recapitulates fidelity: low Progressive dilation and pump failure arising without experimental provocation, which is the part of the human phenotype the mouse model does not reproduce unaided.

Limitations: Fidelity is LOW for a specific and important reason: the mutation was made in acta1b, a *skeletal* actin paralogue standing in for cardiac actin, because zebrafish gene duplication does not map one-to-one onto human ACTC1. The two-chambered zebrafish heart has no left ventricle, so "left ventricular dilation" is an interpretation of ventricular dilation in a single ventricle. The sexual dimorphism, which is the paper's headline finding, has no established counterpart in human ACTC1 disease.

Readouts

Survival of adult mutants

Direction: DECREASED

Interpretation: Reduced survival accompanying progressive dilation, the organism-level consequence.

Show evidence (1 reference)

PMID:42563511 SUPPORT DIRECT Model Organism

"Mutants showed variable onset of cardiac dysfunction, with progressive DCM, pericardial effusion, ventricular dilation, and reduced survival in adults."

The phenotype and the survival readout in one sentence.

nppb transcript at pre-symptomatic stage

Direction: INCREASED

Interpretation: The natriuretic-peptide marker of cardiac stress rising before overt dysfunction, which is what makes this model informative about the pre-symptomatic phase.

Show evidence (1 reference)

PMID:42563511 SUPPORT DIRECT Model Organism

"Molecular profiling at a pre-symptomatic stage identified upregulation of nppb, downregulation of hypertrophic transcription factors (gata4, mef2ca), and sex-specific alterations in calcium handling genes (serca2, pln1, slc8a1a) and proteostasis regulators (hsf1, bag3)."

The pre-symptomatic transcriptional signature, with nppb up and the hypertrophic transcription factors down.

Show evidence (1 reference)

PMID:42563511 SUPPORT DIRECT Model Organism

"These findings demonstrate that the Acta1b p.T126I mutation drives progressive, sex-specific DCM in zebrafish, highlighting biological sex as a critical modifier of sarcomeric cardiomyopathy progression and targeted therapy development."

Establishes the model as informative for a dilated-cardiomyopathy node, and states the sex modifier that its limitations qualify.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1R
category: Mendelian
creation_date: "2026-09-03T00:00:00Z"
synonyms:
- CMD1R
- cardiomyopathy, dilated, 1R
- cardiomyopathy, dilated, type 1R
- dilated cardiomyopathy type 1R
- ACTC1 familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in ACTC1
description: >-
  CMD1R is familial isolated dilated cardiomyopathy caused by variants in ACTC1, the gene
  for cardiac alpha-actin. It was the first sarcomeric gene in which DCM-causing mutations
  were found: in 1998 two missense alleles, R312H and E361G, were shown to cosegregate with
  hereditary idiopathic dilated cardiomyopathy in two unrelated families, and the authors
  argued from their positions - in the regions of actin that anchor the thin filament to Z
  bands and intercalated discs - that the defect was in force transmission rather than force
  generation.

  The thing that makes this entry difficult is that the gene is not the diagnosis. ACTC1
  also causes hypertrophic cardiomyopathy, left ventricular noncompaction, atrial septal
  defect, and, since 2023, a distal arthrogryposis syndrome with congenital heart defects.
  Which disease a carrier gets is set by the allele, not by the gene, and the sharpest
  demonstration of that is a single codon: R312C is found in hypertrophic cardiomyopathy
  patients and R312H in dilated cardiomyopathy patients. Same residue, same gene, opposite
  ventricles. This entry is scoped to the phenotype MONDO defines for this term - familial
  isolated DCM - and deliberately excludes the atrial-septal-defect and distal-arthrogryposis
  literatures, which are larger and would otherwise dominate any search on the gene.

  The mechanism is genuinely unsettled, and the entry carries three competing models rather
  than one. The field's default is the calcium-sensitivity hypothesis: HCM alleles raise
  myofilament calcium sensitivity, DCM alleles lower it, and a desensitised sarcomere
  produces less force and dilates. For ACTC1 this holds only loosely. The most-studied DCM
  allele, R312H, has been reported with increased calcium sensitivity in one laboratory and
  decreased in another, and the most recent work finds it hyperactive under low-calcium
  relaxing conditions - which is the opposite of hypocontractility. The best in vivo evidence
  points somewhere else entirely: the E361G mouse has essentially normal baseline
  contractility and fails only under stress, because the mutation abolishes the normal
  coupling between troponin I phosphorylation and myofilament calcium sensitivity, so the
  heart cannot mount an adrenergic inotropic or lusitropic response and has no cardiac
  reserve to spend.

  A curator should also know the evidential footing. ClinGen's Dilated Cardiomyopathy Gene
  Curation Expert Panel classified ACTC1 for DCM as **Moderate** in March 2026, in a curation
  keyed directly to this MONDO term, while the
  Hypertrophic Cardiomyopathy panel classifies the same gene for HCM as **Definitive**. That
  asymmetry is not a technicality - it is the same allelic point restated as evidence
  strength, and it caps how firmly anything in this entry can be asserted.
disease_term:
  preferred_term: dilated cardiomyopathy 1R
  term:
    id: MONDO:0013261
    label: dilated cardiomyopathy 1R
parents:
- Dilated Cardiomyopathy
references:
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous ACTC1 missense variants transmitted as an autosomal dominant trait. The
    founding evidence is cosegregation in two unrelated kindreds with hereditary idiopathic
    dilated cardiomyopathy. A de novo heterozygous allele has also been reported in a
    sporadic infant case, so absence of family history does not exclude the diagnosis.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families."
    explanation: >-
      The founding cosegregation evidence in two independent families, which is what
      established ACTC1 as a DCM gene.
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "For this reason, it was very interesting to find that the ACTC1 mutation in the subject of study was not segregated by either of the parents, denoting its de novo origin"
    explanation: >-
      A de novo heterozygous allele in a sporadic case, which is why a negative family
      history does not exclude an ACTC1 aetiology.
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy 1R (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy 1R | MONDO:0013261 | AD | Moderate"
    explanation: >-
      ClinGen records the mode of inheritance as autosomal dominant - and, in the same row,
      grades the strength of the ACTC1-DCM relationship as Moderate.
mechanistic_hypotheses:
- hypothesis_group_id: actc1_calcium_desensitization_model
  hypothesis_label: Thin-filament calcium-desensitization model
  status: CANONICAL
  description: >-
    The field's default account of sarcomeric cardiomyopathy: hypertrophic alleles increase
    the calcium sensitivity of the myofilament and dilated alleles decrease it, so at a given
    systolic calcium transient the mutant sarcomere generates less force, the ventricle is
    hypocontractile, and it dilates. Applied to ACTC1 this is the model that predicts the
    R312C/R312H split at a single codon. It is recorded as CANONICAL because it is the frame
    the whole literature is written against, not because ACTC1 confirms it - the direct
    measurements on the ACTC1 DCM alleles are inconsistent with it as often as not, which is
    the substance of the other two hypothesis groups.
  evidence:
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "HCM results from increases in calcium sensitivity and/or force production, while DCM results from reductions in these activities."
    explanation: The model stated in its own terms by a group that then goes on to test it on ACTC1.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Characterization of variants of cardiac actin (ACTC) found in patients with HCM or DCM has generally supported the calcium sensitivity hypothesis."
    explanation: >-
      The general-case support, quoted with its hedge intact. The same paper reports the
      specific failure below.
  - reference: PMID:19799913
    reference_title: "Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro."
    supports: REFUTE
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "In contrast when compared to WT actin, the R312H mutation increased Ca++-sensitivity for velocity in the motility assay without effecting myosin strong-binding activation at pCa 10."
    explanation: >-
      A direct contradiction of the model for the principal ACTC1 DCM allele: the model
      requires R312H to be calcium-desensitising and this measurement makes it sensitising.
      Recorded as REFUTE rather than hidden in a note.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: REFUTE
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "We performed regulated actomyosin assays to investigate the differences between R312H- and R312C-ACTC variants and found that both ACTC variants had similar changes in pCa curves relative to WT-ACTC, disproving the hypothesis that opposite changes should be observed if ACTC changes trigger different disease phenotypes from onset."
    explanation: >-
      The second contradiction, and a different one: the HCM and DCM alleles at residue 312
      shift calcium sensitivity in the same direction, so calcium sensitivity cannot be what
      separates the two diseases here.
  notes: >-
    The two REFUTE items disagree with each other as well as with the model - one laboratory
    reports R312H as calcium-sensitising and the other as desensitising. That disagreement
    is itself curated, in the knowledge-gap discussion, rather than resolved by picking a
    side.
- hypothesis_group_id: actc1_tni_phosphorylation_uncoupling_model
  hypothesis_label: Troponin-I phosphorylation uncoupling and loss of cardiac reserve
  status: ALTERNATIVE
  description: >-
    The model with the best in vivo support in ACTC1. Normally, PKA phosphorylation of
    troponin I during beta-adrenergic stimulation desensitises the myofilament to calcium,
    which speeds relaxation and supplies inotropic and lusitropic reserve. The ACTC1 E361G
    allele abolishes that phosphorylation-dependent shift: calcium sensitivity becomes fixed
    rather than modulable. The predicted consequence is a heart that is normal at rest and
    fails under demand, and that is exactly what the E361G mouse shows - unremarkable
    baseline contractility and cardiac dimensions out to eighteen months, a blunted response
    to dobutamine, and overt systolic dysfunction only after four weeks of angiotensin II
    stress. Under this model the primary lesion is a regulatory one, and dilation is the
    consequence of chronic inability to meet load rather than of weak sarcomeres.
  evidence:
  - reference: PMID:20600154
    reference_title: "Investigation of a transgenic mouse model of familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "We propose that the ACTC E361G mutation uncouples myofilament Ca(2+)-sensitivity from Troponin I phosphorylation and blunts the response to adrenergic stimulation, leading to a reduced cardiac reserve with consequent contractile dysfunction under stress, leading to dilated cardiomyopathy."
    explanation: The model stated in full by the group that generated the mouse.
  - reference: PMID:20600154
    reference_title: "Investigation of a transgenic mouse model of familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "For NTG actin-containing thin filaments EC(50) native/dPTn=3.0+/-0.3 but for E361G-containing thin filaments EC(50) native/dPTn=1.04+/-0.07."
    explanation: >-
      The measurement the model rests on: wild-type thin filaments shift threefold on
      troponin dephosphorylation, E361G filaments do not shift at all.
  - reference: PMID:26432839
    reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "Thus as predicted, the uncoupling of the relationship between Ca2+ sensitivity and TnI phosphorylation by theACTCE361G DCM-causing mutation results in reduced physiological cardiac reserve."
    explanation: >-
      The prediction tested in intact heart muscle five years later, closing the loop from
      the reconstituted-filament measurement to whole-organ physiology.
  notes: >-
    Sourced entirely from one allele (E361G) in one transgenic line from one group. It is the
    most complete mechanistic account in ACTC1-DCM and also the narrowest, and no equivalent
    in vivo work exists for R312H.
- hypothesis_group_id: actc1_residual_activity_relaxation_model
  hypothesis_label: Residual myosin activity under relaxing conditions
  status: EMERGING
  description: >-
    The newest proposal, and the one that most directly displaces calcium sensitivity as the
    discriminator. Characterising R312C and R312H side by side, both variants shifted calcium
    sensitivity in the same direction, but they differed in how much actomyosin activity
    persisted at pCa 10, where tropomyosin should be blocking myosin entirely. R312H filaments
    were the most active of the three under those relaxing conditions - every filament moved,
    where some wild-type filaments did not - while producing lower force under load. The
    proposal is that a sarcomere which never fully switches off cannot relax properly, and
    that chronic failure of relaxation, not weak contraction, is what dilates the ventricle.
  evidence:
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "We observed a gradient of increased residual myosin activity with R312-ACTC variant proteins under relaxing conditions which may trigger different disease development."
    explanation: The proposal, stated with the authors' own hedge.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "As opposed to WT-ACTC and R312C-ACTC where some filaments showed no movement, all R312H-ACTC filaments exhibited a velocity greater than zero."
    explanation: >-
      The concrete observation behind it, at the level of individual filaments under
      conditions where none should be moving.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "R312H-ACTC had the significantly lower displacement force while R312C-ACTC displacement force was significantly higher (Table 2)."
    explanation: >-
      The force half of the same result, and the part that does fit the DCM direction: the
      DCM allele generates less force than wild type, the HCM allele more.
  - reference: PMID:39510186
    reference_title: "Duality in disease: How two amino acid substitutions at actin residue 312 result in opposing forms of cardiomyopathy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "Structural models of actin R312C and R312H variants were developed in silico, identifying structural rearrangements to the 'tropomyosin bumper' (Tm-bumper, residues 222-230) and changes to internal communication networks unique to each variant."
    explanation: >-
      Proposes a structural route from residue 312 to altered tropomyosin positioning, which
      is how a substitution far from the myosin interface could leave the filament
      incompletely switched off. Molecular dynamics, so COMPUTATIONAL and INDIRECT.
  notes: >-
    The same 2024 paper notes that this has a therapeutic consequence which cuts against
    standard reasoning: a myosin activator, the intuitive drug for a hypocontractile DCM,
    would amplify the lesion if the lesion is excess resting activity.
pathophysiology:
- name: ACTC1 Missense Variant in Cardiac Alpha-Actin
  biological_scale: MOLECULAR
  role: initiator
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  mechanism_confidence: ESTABLISHED
  description: >-
    A heterozygous missense substitution in cardiac alpha-actin, the monomer that polymerises
    into the thin filament. The DCM-associated alleles are single amino-acid changes at
    conserved residues; the two founding ones, R312H and E361G, lie in the parts of actin
    that engage the Z band and the intercalated disc rather than in the myosin-binding
    surface, which is why the original interpretation was a force-transmission defect.
    Notably, the intrinsic properties of the mutant protein are barely changed - polymerisation
    kinetics, melting temperature and DNase-I inhibition are close to wild type - so the lesion
    is in how the filament is regulated, not in whether it forms.
  genes:
  - preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  molecular_functions:
  - preferred_term: actin filament binding within the cardiac thin filament
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Altered Thin Filament Regulation of Actomyosin
    causal_link_type: DIRECT
    description: >-
      A substitution in the actin monomer changes the regulated filament it builds, which is
      the immediate molecular consequence.
  evidence:
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs."
    explanation: >-
      The structural localisation of the two founding alleles, and the basis for the original
      force-transmission interpretation.
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure"
    explanation: >-
      The authors' own inference, quoted with its hedge. Indirect: the sentence proposes a
      mechanism from variant position rather than reporting one measured.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Our results here, however, do not reflect major changes in overall actin structure for either the R312C- or R312H-ACTC proteins compared to WT-ACTC, with similar polymerization rates, melting temperatures and DNase-I inhibition IC50 values."
    explanation: >-
      The negative result that localises the defect away from actin folding and
      polymerisation and toward filament regulation.
  - reference: PMID:22590617
    reference_title: "Subdomain location of mutations in cardiac actin correlate with type of functional change."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "The two ACTC mutants associated with DCM are R312H and E361G."
    explanation: >-
      Names the two DCM alleles explicitly, which is the statement the entry needs and which
      the 1998 abstract does not supply - it reports two missense mutations without naming
      them.
  - reference: PMID:22590617
    reference_title: "Subdomain location of mutations in cardiac actin correlate with type of functional change."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "the E361G mutation affects a-actinin binding"
    explanation: >-
      A measured protein-interaction consequence for the second DCM allele, and the closest
      thing to a demonstration of the 1998 force-transmission hypothesis: alpha-actinin is
      the Z-disc actin cross-linker. Indirect because the sentence is this paper's summary of
      prior work rather than its own result.
- name: Altered Thin Filament Regulation of Actomyosin
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    The regulated thin filament - actin plus tropomyosin plus troponin - no longer switches
    between its blocked, closed and open states normally. What exactly goes wrong is where the
    three hypothesis groups diverge, and the downstream edges are tagged accordingly rather
    than being collapsed into one claim. Measurements that are agreed across laboratories:
    maximal calcium-activated filament velocity is reduced, and myosin's ADP release is slowed
    so it detaches more slowly. Measurements that are not agreed: the direction of the shift
    in calcium sensitivity, and whether the filament is fully inhibited in the absence of
    calcium.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of cardiac muscle contraction by the thin filament
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: DYSREGULATED
  - preferred_term: actin-myosin filament sliding
    term:
      id: GO:0033275
      label: actin-myosin filament sliding
    modifier: DECREASED
  locations:
  - preferred_term: myofibril
    term:
      id: GO:0030016
      label: myofibril
  downstream:
  - target: Loss of Adrenergic Contractile and Lusitropic Reserve
    causal_link_type: DIRECT
    hypothesis_groups:
    - actc1_tni_phosphorylation_uncoupling_model
    description: >-
      Under the uncoupling model, fixing calcium sensitivity so that troponin I
      phosphorylation no longer shifts it is precisely what removes the reserve.
    evidence:
    - reference: PMID:26432839
      reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "The uncoupling of Ca2+sensitivity from TnI phosphorylation caused by the thin-filament DCM mutations, includingACTCE361G, blunts the response to adrenergic stimulation, compromising the lusitropic response and adversely affecting cardiac reserve."
      explanation: The edge stated as a causal chain by the group that measured both ends of it.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - actc1_calcium_desensitization_model
    - actc1_residual_activity_relaxation_model
    description: >-
      The direct route from a mis-regulated filament to a dilated ventricle, which the
      desensitisation and residual-activity models both assert and neither has demonstrated
      in an intact ACTC1 heart. Marked INDIRECT_UNKNOWN_INTERMEDIATES for that reason: the
      steps between an in vitro motility measurement and chamber remodelling are not filled in.
  evidence:
  - reference: PMID:19799913
    reference_title: "Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Both the HCM (E99K) and DCM (R312H) human actin mutations resulted in significant reductions in maximal Ca++-regulated thin filament velocity."
    explanation: >-
      One of the two findings that laboratories agree on, and notably one that does not
      separate the HCM allele from the DCM allele.
  - reference: PMID:19799913
    reference_title: "Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Without any demonstrable effect on k+ATP, these data suggest that both the E99K and the R312H mutation result in a decrease in ADP release kinetics"
    explanation: >-
      The kinetic step behind the velocity reduction: slower ADP release keeps myosin bound
      to actin for longer.
  - reference: PMID:22590617
    reference_title: "Subdomain location of mutations in cardiac actin correlate with type of functional change."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "The R312H variant exhibited reduced stability, with a T(m) of 53.6 °C compared to 56.8 °C for WT actin, accompanied with increased polymerization critical concentration and Pi release rate, and a marked increase in nucleotide release rates."
    explanation: >-
      A third laboratory's measurements on R312H, which disagree with the 2022 report of
      near-normal melting temperature and polymerisation quoted on the node above. Both are
      recorded; the disagreement is the point.
  - reference: PMID:26194323
    reference_title: "Do cardiac actin mutations lead to altered actomyosin interactions?"
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Based on our analysis of 8 ACTC mutants, we infer that mutations in ACTC lead to disease through various molecular mechanisms."
    explanation: >-
      A survey of eight ACTC alleles concluding that there is no single ACTC1 mechanism,
      which is the reason this node is PROVISIONAL and carries three hypothesis groups.
  notes: >-
    The same survey states that for the non-E99K mutants, including R312H, measurable changes
    in the core actin-myosin interaction do not appear to drive disease - a negative result
    that argues the lesion is regulatory rather than in the motor itself.
- name: Loss of Adrenergic Contractile and Lusitropic Reserve
  biological_scale: TISSUE
  role: amplifier
  mechanism_confidence: PROVISIONAL
  description: >-
    A ventricle that performs acceptably at rest but cannot increase its output or speed its
    relaxation when driven. In the E361G mouse, dobutamine raised cardiac output by 2,100
    microlitres per minute in wild-type animals and only 900 in mutants, and the relaxation
    indices moved by a quarter to a third of the wild-type amount. Baseline cardiac dimensions
    and systolic function were essentially normal over four to eighteen months. The clinical
    reading is that CMD1R may be a disease of failed reserve, which would explain why human
    onset can be late and why an intercurrent stress can precipitate presentation.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of the force of heart contraction
    term:
      id: GO:0002026
      label: regulation of the force of heart contraction
    modifier: DECREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - actc1_tni_phosphorylation_uncoupling_model
    intermediate_mechanisms:
    - Chronic haemodynamic or neurohormonal stress that a reserve-less ventricle cannot meet.
    description: >-
      In the mouse this step required an experimental stress to appear: four weeks of
      angiotensin II infusion converted a normal-looking heart into a dilated, dysfunctional
      one, while wild-type animals were unaffected.
    evidence:
    - reference: PMID:26432839
      reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG."
      explanation: The stress-dependence of the transition, with the wild-type control stated.
    - reference: PMID:26432839
      reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM."
      explanation: The measured endpoint that the authors read as dilated cardiomyopathy.
  evidence:
  - reference: PMID:26432839
    reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min."
    explanation: The quantified loss of inotropic reserve.
  - reference: PMID:26432839
    reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response."
    explanation: The lusitropic half, measured by conductance catheter in the intact animal.
  - reference: PMID:20600154
    reference_title: "Investigation of a transgenic mouse model of familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: "We measured cardiac performance by cine-MRI, echocardiography and with a conductance catheter over a period of 4 to 18 months and found minimal systematic differences between NTG and ACTC E361G mice under basal conditions."
    explanation: >-
      The baseline-normal half of the phenotype, which is what makes this a reserve defect
      rather than a resting contractile defect.
  notes: >-
    PROVISIONAL and mouse-only. No human CMD1R study has measured contractile reserve - by
    stress echocardiography, cardiopulmonary exercise testing or any other route - so this
    node is a mechanism imported from a transgenic model, not one observed in patients.
- name: Left Ventricular Dilation and Systolic Dysfunction
  biological_scale: ORGANISM
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  mechanism_confidence: ESTABLISHED
  description: >-
    The organ-level phenotype that defines the disease: a dilated left ventricle with impaired
    systolic contraction, in the absence of loading conditions or coronary disease sufficient
    to explain it. Severity spans the range - from an adult diagnosed at 36 to a one-year-old
    with severe dilation and dysfunction who died suddenly.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT
  - target: Reduced Left Ventricular Ejection Fraction
    causal_link_type: DIRECT
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progressive ventricular remodelling and neurohormonal activation following sustained systolic impairment.
  evidence:
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "The present study details the clinical and genetic characterization of a malignant dilated cardiomyopathy (DCM) case in a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD."
    explanation: >-
      The severe end of the reported range, with the chamber phenotype and the outcome in one
      sentence.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The R312H ACTC variant found in patients ranging in age from 2 years to 36 years of age was amongst the first linked to DCM"
    explanation: >-
      The age range across reported R312H carriers. Indirect: this is a 2022 in vitro paper's
      summary of the clinical literature it builds on, not its own patient series.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    The defining phenotype. Left ventricular dilation with impaired systolic contraction, not
    attributable to loading conditions or coronary disease.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "To test the hypothesis that actin dysfunction leads to heart failure, patients with hereditary idiopathic dilated cardiomyopathy (IDC) were examined for mutations in the cardiac actin gene (ACTC)."
    explanation: >-
      The ascertainment: these families were collected as hereditary idiopathic DCM, which
      is the phenotype the gene was found in.
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy 1R (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy 1R | MONDO:0013261 | AD | Moderate"
    explanation: >-
      ClinGen's expert-panel assertion that this gene-disease pair exists, at Moderate
      strength.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: >-
    The functional measure that tracks the dilation. Reported in human CMD1R cases as severe
    left ventricular dysfunction, and measured directly in the E361G mouse after chronic
    angiotensin II stress.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD"
    explanation: Severe systolic dysfunction in the one CMD1R case with detailed reporting.
  notes: >-
    No `frequency` is asserted. Impaired systolic contraction is definitional for DCM so the
    phenotype is certainly present, but no CMD1R series reports ejection fractions across a
    cohort, and FrequencyEnum has no value for "present but unquantified". A band here would
    have been a number invented from the disease definition rather than counted in ACTC1
    carriers.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    The clinical syndrome the dilated, hypocontractile ventricle produces. In the founding
    report the whole point of testing ACTC was that actin dysfunction might be a mechanism of
    heart failure.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Coupled with previous data showing that dystrophin mutations also cause dilated cardiomyopathy, these results raise the possibility that defective transmission of force in cardiac myocytes is a mechanism underlying heart failure."
    explanation: >-
      Indirect: the sentence frames DCM as a heritable form of heart failure rather than
      reporting heart-failure events in the ACTC families, whose clinical detail is not in the
      cached abstract.
  notes: >-
    No `frequency` is asserted. No CMD1R report gives a proportion of carriers reaching
    symptomatic heart failure, and a grade derived from the disease definition rather than
    from a counted series would be a fabricated denominator.
- name: Sudden Death
  category: Cardiovascular
  description: >-
    Reported in the severe infantile end of the spectrum. This is a single case, and it
    carried a second sarcomeric variant, so it should not be read as an ACTC1-specific
    arrhythmic risk.
  phenotype_term:
    preferred_term: Sudden death
    term:
      id: HP:0001699
      label: Sudden death
  evidence:
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD"
    explanation: The sudden-death outcome in the reported infant case.
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "it is also suggestive that the cause of the malignant condition reported here may be derived from a polygenic synergistic effect of both ACTC1 and TTN variants, where this double hit is necessary to impair the phenotypic manifestation of an early and severe DCM"
    explanation: >-
      Recorded as NO_EVIDENCE because the authors themselves raise the possibility that the
      severity required both variants, which means this case does not establish that an ACTC1
      allele alone confers this outcome. It bears on interpretation without supporting or
      refuting the phenotype claim.
  notes: >-
    No `frequency` is asserted, and this is the case where a band would have been most
    misleading. The evidence is a single infant who also carried a TTN variant. No arrhythmic
    risk estimate exists for CMD1R, and none should be inferred from this entry.
prevalence:
- population: Reported literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence has been published for ACTC1-related dilated cardiomyopathy, and
    none is asserted here. What exists is a small set of reported families and cases beginning
    with the two 1998 kindreds. ACTC1 is not among the genes that account for most familial
    DCM; the strongest quantitative statement available about it is ClinGen's Moderate
    gene-disease validity grade, which is a statement about evidence rather than about
    frequency.
  evidence:
  - reference: PMID:9563954
    reference_title: "Actin mutations in dilated cardiomyopathy, a heritable form of heart failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "Missense mutations in ACTC that cosegregate with IDC were identified in two unrelated families."
    explanation: The founding case count.
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy 1R (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy 1R | MONDO:0013261 | AD | Moderate"
    explanation: >-
      Indirect for a prevalence record: a Moderate rather than Definitive validity grade
      reflects a limited accumulated case count, which is why it is quoted here, but it is not
      a frequency measurement.
progression:
- phase: Infantile severe presentation
  notes: >-
    The severe extreme of the reported range. A one-year-old with severe left ventricular
    dilation and dysfunction, carrying a de novo ACTC1 p.Ala222Thr allele together with a
    paternally inherited TTN variant, died suddenly. The fatal outcome is recorded here rather
    than as a phenotype because HPO files death in infancy under clinical course. The double
    genotype means this case cannot be used to characterise the ACTC1 allele on its own.
  evidence:
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "In conclusion, our findings suggest a likely pathogenic de novo mutation in ACTC1 in coexpression of a TTN variant as possible causes of an early onset of a severe DCM and premature death."
    explanation: >-
      The authors' conclusion, quoted with both variants named, because the attribution to
      ACTC1 alone is exactly what they decline to make.
- phase: Adult-onset dilated cardiomyopathy
  notes: >-
    The typical presentation, and the one the founding families represent: hereditary
    idiopathic dilated cardiomyopathy diagnosed in adulthood. Across reported R312H carriers
    the age range runs from two to thirty-six years, so childhood presentation is possible but
    the mode is adult. The E361G mouse suggests a mechanism for late onset - the heart is
    normal until it is stressed - but that link has not been tested in patients.
  evidence:
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The R312H ACTC variant found in patients ranging in age from 2 years to 36 years of age was amongst the first linked to DCM [15]"
    explanation: >-
      The reported age range for the principal DCM allele. Indirect because it is a citing
      summary rather than a primary clinical series.
genetic:
- name: ACTC1
  notes: >-
    ACTC1 at 15q14 encodes cardiac alpha-actin, the thin-filament monomer of the cardiac
    sarcomere, and it was the first sarcomeric gene in which DCM-causing mutations were
    reported. The essential curation problem with this gene is that its alleles do not
    converge on one disease. The same gene underlies hypertrophic cardiomyopathy, left
    ventricular noncompaction, atrial septal defect and a distal arthrogryposis syndrome with
    congenital heart defects, and the HCM and congenital-heart literatures are considerably
    larger than the DCM one. A search on the gene symbol will return mostly material that does
    not belong in this entry.

    The evidence asymmetry is recorded by ClinGen: the Hypertrophic Cardiomyopathy Gene
    Curation Expert Panel classified ACTC1 for HCM as Definitive in 2021, while the Dilated
    Cardiomyopathy Gene Curation Expert Panel classified the same gene for DCM as Moderate in
    2026, in a curation keyed to MONDO:0013261 itself. ACTC1-DCM is a real gene-disease
    relationship on a weaker evidential footing than
    ACTC1-HCM.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  variants:
  - name: p.Arg312His (R312H)
    description: >-
      The principal DCM allele and one of the two identified in 1998. Its interest is that the
      same codon carries an HCM allele: R312C is found in hypertrophic cardiomyopathy patients
      and R312H in dilated cardiomyopathy patients, which makes this pair the cleanest
      available demonstration that in ACTC1 the allele determines the phenotype. The
      biophysical characterisation of R312H is inconsistent across laboratories and is the
      basis for the three hypothesis groups in this entry. One source notes it has also been
      seen in HCM patients, so even this allele is not phenotypically exclusive.
    clinical_significance: PATHOGENIC
    type: missense_variant
    gene:
      preferred_term: ACTC1
      term:
        id: hgnc:143
        label: ACTC1
    evidence:
    - reference: PMID:39802493
      reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "Of interest are two different substitution mutations at R312 on ACTC: R312H leads to DCM, while R312C was found in patients with HCM."
      explanation: The allele-determines-phenotype statement at a single codon.
    - reference: PMID:39510186
      reference_title: "Duality in disease: How two amino acid substitutions at actin residue 312 result in opposing forms of cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Though the pathogenicity is difficult to determine, R312C was found in patients clinically presenting with HCM (4), while R312H has been found in both HCM and DCM patients (3)"
      explanation: >-
        The important qualifier, and the reason this entry does not claim a clean one-allele
        one-disease rule: R312H itself has been reported in both phenotypes. Indirect because
        it is this paper's summary of the clinical literature rather than its own cohort.
    - reference: PMID:22590617
      reference_title: "Subdomain location of mutations in cardiac actin correlate with type of functional change."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "The two ACTC mutants associated with DCM are R312H and E361G."
      explanation: >-
        Names this allele as one of the two ACTC1 variants associated with dilated
        cardiomyopathy, which is the attribution the 1998 abstract leaves implicit.
  - name: p.Glu361Gly (E361G)
    description: >-
      The second 1998 allele, and the only ACTC1 DCM variant modelled in a transgenic animal.
      All of the in vivo mechanistic evidence in this entry comes from that mouse.
    clinical_significance: PATHOGENIC
    type: missense_variant
    gene:
      preferred_term: ACTC1
      term:
        id: hgnc:143
        label: ACTC1
    evidence:
    - reference: PMID:20600154
      reference_title: "Investigation of a transgenic mouse model of familial dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "We have investigated a transgenic mouse model of inherited dilated cardiomyopathy that stably expresses the ACTC E361G mutation at around 50% of total actin in the heart."
      explanation: >-
        Names the allele and its identity as an inherited DCM mutation. Indirect for the
        human variant claim because this is the mouse paper; the human ascertainment is in
        the 1998 report.
    - reference: PMID:22590617
      reference_title: "Subdomain location of mutations in cardiac actin correlate with type of functional change."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      snippet: "The two ACTC mutants associated with DCM are R312H and E361G."
      explanation: >-
        Names this allele as one of the two ACTC1 variants associated with dilated
        cardiomyopathy, which is the attribution the 1998 abstract leaves implicit.
  - name: p.Thr126Ile (T126I)
    description: >-
      A DCM-associated ACTC1 allele modelled in zebrafish through the orthologous Acta1b
      substitution. No human clinical report of this allele is cited here; it enters the entry
      through the animal model, which is why no clinical_significance is asserted for it.
    type: missense_variant
    gene:
      preferred_term: ACTC1
      term:
        id: hgnc:143
        label: ACTC1
    evidence:
    - reference: PMID:42563511
      reference_title: "Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with human actin mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Although sarcomere mutations such as cardiac actin ACTC1 p.T126I contribute to familial DCM, the in vivo effects and sex-specific consequences remain unclear."
      explanation: >-
        Names the allele and assigns it to familial DCM. Indirect for a human-variant claim:
        this is the introductory framing of a zebrafish paper, not a clinical report, which is
        why the entry does not grade the allele's pathogenicity.
  - name: p.Ala222Thr (c.664G>A)
    description: >-
      A de novo allele in a one-year-old with severe DCM and sudden cardiac death. Absent from
      gnomAD and the other control databases, and reported in ClinVar by other submitters,
      including two likely-pathogenic de novo DCM classifications. The case also carried a
      paternally inherited TTN variant classified as uncertain, and the authors do not
      attribute the phenotype to ACTC1 alone.
    clinical_significance: LIKELY_PATHOGENIC
    type: missense_variant
    gene:
      preferred_term: ACTC1
      term:
        id: hgnc:143
        label: ACTC1
    evidence:
    - reference: PMID:39759977
      reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: "Notwithstanding, it is of important notice that there are five previous reports of this variant from different submitters in ClinVar database, two of them being classified as likely pathogenic in DCM cases also with a de novo origin."
      explanation: >-
        Independent ClinVar submissions of the same allele in DCM, which is the basis for the
        LIKELY_PATHOGENIC grade rather than the single case alone.
    - reference: PMID:39759977
      reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: "Ala222Thr variant in the available literature or in databases such as PubMed, and it is absent in control cohorts as 1000 genomes, exome sequencing project, the exome aggregation consortium (ExAC), or the genome aggregation database (gnomAD)."
      explanation: Absence from population databases, the rarity criterion.
  evidence:
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy 1R (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy 1R | MONDO:0013261 | AD | Moderate"
    explanation: >-
      The ClinGen DCM expert panel assertion, at Moderate strength, dated 2026-03-04, and
      keyed directly to MONDO:0013261 rather than to the generic dilated-cardiomyopathy term.
  - reference: CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z
    reference_title: "ACTC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      The comparison that makes the Moderate grade above meaningful: the same gene is
      Definitive for the other cardiomyopathy. Indirect for a DCM entry, and included solely
      to fix the evidential asymmetry in place.
  - reference: PMID:37457373
    reference_title: "Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction."
    explanation: >-
      The allelic spectrum of the gene stated in one sentence. Cited only for that scoping
      purpose - the study itself is about distal arthrogryposis and contributes nothing to the
      DCM mechanism.
  - reference: CGGV:assertion_748d4255-ef43-4b42-b9f1-1cdbc50de763-2019-03-15T160000.000Z
    reference_title: "ACTC1 / arrhythmogenic right ventricular cardiomyopathy (No Known Disease Relationship)"
    supports: REFUTE
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | arrhythmogenic right ventricular cardiomyopathy | MONDO:0016587 | AD | No Known Disease Relationship"
    explanation: >-
      A curated negative, and the one boundary of the ACTC1 spectrum that is settled rather
      than merely unexplored: ClinGen's ARVC expert panel found no known relationship. Graded
      REFUTE because it contradicts an ACTC1-ARVC claim, and recorded here so that ARVC
      material appearing in an ACTC1 search can be dismissed on an authority rather than on
      absence of evidence.
diagnosis:
- name: Genetic testing on a dilated cardiomyopathy panel
  description: >-
    CMD1R has no distinguishing clinical or imaging feature. It is diagnosed by finding a
    pathogenic ACTC1 variant in a patient whose ventricle is dilated and hypocontractile
    without an adequate acquired explanation, usually on a multigene cardiomyopathy panel or
    exome sequencing. Two interpretation problems are specific to this gene. First, the ACTC1
    result must be read against the phenotype: the same gene yields HCM, LVNC, atrial septal
    defect and a skeletal-muscle syndrome, so the variant, not the gene, carries the
    diagnosis. Second, ClinGen grades the gene-disease relationship for DCM as Moderate, which
    is the tier at which a variant of uncertain significance should not be over-read.
  evidence:
  - reference: CGGV:assertion_3e9b4048-3003-4180-b891-fcf10d25a814-2026-03-04T170000.000Z
    reference_title: "ACTC1 / dilated cardiomyopathy 1R (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | dilated cardiomyopathy 1R | MONDO:0013261 | AD | Moderate"
    explanation: >-
      The validity grade that should temper interpretation of an ACTC1 finding in a DCM
      patient.
  - reference: PMID:37457373
    reference_title: "Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction."
    explanation: >-
      Why an ACTC1 hit does not by itself make a CMD1R diagnosis: four other phenotypes share
      the gene.
differential_diagnoses:
- name: ACTC1-related hypertrophic cardiomyopathy
  description: >-
    The same gene with a different allele, and the commonest way an ACTC1 result is
    misattributed. ClinGen grades ACTC1 for HCM as Definitive, against Moderate for DCM, and
    the HCM literature on this gene is substantially larger. The R312 pair is the sharpest
    example, with R312C in HCM patients and R312H in DCM patients.
  distinguishing_features:
  - The imaging phenotype decides it - a thickened, non-dilated left ventricle with preserved or supranormal ejection fraction is HCM, not CMD1R.
  - Approximately 10 to 20 percent of HCM progresses to a dilated, hypokinetic stage, so a dilated ventricle in a known ACTC1 carrier may be end-stage HCM rather than primary DCM.
  evidence:
  - reference: CGGV:assertion_2f62793b-0015-46eb-bb51-bddbae25ba0d-2021-06-23T201616.296Z
    reference_title: "ACTC1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "ACTC1 | HGNC:143 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: The competing ACTC1 gene-disease relationship, at the higher validity tier.
  - reference: PMID:39802493
    reference_title: "A gradient of force generation at rest differentiates cardiomyopathy outcomes with variants of actin located at the same residue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: "Even when a mutation causes a shift in contraction, long term effects can complicate diagnosis and treatment; for example, approximately 10-20 % of HCM cases are believed to progress into DCM (known as H-DCM)"
    explanation: >-
      The quantitative basis for the second distinguishing feature, and the reason a dilated
      ACTC1 ventricle is not automatically CMD1R.
- name: ACTC1-related atrial septal defect with late-onset dilated cardiomyopathy
  description: >-
    A distinct ACTC1 phenotype in which a congenital septal defect is the presenting feature
    and dilated cardiomyopathy appears decades later. It is excluded from this entry because
    MONDO scopes this term to familial *isolated* dilated cardiomyopathy, and a kindred with
    penetrant atrial septal defect is not that. The distinction matters practically: the
    ACTC1 congenital-heart-defect literature is larger than the DCM literature and will
    otherwise be pulled into a CMD1R search.
  distinguishing_features:
  - A structural septal defect from birth, usually with a family history of the same defect, points to the ASD phenotype rather than to isolated CMD1R.
  - In CMD1R the ventricle is structurally normal until it dilates; there is no congenital malformation.
  evidence:
  - reference: PMID:37457373
    reference_title: "Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction."
    explanation: >-
      Establishes atrial septal defect as a separate ACTC1 phenotype from dilated
      cardiomyopathy. Indirect because the sentence is background in a paper about a fifth
      phenotype.
- name: ACTC1-related distal arthrogryposis with congenital heart defects
  description: >-
    Reported in 2023 in five families: heterozygous ACTC1 missense variants causing a distal
    arthrogryposis syndrome, sometimes with cardiac malformation. It is a skeletal-muscle
    phenotype and is out of scope here, but it is the newest and largest reason that a
    literature search on ACTC1 returns material irrelevant to CMD1R.
  distinguishing_features:
  - Congenital contractures of the distal limbs are the presenting feature; CMD1R has no skeletal-muscle phenotype.
  evidence:
  - reference: PMID:37457373
    reference_title: "Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1)."
    explanation: The primary report of this distinct ACTC1 phenotype.
- name: TTN-truncating and other higher-evidence genetic dilated cardiomyopathy
  description: >-
    TTN truncating variants are the commonest identifiable genetic cause of DCM, and LMNA,
    BAG3, FLNC, RBM20, DES and PLN account for much of the rest. All are clinically
    indistinguishable from CMD1R; the separation is molecular. This differential is not
    academic for ACTC1 - the one detailed CMD1R case in the literature also carried a TTN
    variant, and its authors could not assign causality to either gene alone.
  distinguishing_features:
  - Only sequencing separates the genotypes; imaging and clinical course overlap.
  - A second variant in a higher-evidence DCM gene in the same patient weakens attribution to ACTC1, as in the reported infant case.
  evidence:
  - reference: PMID:39759977
    reference_title: "A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: "For a matter of fact, its crucial role and its nucleotide length make TTN the major affected gene in DCM cases [38, 39]."
    explanation: >-
      TTN as the dominant genetic cause of DCM, stated in the very paper where a TTN variant
      complicated an ACTC1 attribution.
- name: Acquired dilated cardiomyopathy
  description: >-
    Coronary disease, hypertension, valvular disease, sustained tachyarrhythmia, alcohol and
    other cardiotoxins, myocarditis and the peripartum state all produce a dilated,
    hypocontractile ventricle and must be excluded before a genetic diagnosis is made.
  distinguishing_features:
  - A coronary-territory wall-motion abnormality or an ischaemic pattern of late gadolinium enhancement favours ischaemic cardiomyopathy.
  - An identified exposure or loading condition with recovery after its removal, and no family history, favours an acquired cause.
treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard medical therapy for heart failure with reduced ejection fraction: the four
    contemporary pillars - an angiotensin receptor-neprilysin inhibitor or ACE inhibitor or
    ARB, an evidence-based beta blocker, a mineralocorticoid receptor antagonist and an SGLT2
    inhibitor - with diuresis for congestion as required. It is not directed at the actin lesion, and no CMD1R
    outcome data exist. Recorded because it is what these patients actually receive, and
    without an efficacy claim.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin receptor-neprilysin inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: evidence-based beta blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  notes: >-
    All four pillars of contemporary HFrEF therapy are bound. The mineralocorticoid receptor
    antagonist is bound to `NCIT:C101255` Aldosterone Receptor Antagonist, which is the class
    term NCIT files it under; searching the "mineralocorticoid" spelling does not surface it.

    No treatment_effect and no target_mechanisms link. Neither exists in the CMD1R literature,
    and asserting one would claim a mechanism-level effect that has not been shown for this
    genotype. The E361G mouse suggests, without testing, that a therapy acting through
    beta-adrenergic signalling faces a sarcomere that cannot transduce it.
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for prevention of sudden cardiac death, indicated by general cardiomyopathy
    and arrhythmia criteria. There is no ACTC1-specific arrhythmic risk stratification, and
    the single reported sudden death in a CMD1R patient occurred in an infant who also carried
    a TTN variant, which is not a basis for a genotype-specific rule.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  notes: >-
    Deliberately carries no evidence item. Quoting the general DCM device literature here
    would attach a cohort denominator that is not CMD1R's.
- name: Heart Transplantation
  description: >-
    The endpoint for refractory advanced heart failure, on the same criteria as any other
    dilated cardiomyopathy. No CMD1R-specific transplant series exists.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
- name: Cascade Screening of At-Risk Relatives
  description: >-
    Cardiac surveillance of first-degree relatives with genetic testing where the familial
    variant is known. The rationale in CMD1R is the disease's own history: the gene was found
    by cosegregation in families, and the E361G mouse suggests carriers may look normal at
    rest until stressed, which is an argument for imaging relatives rather than waiting for
    symptoms. Contemporary implementation guidance for genotype-positive relatives of any
    cardiomyopathy gene suggests ECG plus echocardiography every one to three years before
    age sixty and every three to five years thereafter, individualised by variant, family
    history and phenotype. That interval is general cardiomyopathy practice, not an ACTC1
    finding, and no CMD1R-specific surveillance schedule has been validated.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic screening of at-risk relatives
    term:
      id: NCIT:C92803
      label: Genetic Screening
  evidence:
  - reference: PMID:20301486
    reference_title: "Dilated Cardiomyopathy Overview."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Provide a basic view of genetic risk assessment of at-risk asymptomatic"
    explanation: >-
      GeneReviews names risk assessment of asymptomatic relatives as one of the overview's
      purposes. Quoted short because the cached record for this chapter holds only the front
      matter, and indirect because it is generic to DCM rather than to ACTC1.
animal_models:
- name: ACTC E361G transgenic mouse
  species: Mouse
  genotype: Transgenic expressing human ACTC E361G at approximately 50% of total cardiac actin
  publication: PMID:20600154
  description: >-
    The only animal model of an ACTC1 dilated-cardiomyopathy allele. It expresses the human
    E361G actin at about half of total cardiac actin, which approximates the heterozygous
    human state better than most sarcomeric transgenics do. Its scientific value is that it
    is almost normal: baseline contractility, cardiac dimensions and myocyte function are
    unremarkable, and the phenotype only appears when the animal is challenged with
    dobutamine or with four weeks of angiotensin II.
  modeled_mechanisms:
  - target: Loss of Adrenergic Contractile and Lusitropic Reserve
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      This node is defined by the mouse rather than merely supported by it. Blunted inotropic
      and lusitropic responses to dobutamine, measured by papillary muscle mechanics,
      conductance catheter and echocardiography, are the primary observations.
    limitations: >-
      A transgenic overexpression model rather than a knock-in, so the mutant protein competes
      with endogenous mouse actin at a ratio set by the transgene rather than by allelic
      balance. Mouse and human cardiac beta-adrenergic signalling and heart rates differ
      substantially, and the corresponding measurement - contractile reserve on stress testing
      - has never been made in a human ACTC1 carrier.
    readouts:
    - name: Dobutamine-stimulated increase in cardiac output
      target: Loss of Adrenergic Contractile and Lusitropic Reserve
      direction: DECREASED
      interpretation: >-
        The standard measure of inotropic reserve, and the one that falls furthest - from
        2,100 to 900 microlitres per minute.
      evidence:
      - reference: PMID:26432839
        reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "The combination of these effects is to reduce the dobutamine-stimulated increase in CO (a measure of cardiac reserve) from 2,100 to 900 μl/min."
        explanation: The measurement, with both values.
    - name: Peak rate of force decline normalised to force in papillary muscle under dobutamine
      target: Loss of Adrenergic Contractile and Lusitropic Reserve
      direction: DECREASED
      interpretation: >-
        The lusitropic readout. DECREASED refers to the dobutamine-induced *increment*: wild
        type gains about 50% and the mutant only 20 to 30%, so the drug-stimulated relaxation
        response is smaller, not that relaxation is slower at baseline.
      evidence:
      - reference: PMID:26432839
        reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz."
        explanation: >-
          The wild-type and mutant increments side by side, which is what makes this a blunted
          response rather than an absolute deficit.
    evidence:
    - reference: PMID:20600154
      reference_title: "Investigation of a transgenic mouse model of familial dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "However, the increase in septal thickening, ejection fraction, heart rate and cardiac output following dobutamine treatment was significantly less in ACTC E361G mice compared with NTG."
      explanation: >-
        Establishes the model as informative for this node: the reserve deficit is the
        phenotype it has.
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reaches a dilated, dysfunctional ventricle, but only after four weeks of
      angiotensin II infusion, and it passes through a hypertrophic stage on the way.
    limitations: >-
      PARTIALLY_RECAPITULATES because the model does not develop spontaneous dilated
      cardiomyopathy: over 4 to 18 months unstressed it is indistinguishable from wild type,
      and the DCM phenotype requires an experimental pressor stress that has no counterpart in
      the human disease. The authors also note that the response to chronic angiotensin II is
      strongly mouse-strain dependent, and that C57BL/6 animals are particularly resistant,
      which limits how far the stress protocol generalises.
    readouts:
    - name: Left ventricular ejection fraction after chronic angiotensin II
      target: Left Ventricular Dilation and Systolic Dysfunction
      direction: DECREASED
      interpretation: >-
        The endpoint the authors interpret as dilated cardiomyopathy in this model.
      evidence:
      - reference: PMID:26432839
        reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM."
        explanation: The measured drop and the authors' reading of it.
    evidence:
    - reference: PMID:26432839
      reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "Altogether, these data suggest that under chronic angiotensin-induced stress,ACTCE361G mouse hearts develop hypertrophy initially and later dilation."
      explanation: >-
        Supports the model as informative for the dilation node, and states the hypertrophic
        intermediate stage that makes the recapitulation partial rather than complete.
    - reference: PMID:26432839
      reference_title: "A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress."
      supports: NO_EVIDENCE
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "A number of studies point to a significant effect of mouse strain, or even substrain, in determining the response to chronic cardiac stress, including chronic isoprenaline or angiotensin infusion (1,7,9,10,30), and it appears that C57BL/6 mice are particularly resistant to ANG II (25)."
      explanation: >-
        NO_EVIDENCE rather than REFUTE: the authors are stating a limitation of the stress
        protocol, not reporting an experiment that contradicts the finding. It bears on how
        far the model generalises without cutting either way on the claim.
- name: Acta1b p.T126I zebrafish
  species: Zebrafish
  genotype: Acta1b p.T126I, orthologous to human ACTC1 p.T126I
  publication: PMID:42563511
  description: >-
    A zebrafish knock-in carrying the fish orthologue of a human ACTC1 DCM allele, followed
    longitudinally and analysed separately by sex. Unlike the E361G mouse it develops
    spontaneous progressive dilated cardiomyopathy with ventricular dilation, pericardial
    effusion and reduced survival, without an imposed stress. Its most striking result is a
    sex effect: female mutants had earlier and sustained diastolic dysfunction, more
    remodelling and significantly worse survival.
  modeled_mechanisms:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Progressive dilation and pump failure arising without experimental provocation, which
      is the part of the human phenotype the mouse model does not reproduce unaided.
    limitations: >-
      Fidelity is LOW for a specific and important reason: the mutation was made in acta1b, a
      *skeletal* actin paralogue standing in for cardiac actin, because zebrafish gene
      duplication does not map one-to-one onto human ACTC1. The two-chambered zebrafish heart
      has no left ventricle, so "left ventricular dilation" is an interpretation of ventricular
      dilation in a single ventricle. The sexual dimorphism, which is the paper's headline
      finding, has no established counterpart in human ACTC1 disease.
    readouts:
    - name: Survival of adult mutants
      target: Left Ventricular Dilation and Systolic Dysfunction
      direction: DECREASED
      interpretation: >-
        Reduced survival accompanying progressive dilation, the organism-level consequence.
      evidence:
      - reference: PMID:42563511
        reference_title: "Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with human actin mutation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "Mutants showed variable onset of cardiac dysfunction, with progressive DCM, pericardial effusion, ventricular dilation, and reduced survival in adults."
        explanation: The phenotype and the survival readout in one sentence.
    - name: nppb transcript at pre-symptomatic stage
      target: Left Ventricular Dilation and Systolic Dysfunction
      direction: INCREASED
      interpretation: >-
        The natriuretic-peptide marker of cardiac stress rising before overt dysfunction,
        which is what makes this model informative about the pre-symptomatic phase.
      evidence:
      - reference: PMID:42563511
        reference_title: "Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with human actin mutation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: "Molecular profiling at a pre-symptomatic stage identified upregulation of nppb, downregulation of hypertrophic transcription factors (gata4, mef2ca), and sex-specific alterations in calcium handling genes (serca2, pln1, slc8a1a) and proteostasis regulators (hsf1, bag3)."
        explanation: >-
          The pre-symptomatic transcriptional signature, with nppb up and the hypertrophic
          transcription factors down.
    evidence:
    - reference: PMID:42563511
      reference_title: "Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with human actin mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: "These findings demonstrate that the Acta1b p.T126I mutation drives progressive, sex-specific DCM in zebrafish, highlighting biological sex as a critical modifier of sarcomeric cardiomyopathy progression and targeted therapy development."
      explanation: >-
        Establishes the model as informative for a dilated-cardiomyopathy node, and states the
        sex modifier that its limitations qualify.
discussions:
- discussion_id: cmd1r_r312h_biophysics_disagreement
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Thin Filament Regulation of Actomyosin
  - mechanistic_hypotheses#actc1_calcium_desensitization_model
  prompt: >-
    Does the ACTC1 R312H variant increase or decrease myofilament calcium sensitivity, and is
    the DCM allele hypocontractile at all?
  rationale: >-
    Three laboratories have measured R312H and reached incompatible answers. In 2010 it
    increased calcium sensitivity of velocity in the motility assay. In 2012 it had reduced
    thermal stability, a raised polymerisation critical concentration and markedly faster
    nucleotide release. In 2022 its melting temperature and polymerisation kinetics were
    indistinguishable from wild type, its calcium sensitivity was reduced rather than raised,
    and it was the most active of the three proteins under relaxing conditions. These are not
    small quantitative differences; they point in opposite directions on the axis the
    canonical model uses to separate DCM from HCM. Until they are reconciled, the mechanistic
    account of the principal ACTC1 DCM allele is unsettled, and this matters therapeutically:
    a myosin activator is the obvious drug for a hypocontractile sarcomere and would worsen
    one whose problem is that it never switches off.
  proposed_experiments:
  - experiment_id: cmd1r_exp_r312h_knockin_mouse
    name: Knock-in mouse or human iPSC-cardiomyocyte carrying ACTC1 R312H
    description: >-
      Generate a heterozygous R312H knock-in - in mouse, and independently in isogenic human
      iPSC-derived cardiomyocytes - and measure myofilament calcium sensitivity, resting
      tension, relaxation kinetics and contractile reserve in the same preparation, avoiding
      the recombinant-protein purification differences the authors themselves blame for the
      disagreement.
    would_support:
    - mechanistic_hypotheses#actc1_residual_activity_relaxation_model
    supporting_outcome:
    - >-
      Elevated resting tension and impaired relaxation with normal or near-normal peak systolic
      force, matching the residual-activity model rather than simple hypocontractility.
    would_refute:
    - mechanistic_hypotheses#actc1_residual_activity_relaxation_model
    refuting_outcome:
    - >-
      Reduced calcium sensitivity and reduced peak force with normal resting tension and normal
      relaxation, which would return the canonical desensitisation model to the field.
  notes: >-
    The 2022 authors propose a zebrafish knock-in as their own next step. A mammalian knock-in
    or an isogenic human iPSC pair is proposed here instead because the open question is
    calcium handling and adrenergic reserve, where zebrafish physiology diverges most.
- discussion_id: cmd1r_no_human_reserve_measurement
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve
  prompt: >-
    Do human ACTC1 carriers actually have reduced contractile reserve before their ventricles
    dilate?
  rationale: >-
    The most complete mechanistic account in this entry - troponin-I phosphorylation
    uncoupling producing a heart that is normal at rest and fails under stress - rests entirely
    on one transgenic mouse line carrying one allele, studied by one group. It is coherent and
    it is corroborated across reconstituted filaments, papillary muscle and intact animals, but
    every step of it is murine. No human CMD1R carrier has had contractile reserve measured. If
    the model is right it has an immediate clinical consequence: a genotype-positive relative
    with a normal resting echocardiogram might still be abnormal on stress testing, which would
    make stress echocardiography or cardiopulmonary exercise testing the right surveillance
    tool rather than serial resting imaging. If it is wrong, the mouse is describing a
    transgene artefact.
  proposed_experiments:
  - experiment_id: cmd1r_exp_human_stress_echo
    name: Stress echocardiography and cardiopulmonary exercise testing in genotype-positive ACTC1 carriers
    description: >-
      Recruit ACTC1 variant carriers identified by cascade screening, including those with
      normal resting ventricular dimensions and ejection fraction, and measure contractile and
      lusitropic reserve by dobutamine or exercise stress echocardiography alongside peak
      oxygen uptake, against genotype-negative relatives as controls.
    would_support:
    - pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve
    supporting_outcome:
    - >-
      Blunted augmentation of ejection fraction and of relaxation indices on stress in carriers
      with normal resting studies, mirroring the dobutamine response of the E361G mouse.
    would_refute:
    - pathophysiology#Loss of Adrenergic Contractile and Lusitropic Reserve
    refuting_outcome:
    - >-
      Normal contractile and lusitropic reserve in phenotype-negative carriers, which would
      confine the uncoupling mechanism to the transgenic mouse and leave human dilation
      unexplained by it.
- discussion_id: cmd1r_zebrafish_sex_dimorphism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Zebrafish
  notes: >-
    The anchor is `animal_models#Zebrafish` rather than the model's `name`, because the
    schema resolves `animal_models#` against the `species` slot. It reads oddly beside the
    model's own name and is nonetheless the correct reference.
  prompt: >-
    Is the sex difference in the zebrafish ACTC1 model - earlier diastolic dysfunction and
    worse survival in females - present in human ACTC1 carriers?
  rationale: >-
    The zebrafish acta1b p.T126I model reports pronounced sexual dimorphism as its central
    finding, with female mutants showing earlier and sustained diastolic dysfunction, greater
    remodelling and significantly lower survival. Human dilated cardiomyopathy in general does
    show sex differences, but in the opposite direction from what is usually assumed for
    sarcomeric disease, and no sex-stratified analysis of ACTC1 carriers exists. Two
    features make the translation genuinely uncertain rather than merely untested: the mutation
    is in a skeletal actin paralogue rather than a cardiac one, and zebrafish sex determination
    and cardiac physiology differ substantially from human. Recorded as a mismatch rather than a
    plain knowledge gap because the model evidence is strong and specific while its human
    validity is what is open.
  proposed_experiments:
  - experiment_id: cmd1r_exp_sex_stratified_carriers
    name: Sex-stratified natural-history analysis of ACTC1 dilated-cardiomyopathy carriers
    description: >-
      Pool ACTC1 DCM carriers across cardiomyopathy registries and analyse age at diagnosis,
      diastolic indices, remodelling and event-free survival stratified by sex, with
      non-ACTC1 sarcomeric DCM carriers as the comparison group so that any effect can be
      attributed to the gene rather than to DCM in general.
    would_support:
    - animal_models#Zebrafish
    supporting_outcome:
    - >-
      Earlier onset and worse outcomes in female ACTC1 carriers relative to male carriers, and
      relative to the sex difference seen in non-ACTC1 sarcomeric DCM.
    would_refute:
    - animal_models#Zebrafish
    refuting_outcome:
    - >-
      No sex difference in ACTC1 carriers beyond that seen in sarcomeric DCM generally, which
      would make the zebrafish dimorphism a property of the model rather than of the gene.
notes: >-
  Curated as a DISEASE. MONDO defines this term as familial isolated dilated cardiomyopathy
  caused by ACTC1 mutation, and per-subtype DCM entries are settled convention in this
  knowledge base. The entry has one conserved pathograph from an ACTC1 missense allele through
  altered thin-filament regulation to left ventricular dilation, so it is not a grouping, and
  it has a MONDO term and an OMIM entry of its own, so it is not a subtype line on the DCM
  umbrella. The stub is deleted.

  **How the ACTC1 HCM and congenital-heart literatures were kept out.** The gene-level
  preflight check passes trivially - ACTC1 is mentioned 89 times in the deep-research report -
  and tells you nothing, because every ACTC1 paper mentions ACTC1. The filter used instead was
  MONDO's own definition of this term, familial *isolated* dilated cardiomyopathy, applied
  per citation. Three candidate sources were excluded from the pathograph on that basis and
  moved to differential_diagnoses where they belong: the 2019 report of an ACTC1 p.Gly247Asp
  kindred with penetrant atrial septal defect plus late-onset dilated cardiomyopathy, whose
  myocardial ultrastructure and cardiomyocyte work is real DCM mechanism but comes from a
  non-isolated phenotype; the 2023 report of ACTC1 distal arthrogryposis with congenital heart
  defects, cited only for its one-sentence statement of the gene's allelic spectrum; and a
  2026 case of ACTC1-associated left ventricular noncompaction in a patient who also carried a
  COL4A4 variant. Every pathophysiology citation in this entry is about a DCM-phenotype
  allele - R312H, E361G or A222Thr.

  **Dual MONDO parentage and grouping membership.** MONDO:0013261 has two superclasses -
  familial isolated dilated cardiomyopathy (MONDO:0700335) and left ventricular noncompaction
  (MONDO:0018901) - and "left ventricular noncompaction 4" is among its synonyms. That matters
  because `kb/groupings/Familial_Dilated_Cardiomyopathy.yaml` deliberately excludes the left
  ventricular noncompaction entries as a distinct morphological entity. This entry is
  therefore **not** added to that grouping in this pull request. The reason is not that CMD1R
  fails to belong, but that adding a dual-parented CMD/LVNC term is a change to the grouping's
  own inclusion rule and should be argued in a pull request against the grouping, where the
  same question can be settled for every other dual-parented term at once, rather than settled
  by side effect here. The `parents:` list carries `Dilated Cardiomyopathy`, which is the
  claim the evidence in this entry actually supports.

  **Cross-reference.** `Hypertrophic_Cardiomyopathy_11` is the ACTC1 hypertrophic entry
  (CMH11) and already records that ACTC1 is allelically pleiotropic. The two entries are the
  same gene at opposite ends of the R312 contrast and should be read together.

  ClinGen's arrhythmogenic right ventricular cardiomyopathy panel classifies ACTC1 for ARVC as
  No Known Disease Relationship, which is cited in the genetic section. It is the one boundary
  of this gene's phenotype spectrum that is settled by an expert panel rather than merely
  unexplored.

  What is deliberately not curated: no biochemical markers, no clinical trials, no datasets,
  no environmental factors and no histopathology. Cardiomyocyte apoptosis, sarcomeric disarray
  and extracellular-matrix expansion have been described for an ACTC1 allele, but only in the
  atrial-septal-defect kindred, so importing them would breach the scoping rule above. No
  prevalence rate is asserted: DCM cohort denominators are not ACTC1 denominators.

📚

References & Deep Research

References

1

PMID:20301486

Dilated Cardiomyopathy Overview.

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 (2)

Record notes

Curated as a DISEASE. MONDO defines this term as familial isolated dilated cardiomyopathy caused by ACTC1 mutation, and per-subtype DCM entries are settled convention in this knowledge base. The entry has one conserved pathograph from an ACTC1 missense allele through altered thin-filament regulation to left ventricular dilation, so it is not a grouping, and it has a MONDO term and an OMIM entry of its own, so it is not a subtype line on the DCM umbrella. The stub is deleted. **How the ACTC1 HCM and congenital-heart literatures were kept out.** The gene-level preflight check passes trivially - ACTC1 is mentioned 89 times in the deep-research report - and tells you nothing, because every ACTC1 paper mentions ACTC1. The filter used instead was MONDO's own definition of this term, familial *isolated* dilated cardiomyopathy, applied per citation. Three candidate sources were excluded from the pathograph on that basis and moved to differential_diagnoses where they belong: the 2019 report of an ACTC1 p.Gly247Asp kindred with penetrant atrial septal defect plus late-onset dilated cardiomyopathy, whose myocardial ultrastructure and cardiomyocyte work is real DCM mechanism but comes from a non-isolated phenotype; the 2023 report of ACTC1 distal arthrogryposis with congenital heart defects, cited only for its one-sentence statement of the gene's allelic spectrum; and a 2026 case of ACTC1-associated left ventricular noncompaction in a patient who also carried a COL4A4 variant. Every pathophysiology citation in this entry is about a DCM-phenotype allele - R312H, E361G or A222Thr. **Dual MONDO parentage and grouping membership.** MONDO:0013261 has two superclasses - familial isolated dilated cardiomyopathy (MONDO:0700335) and left ventricular noncompaction (MONDO:0018901) - and "left ventricular noncompaction 4" is among its synonyms. That matters because `kb/groupings/Familial_Dilated_Cardiomyopathy.yaml` deliberately excludes the left ventricular noncompaction entries as a distinct morphological entity. This entry is therefore **not** added to that grouping in this pull request. The reason is not that CMD1R fails to belong, but that adding a dual-parented CMD/LVNC term is a change to the grouping's own inclusion rule and should be argued in a pull request against the grouping, where the same question can be settled for every other dual-parented term at once, rather than settled by side effect here. The `parents:` list carries `Dilated Cardiomyopathy`, which is the claim the evidence in this entry actually supports. **Cross-reference.** `Hypertrophic_Cardiomyopathy_11` is the ACTC1 hypertrophic entry (CMH11) and already records that ACTC1 is allelically pleiotropic. The two entries are the same gene at opposite ends of the R312 contrast and should be read together. ClinGen's arrhythmogenic right ventricular cardiomyopathy panel classifies ACTC1 for ARVC as No Known Disease Relationship, which is cited in the genetic section. It is the one boundary of this gene's phenotype spectrum that is settled by an expert panel rather than merely unexplored. What is deliberately not curated: no biochemical markers, no clinical trials, no datasets, no environmental factors and no histopathology. Cardiomyocyte apoptosis, sarcomeric disarray and extracellular-matrix expansion have been described for an ACTC1 allele, but only in the atrial-septal-defect kindred, so importing them would breach the scoping rule above. No prevalence rate is asserted: DCM cohort denominators are not ACTC1 denominators.

Create: Dilated Cardiomyopathy 1R (CMD1R, ACTC1) · 2026-09-03T20:48:23Z · View source

New Disease entry for MONDO:0013261 (CMD1R, ACTC1). entry_type decision: DISEASE - one conserved pathograph from an ACTC1 missense allele through altered thin-filament regulation to left ventricular dilation, its own MONDO term and OMIM 613424, and per-subtype DCM entries are settled convention here. Stub deleted. Named Entity Confusion handling. ACTC1 also causes hypertrophic cardiomyopathy, left ventricular noncompaction, atrial septal defect and a distal arthrogryposis syndrome, and those literatures are larger than the DCM one. The gene-level preflight passes trivially (ACTC1 mentioned 89 times) and is uninformative. The filter used instead was MONDO's own definition of this term - familial ISOLATED dilated cardiomyopathy - applied per citation. Three sources were excluded from the pathograph and moved to differential_diagnoses: PMID:31430208 (ACTC1 p.Gly247Asp kindred with penetrant atrial septal defect plus late-onset DCM - its myocardial ultrastructure and cardiomyocyte apoptosis work is genuine DCM mechanism but comes from a non-isolated phenotype, so the histopathology it would have supplied is deliberately not curated); PMID:37457373 (distal arthrogryposis with congenital heart defects, cited only for its one-sentence statement of the gene's allelic spectrum); and PMID:41033995 (LVNC in a patient also carrying COL4A4). Every pathophysiology citation is about a DCM-phenotype allele - R312H, E361G or A222Thr. Mechanism curated as three competing hypothesis groups rather than one story, because the ACTC1 literature genuinely disagrees: canonical calcium-desensitization (CANONICAL, carrying two REFUTE evidence items against itself), troponin-I phosphorylation uncoupling with loss of cardiac reserve (ALTERNATIVE, the E361G mouse, best in vivo support), and residual myosin activity under relaxing conditions (EMERGING, the 2022/2024 R312 work). A KNOWLEDGE_GAP discussion records that three laboratories measured R312H and disagree on the direction of the calcium-sensitivity shift, with the therapeutic consequence spelled out. A HUMAN_MODEL_MISMATCH discussion records that no human ACTC1 carrier has had contractile reserve measured. Evidential footing recorded explicitly: ClinGen grades ACTC1-DCM as Moderate (2025, DCM GCEP) against Definitive for ACTC1-HCM (2021, HCM GCEP). Both CGGV assertions are cited, the HCM one flagged directness INDIRECT and included solely to fix the asymmetry. No prevalence rate asserted - DCM cohort denominators are not ACTC1 denominators. Fatal infant outcome placed in progression rather than as a phenotype. No treatment carries a TreatmentEffectEnum value or a target_mechanisms link, since no CMD1R outcome data exist. Deep research: falcon provider, preflight-dr PASS. The report surfaced PMID:39759977 (de novo A222Thr infant case) and PMID:37457373, both used; it also surfaced the p.Gly247Asp ASD material, which is the contamination the entry fences off. Validation: just validate, validate-terms, count-verified-snippets 61/61, validate-disorders, check-duplicate-keys, check-entity-refs, check-causal-targets, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-folded-hyphens, check-stubs - all exit 0.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 18 citations 2026-09-03T13:17:49.753203

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Dilated Cardiomyopathy 1R (CMD1R, ACTC1-related dilated cardiomyopathy)
MONDO ID: MONDO:0013261 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1R (CMD1R, ACTC1-related dilated cardiomyopathy) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1R (CMD1R): ACTC1-related dilated cardiomyopathy

Executive summary and evidence boundaries

CMD1R is an exceptionally rare, usually autosomal-dominant sarcomeric cardiomyopathy caused by pathogenic germline variants in ACTC1, encoding α-cardiac actin. The core phenotype is left-ventricular or biventricular dilation with systolic dysfunction not sufficiently explained by coronary disease, loading conditions, valvular disease, or congenital heart disease. ACTC1 alleles are markedly pleiotropic: different variants can cause isolated DCM, hypertrophic cardiomyopathy (HCM), left-ventricular noncompaction (LVNC), atrial septal defect (ASD), or a congenital-contracture syndrome with cardiac abnormalities. Consequently, pathogenicity and prognosis must be assessed at the variant–phenotype level rather than inferred merely from the gene name. Open Targets independently links ACTC1 (ENSG00000159251) to DCM, familial DCM, and familial isolated DCM, drawing partly on landmark human genetic studies (PMIDs 9563954 and 20301486). (OpenTargets Search: dilated cardiomyopathy-ACTC1)

The evidence base consists mainly of a few pedigrees, individual cases, myocardial pathology, cultured cardiomyocytes, purified-protein assays, and computational modeling. Disease-specific prevalence, prospective natural history, treatment-response rates, quality-of-life data, and ACTC1-directed trials are unavailable. General DCM statistics and recommendations are therefore labeled explicitly as extrapolations.

The following table summarizes the most actionable evidence.

Domain	Best-supported finding	Evidence type	Key ontology/identifier	Important limitation
Disease identity	CMD1R denotes ACTC1-related familial dilated cardiomyopathy, a rare sarcomeric cardiomyopathy characterized by ventricular dilation and systolic dysfunction.	Aggregated disease-level resources plus human pedigrees	ACTC1: MIM 102540; DCM: MONDO:0005021	The requested MONDO:0013261 should be independently verified before database ingestion; some resources map ACTC1 to broad familial DCM rather than a uniquely resolved CMD1R concept. (OpenTargets Search: dilated cardiomyopathy-ACTC1, chong2023variantsinactc1 pages 7-10)
Genetic architecture	Best-established disease mechanism is heterozygous germline missense variation with autosomal-dominant segregation; de novo cases also occur.	Human familial segregation and case reports	ACTC1; chr15q14; AD inheritance	Penetrance and phenotype are variant-specific; an ACTC1 variant associated with another phenotype cannot automatically be classified as pathogenic for DCM. (frank2019cardiacαactin(actc1) pages 1-2, chong2023variantsinactc1 pages 7-10, acunaochoa2024adenovo pages 1-2)
Foundational evidence	Olson et al. identified ACTC1 missense variants cosegregating with hereditary idiopathic DCM in two unrelated families and proposed defective force transmission through Z-band/intercalated-disc interfaces.	Primary human genetic study	Science, May 1998; DOI: 10.1126/science.280.5364.750	Small pedigree-based discovery study predating modern population databases and ACMG/AMP classification. (chong2023variantsinactc1 pages 22-24)
Quantitative familial evidence	p.Gly247Asp was present in 15 affected relatives and absent from 63 unaffected relatives; ASD-II occurred in about 88% of carriers, while DCM generally emerged in the fourth–fifth decades. Outcomes included transplantation at ages 51 and 55 and sudden death at 63.	Human linkage, segregation, imaging, and myocardial pathology	ACTC1 p.Gly247Asp; ASD: HP:0001631; DCM: HP:0001644	“Fully penetrant” referred to the combined familial phenotype; DCM itself affected only a subset and was age-dependent. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)
2023 phenotypic expansion	Five families with heterozygous ACTC1 missense variants established a syndromic spectrum of distal arthrogryposis with congenital heart defects; one p.Arg185Trp carrier had borderline LV systolic function (LVEF 52%) and reduced strain.	Human case series plus molecular-dynamics modeling	DOI: 10.1016/j.xhgg.2023.100213; ACTC1 MIM 102540	This is not a classical isolated-CMD1R cohort; it demonstrates allelic and tissue pleiotropy rather than DCM prevalence. (chong2023variantsinactc1 pages 13-16, chong2023variantsinactc1 pages 7-10)
2024 infant case	A 1-year-old with severe LV dilation/dysfunction and sudden death carried apparently de novo ACTC1 c.664G>A (p.Ala222Thr) plus paternally inherited TTN p.Glu11084Lys.	Single human case; NGS, Sanger validation, and computational modeling	DOI: 10.1155/crig/9517735; HP:0001644; HP:0001699	Causality cannot be assigned to ACTC1 alone because of the co-occurring TTN variant and absence of direct functional validation. (acunaochoa2024adenovo pages 1-2)
Mechanism	Mutant α-cardiac actin can impair actin polymerization/turnover, thin-filament organization, actomyosin regulation, and force transmission, leading to hypocontractility, sarcomeric disarray, myofibrillar degeneration, apoptosis, extracellular-matrix expansion, remodeling, and heart failure.	Human myocardial pathology, cultured rat cardiomyocytes, purified-protein assays, and computational modeling	Suggested GO: actin filament organization (GO:0007015), muscle contraction (GO:0006936), cardiac muscle contraction (GO:0060048), apoptotic process (GO:0006915)	Mechanisms differ among substitutions; calcium-desensitization and dominant-negative models are plausible but not universal across ACTC1 variants. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6, jones2023divergenceofdisease pages 68-73)
Diagnosis	Diagnosis requires DCM phenotyping with history/pedigree, ECG, echocardiography, ambulatory rhythm monitoring, and usually CMR, followed by a curated cardiomyopathy panel including ACTC1 and ACMG/AMP variant interpretation; a pathogenic familial variant enables cascade testing.	Contemporary cardiomyopathy guidance extrapolated to ACTC1	DCM: HP:0001644; reduced LVEF: HP:0012664; genetic testing intervention	No ACTC1-specific diagnostic threshold exists; a VUS must not establish diagnosis or direct predictive testing. (jurcut2025keyprioritiesfor pages 6-7, sorella2025diagnosisandmanagement pages 12-13, mcnally2017dilatedcardiomyopathygenetic pages 3-4)
Treatment	Management is phenotype-based guideline-directed therapy for HFrEF and complications: neurohormonal therapy, diuretics for congestion, rhythm/thromboembolism management, ICD/CRT when standard criteria are met, and mechanical support or transplantation for refractory advanced disease.	General DCM/heart-failure guidelines and limited ACTC1 case experience	Suggested NCIT: pharmacologic therapy, implantable cardioverter-defibrillator, cardiac resynchronization therapy, heart transplantation	No drug, device criterion, or pharmacogenomic recommendation is validated specifically for ACTC1-CMD1R. (frustaci2018novelα‐actingene pages 6-7, sorella2025diagnosisandmanagement pages 12-13)
Epidemiology	ACTC1-CMD1R is exceptionally rare; no reliable disease-specific prevalence, incidence, carrier frequency, sex ratio, founder effect, or geographic enrichment has been established.	Evidence-gap assessment from sparse pedigrees/cases	Orphan/Mendelian disease; broad DCM only: MONDO:0005021	General DCM estimates must not be reported as ACTC1-specific epidemiology. (OpenTargets Search: dilated cardiomyopathy-ACTC1, acunaochoa2024adenovo pages 1-2)
Clinical trials	No interventional trial specifically targeting ACTC1-CMD1R was identified; available genetic/familial DCM studies enroll mixed genotypes and test early neurohormonal or precision-care strategies.	Clinical-trial registry search	Example mixed-genotype study: NCT05321875	Results from unselected or mixed-genotype DCM trials cannot be assumed to show ACTC1-specific efficacy. (frank2019cardiacαactin(actc1) pages 1-2, chong2023variantsinactc1 pages 1-5)

Table: Compact evidence table distinguishing well-supported ACTC1-specific findings from general DCM guidance and unresolved evidence gaps. It highlights foundational pedigrees, recent phenotypic expansion, mechanisms, and the absence of disease-specific epidemiology or therapy.

1. Disease information

Definition and nomenclature

Preferred name: Dilated cardiomyopathy 1R; CMD1R; ACTC1-related dilated cardiomyopathy. Common alternatives include familial dilated cardiomyopathy due to ACTC1, cardiac α-actin–related DCM, and historically ACTC/ACTC1-associated idiopathic dilated cardiomyopathy.

Key identifiers and mappings

Gene: ACTC1, actin alpha cardiac muscle 1; OMIM/MIM 102540; Ensembl ENSG00000159251; chromosome 15q14. (OpenTargets Search: dilated cardiomyopathy-ACTC1, chong2023variantsinactc1 pages 7-10)
Broad DCM: MONDO MONDO:0005021; familial DCM MONDO:0016333; familial isolated DCM MONDO:0700335 in Open Targets. (OpenTargets Search: dilated cardiomyopathy-ACTC1)
Requested disease identifier: MONDO:0013261 should be verified directly against the current MONDO release before ingestion; the retrieved authoritative mappings did not independently resolve that identifier to CMD1R.
OMIM disease number: commonly reported for CMD1R as 613424, but the retrieved text also associated MIM 613424 with ACTC1-related LVNC. Because historical ACTC1 phenotype labels overlap, this number likewise requires direct OMIM verification before database loading. (chong2023variantsinactc1 pages 7-10)
MeSH: Cardiomyopathy, Dilated; no ACTC1-specific MeSH descriptor identified.
ICD-10-CM: I42.0, dilated cardiomyopathy. ICD-11: use the current dilated-cardiomyopathy category with genetic etiology extension where locally supported; there is no ACTC1-specific billing code.
SNOMED CT: inherited/familial dilated cardiomyopathy and genetic disorder concepts may be combined; verify release-specific identifiers.

This report is an aggregated disease-level synthesis from published patients, pedigrees, experimental systems, guidelines, and databases—not an individual EHR-derived record.

Foundational evidence

Olson et al. reported ACTC1 missense mutations cosegregating with hereditary idiopathic DCM in two unrelated families. Their abstract states: “Both mutations affect universally conserved amino acids in domains of actin that attach to Z bands and intercalated discs” and proposes defective force transmission as a mechanism of heart failure. Science, 1 May 1998; DOI 10.1126/science.280.5364.750; PMID 9563954. (chong2023variantsinactc1 pages 22-24, OpenTargets Search: dilated cardiomyopathy-ACTC1)

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The initiating lesion is usually a heterozygous germline ACTC1 missense variant. Familial segregation supports autosomal-dominant inheritance; de novo alleles also occur. The principal molecular etiologies are variant-dependent disruption of α-cardiac-actin polymerization, thin-filament assembly/regulation, actomyosin mechanics, or force transmission to Z-discs and intercalated discs. (frank2019cardiacαactin(actc1) pages 1-2, acunaochoa2024adenovo pages 1-2, jones2023divergenceofdisease pages 68-73)

Genetic risk factors

A pathogenic/likely pathogenic ACTC1 variant is the major causal risk factor.
Family history of DCM, unexplained heart failure, transplant, sudden death, ASD, HCM, LVNC, arrhythmia, or congenital contractures increases prior probability.
Additional variants may modify severity. In the 2024 infant report, ACTC1 p.Ala222Thr occurred with a paternally inherited TTN p.Glu11084Lys variant; the contribution of each allele cannot be disentangled. (acunaochoa2024adenovo pages 1-2)
ACTC1 had only moderate monogenic DCM evidence in the 2021 ClinGen-style assessment, emphasizing that even in a valid disease gene, individual variants require rigorous ACMG/AMP evaluation.

No reproducible CMD1R modifier gene, polygenic score, founder allele, or protective ACTC1 allele has been established.

Environmental and lifestyle factors

There is no ACTC1-specific quantified environmental risk. By analogy with genetic DCM, myocardial stressors—heavy alcohol exposure, cardiotoxic chemotherapy, myocarditis, pregnancy/peripartum stress, uncontrolled hypertension, tachyarrhythmia, and extreme sustained exercise—may unmask or worsen a susceptible myocardium, but this interaction has not been demonstrated specifically for ACTC1. Infectious agents do not cause the Mendelian lesion, although viral myocarditis can be a competing or superimposed myocardial insult.

Protective factors

No genetic or nutritional protective factor is validated. Practical risk reduction consists of avoiding cardiotoxic exposure, treating hypertension and arrhythmias, limiting alcohol, maintaining vaccination and infection prevention appropriate for heart-failure patients, and detecting ventricular dysfunction early. These are tertiary/secondary prevention measures, not prevention of inheriting the variant.

3. Phenotypes

Phenotype	Type and course	Disease-specific evidence	Suggested HPO
Dilated cardiomyopathy	Structural/functional sign; onset ranges from infancy to middle age; often progressive	Core CMD1R phenotype	HP:0001644
LV dilation	Imaging sign; severity variable	Severe in the 1-year-old 2024 case	HP:0001711
Reduced systolic function/LVEF	Imaging/functional abnormality	Borderline LVEF 52% in one 2023 p.Arg185Trp carrier; severe dysfunction in the infant case	HP:0012664
Heart failure	Symptom complex/sign; progressive or episodically decompensated	Late onset in p.Gly247Asp carriers; advanced cases required transplant	HP:0001635
Dyspnea/exercise intolerance/fatigue	Symptoms	Expected with overt DCM; variant-specific frequencies unavailable	HP:0002094, HP:0003546, HP:0012378
Ventricular/atrial arrhythmia	Electrophysiologic sign	Atrial flutter/fibrillation reported after ASD closure; sudden death occurred in severe cases	HP:0001663, HP:0005110, HP:0001699
Secundum ASD	Congenital structural sign	About 88% of p.Gly247Asp carriers in the reported families	HP:0001631
LVNC/trabeculation	Imaging/pathology sign	Part of broader ACTC1 allelic spectrum, not obligatory CMD1R	HP:0030680
Sarcomeric/myofibrillar disarray	Histopathology	Demonstrated in p.Gly247Asp myocardium	HP:0003198 or local pathology term
Distal arthrogryposis/contractures	Musculoskeletal manifestation	2023 allelic syndrome; not typical isolated CMD1R	HP:0002804, HP:0001371

In the p.Gly247Asp family, DCM generally emerged in the fourth or fifth decade. Documented severe outcomes were transplant at ages 51 and 55 and sudden death at 63. This demonstrates age-dependent expression of DCM even though the combined ASD/cardiomyopathy familial phenotype was described as fully penetrant. (frank2019cardiacαactin(actc1) pages 4-6)

At the opposite temporal extreme, a 1-year-old Mexican child had severe LV dilation and dysfunction followed by sudden cardiac death. Because the child carried ACTC1 p.Ala222Thr plus a TTN variant, this is evidence for possible oligogenic severe infantile disease, not proof that p.Ala222Thr alone causes CMD1R. Case Reports in Genetics, 2024; DOI 10.1155/crig/9517735. (acunaochoa2024adenovo pages 1-2)

Quality of life: no ACTC1-specific EQ-5D, SF-36, PROMIS, or disease-specific patient-reported outcome study was found. Overt heart failure predictably impairs exertion, employment/school participation, sleep, and psychosocial well-being; arrhythmia and sudden-death risk add anxiety and device burden. These are general DCM effects rather than quantified CMD1R estimates.

4. Genetic and molecular information

Gene and protein

ACTC1 encodes α-cardiac actin, the dominant actin isoform in adult myocardium—reported as approximately 80% of adult cardiac actin—and an important fetal cardiac and skeletal-muscle protein. Actin monomers polymerize into F-actin, the sarcomeric thin-filament backbone that binds tropomyosin, troponin, myosin, and cytoskeletal anchoring complexes. (chong2023variantsinactc1 pages 13-16)

Suggested annotations include HGNC:143, UniProt P68032 (verify current releases); GO cellular components sarcomere (GO:0030017), myofibril (GO:0030016), actin filament (GO:0005884), Z disc (GO:0030018), and intercalated disc (GO:0014704).

Variant evidence

Foundational DCM variants: Olson et al. identified two cosegregating missense substitutions in conserved force-transmission domains. The retrieved material did not provide reliable HGVS strings; these should be obtained from the original sequence table rather than reconstructed. (chong2023variantsinactc1 pages 22-24)
p.Gly247Asp: heterozygous exon-5 missense variant, absent from gnomAD/control databases and predicted deleterious by 20/22 algorithms. It occurred in 15 affected relatives and no 63 unaffected relatives in the principal genotyped cohort; a second family also supported segregation. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)
c.664G>A, p.Ala222Thr: apparently de novo in the 2024 infant case; called likely pathogenic by the authors using computational evidence, but direct functional validation and independent cases are absent. Co-occurring TTN variation weakens single-gene attribution. (acunaochoa2024adenovo pages 1-2)
p.Arg312His and p.Glu361Gly: reported DCM-associated substitutions used in mechanistic studies; biochemical effects are assay- and variant-dependent. Purified R312H showed altered regulation and increased residual motility under relaxing conditions in one study. (jones2023divergenceofdisease pages 68-73)
2023 syndromic variants: p.Gly199Ser, p.Arg374Ser, p.Thr68Asn, p.Arg185Trp, and p.Arg374His were de novo or dominantly segregating and absent or exceedingly rare in gnomAD, with CADD >20. They principally caused distal arthrogryposis/congenital defects; they should not automatically be labeled CMD1R variants. (chong2023variantsinactc1 pages 7-10)

The established alleles are overwhelmingly missense and germline. A dominant-negative or altered-function mechanism is more plausible than simple haploinsufficiency for many variants, but it has not been demonstrated uniformly. Population allele frequencies are usually absent or extremely low; exact current gnomAD counts must be reported per transcript/build and ancestry. No recurrent pathogenic copy-number change, translocation, repeat expansion, mitochondrial mutation, or somatic ACTC1 mechanism defines CMD1R.

Modifier and epigenetic data

No CMD1R-specific modifier or epigenetic signature is validated. Increased extracellular-matrix proteins in p.Gly247Asp myocardium indicate downstream remodeling, not a primary inherited epigenetic lesion. No disease-specific methylome, chromatin, single-cell, spatial-transcriptomic, metabolomic, or lipidomic dataset was identified. (frank2019cardiacαactin(actc1) pages 1-2)

5. Environmental information

CMD1R is not infectious, toxic, occupational, or radiation-induced. Environmental insults can nevertheless contribute to penetrance or progression of genetic DCM. A clinical work-up should assess alcohol and stimulant use, anthracyclines and other cardiotoxins, pregnancy timing, endurance exercise, endocrine/nutritional disorders, viral illness, and occupational exposures. Evidence that any one exposure interacts specifically with ACTC1 is unavailable. Smoking is a cardiovascular risk factor but is not known to cause CMD1R.

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous ACTC1 missense variant leads to incorporation of structurally or dynamically altered α-cardiac actin into sarcomeric thin filaments.
Altered actin leads to variant-specific defects in polymerization/turnover, inter-subunit contacts, tropomyosin–troponin regulation, myosin interaction, or attachment-mediated force transmission; the precise defect is experimentally demonstrated for selected variants but inferred for others. (frank2019cardiacαactin(actc1) pages 1-2, chong2023variantsinactc1 pages 13-16, jones2023divergenceofdisease pages 68-73)
Thin-filament dysfunction results in impaired or dysregulated actomyosin force generation and relaxation, with reduced effective contractile reserve.
Chronic mechanical inefficiency leads to myofibrillar/Z-disc disarray and degeneration; a branch leads to abnormal calcium-regulated activity, while another branch leads to cytoskeletal/intercalated-disc stress.
Cellular stress results in cardiomyocyte shape abnormalities, apoptosis and probably altered autophagy/mitochondrial handling; apoptosis, autophagic vacuoles, and mitochondrial accumulation were observed in p.Gly247Asp-associated tissue, but causal ordering is partly inferred. (frank2019cardiacαactin(actc1) pages 4-6)
Cardiomyocyte loss and mechanical stress lead to extracellular-matrix expansion/fibrosis and adverse ventricular remodeling.
Remodeling results in chamber dilation and reduced ejection fraction, which lead to heart failure, functional mitral regurgitation, thromboembolic risk, and atrial or ventricular arrhythmias.
Severe pump failure or malignant arrhythmia leads to transplantation or premature/sudden death in a subset. (frank2019cardiacαactin(actc1) pages 4-6, acunaochoa2024adenovo pages 1-2)
Developmental branch: fetal ACTC1 dysfunction leads to disturbed actin-dependent morphogenesis and force signaling—an inferred bridge to ASD, LVNC, and contractures—while the same allele may later lead to DCM. (frank2019cardiacαactin(actc1) pages 1-2, chong2023variantsinactc1 pages 13-16)

Mechanistic evidence by system

Human myocardium: p.Gly247Asp tissue showed sarcomeric/Z-band disarray, myofibrillar degeneration, wavy/streaming Z-discs, autophagic vacuoles, mitochondrial accumulation, apoptosis, and increased extracellular-matrix proteins. This is direct disease-tissue evidence, although based on very limited sampling. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)

Cultured cardiomyocytes: neonatal rat ventricular cardiomyocytes overexpressing p.Gly247Asp developed abnormal morphology, sarcomeric defects, and increased apoptosis compared with wild-type ACTC1. Overexpression and immature rat cells limit quantitative translation to heterozygous adult human myocardium. (frank2019cardiacαactin(actc1) pages 1-2)

Computational structure: molecular dynamics implicated impaired G247D polymerization/turnover. Modeling of 2023 contracture-associated variants predicted D-loop/subdomain-2 contact disruption, increased filament disorder, weaker force or slower force development. These are mechanistic predictions, not direct measurements in affected human hearts. (chong2023variantsinactc1 pages 13-16)

Purified proteins: R312H/R312C experiments found altered calcium response, incomplete inhibition under relaxing conditions, and possible changed tropomyosin/blocked-state energetics. The authors explicitly treated the link between resting activity and divergent HCM/DCM phenotypes as a hypothesis. (jones2023divergenceofdisease pages 68-73)

Suggested GO biological processes: actin filament organization (GO:0007015), actin filament polymerization (GO:0030041), muscle contraction (GO:0006936), cardiac muscle contraction (GO:0060048), sarcomere organization (GO:0045214), regulation of heart contraction (GO:0008016), apoptotic process (GO:0006915), extracellular-matrix organization (GO:0030198), and cardiac chamber morphogenesis (GO:0003206).

Principal cell types are cardiac muscle cell/cardiomyocyte (CL:0000746), atrial cardiomyocyte, ventricular cardiomyocyte, and downstream cardiac fibroblast. Immune activation, canonical Wnt/MAPK/mTOR pathways, or a disease-specific metabolic pathway has not been established for CMD1R.

7. Anatomical structures affected

The primary organ is the heart (UBERON:0000948), especially myocardium (UBERON:0002349) and left ventricle (UBERON:0002084); biventricular involvement can occur. The atrial septum is affected in developmental ACTC1 phenotypes. At tissue level, the lesion is cardiac striated muscle; at cellular level, ventricular cardiomyocytes predominate. Subcellular sites are thin filaments, sarcomeres, myofibrils, Z-discs, intercalated discs, and secondarily mitochondria/autophagic compartments. Disease is diffuse rather than unilateral; lateralization is not applicable.

Secondary structures may include atria through dilation/arrhythmia, valves through functional regurgitation, lungs through venous congestion, liver and kidneys through advanced low-output/congestive failure, and systemic arteries/brain through thromboembolism. Skeletal-muscle/joint abnormalities belong principally to the recently delineated syndromic ACTC1 spectrum. (chong2023variantsinactc1 pages 13-16, chong2023variantsinactc1 pages 7-10)

8. Temporal development

Onset is highly variable—from severe infantile disease to asymptomatic childhood carrier status and late-onset DCM in the fourth or fifth decade. The usual pattern is chronic and initially insidious: genotype-positive/phenotype-negative state → subtle ECG, strain, or chamber changes → overt LV systolic dysfunction/dilation → symptomatic heart failure/arrhythmia → advanced heart failure or sudden death in severe cases.

The p.Gly247Asp pedigree demonstrates a critical need for lifelong surveillance, because congenital ASD preceded late DCM by decades. (frank2019cardiacαactin(actc1) pages 4-6) Reverse remodeling can occur with general heart-failure therapy, but genetic substrate persists; apparent remission does not eliminate relapse risk. No ACTC1-specific progression rate or remission proportion is available.

9. Inheritance and population

Inheritance

Inheritance is predominantly autosomal dominant, with vertical transmission and male-to-male transmission possible. De novo missense alleles occur. Penetrance is variant- and age-dependent, and expressivity is broad: DCM, ASD, HCM, LVNC, or syndromic contractures may occur. The G247D combined familial phenotype showed strong/nominally complete segregation, but only a subset developed DCM and generally later in life. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)

Genetic anticipation is not established. Germline mosaicism is theoretically possible after an apparently de novo result but has not been documented. Consanguinity is not a typical driver of this dominant disease. No validated founder effect, ethnic enrichment, carrier frequency, geographic cluster, or sex ratio exists.

Epidemiology

ACTC1-specific prevalence and incidence are unknown. Published evidence consists of rare families and cases; broad DCM rates must not be assigned to CMD1R. One 2024 report cited general DCM prevalence of approximately 1:250–400 and incidence of 5–7 per 100,000 person-years, but those are not ACTC1-specific estimates. (acunaochoa2024adenovo pages 1-2)

10. Diagnostics

Clinical diagnosis

The 2023 ESC phenotype-first framework defines cardiomyopathy by myocardial structural/functional abnormality not sufficiently explained by coronary disease, hypertension, valvular disease, or congenital disease. In ACTC1 carriers, congenital ASD does not exclude superimposed primary myocardial disease if its severity does not account for the cardiomyopathy.

Recommended evaluation, extrapolated from genetic DCM guidance, comprises:

Three- to four-generation pedigree and history of heart failure, transplant, sudden death, arrhythmia, stroke, ASD/LVNC/HCM, pregnancy-related disease, and contractures.
Examination, 12-lead ECG, transthoracic echocardiography including LV/RV size, LVEF and preferably global longitudinal strain.
Ambulatory ECG for ectopy, atrial arrhythmia, conduction disease, or nonsustained ventricular tachycardia.
CMR for ventricular phenotype, LVNC assessment, edema, scar/fibrosis and alternative diagnoses.
Laboratory testing guided by phenotype: BNP/NT-proBNP, high-sensitivity troponin, blood count, renal/liver/thyroid studies, iron studies, electrolytes, and creatine kinase if skeletal involvement is suspected.
Exclusion of ischemic disease, significant valve/loading disease, toxins, endocrine/metabolic causes, tachycardia-mediated cardiomyopathy, and myocarditis.
Endomyocardial biopsy only when inflammatory, infiltrative, storage, or other biopsy-addressable disease is suspected; ACTC1 cannot be diagnosed histologically alone.

General inherited-DCM evaluation supports family history, ECG, echo, Holter, CMR and CK, with CMR late gadolinium enhancement helping detect early disease and refine arrhythmic risk. (mcnally2017dilatedcardiomyopathygenetic pages 3-4)

Genetic testing

Use a curated cardiomyopathy multigene panel that includes ACTC1 and well-validated DCM genes, with deletion/duplication analysis where technically appropriate. Panels usually outperform ACTC1-only testing because phenotype overlap and multilocus findings are possible. Analyze an affected proband first and classify variants under ACMG/AMP/ClinGen specifications.

Pathogenic/likely pathogenic: supports molecular diagnosis and enables targeted cascade testing.
VUS: does not establish CMD1R and should not be used for predictive testing or irreversible management; segregation and functional evidence may aid reclassification.
Negative panel: does not exclude genetic DCM. Exome/genome sequencing may detect less typical genes or structural/noncoding variants, ideally with periodic reanalysis.
CMA/karyotype/FISH: low yield for isolated CMD1R; consider for syndromic congenital anomalies.
mtDNA and repeat-expansion testing: not routine unless phenotype suggests another diagnosis.
RNA sequencing: potentially useful for unresolved splice variants, but no validated CMD1R transcriptomic diagnostic exists.

Family screening

After identifying a familial P/LP variant, offer counseling and targeted testing to first-degree relatives regardless of current symptoms. Genotype-positive relatives require serial ECG and imaging; genotype-negative, phenotype-negative relatives can generally be discharged from disease-specific surveillance unless the family has unresolved complexity. Contemporary implementation guidance suggests ECG plus echocardiography every 1–3 years before age 60 and every 3–5 years thereafter, individualized for variant, family history, symptoms and phenotype. (jurcut2025keyprioritiesfor pages 6-7, sorella2025diagnosisandmanagement pages 12-13)

Differential diagnoses include TTN-, LMNA-, FLNC-, DSP-, RBM20-, BAG3-, MYH7-, TNNT2-, TPM1-, TNNI3-, and TNNC1-related cardiomyopathies; myocarditis; ischemic, alcohol-, chemotherapy-, tachycardia-, endocrine- or peripartum cardiomyopathy; muscular dystrophy; mitochondrial disease; HCM transitioning to dilation; and LVNC-associated cardiomyopathy.

11. Outcome and prognosis

There are no valid ACTC1-specific 5- or 10-year survival curves, mortality rates, or life-expectancy estimates. Prognosis ranges from late asymptomatic carrier status to infantile sudden death. Within the G247D families, advanced outcomes included transplant in the sixth decade and sudden death at 63. (frank2019cardiacαactin(actc1) pages 4-6)

General adverse markers include lower LVEF, RV dysfunction, progressive dilation, myocardial fibrosis/LGE, ventricular arrhythmia, syncope, conduction disease, elevated natriuretic peptide/troponin, recurrent hospitalization, and failure to reverse remodel. Family history of early sudden death or transplant increases concern. ACTC1 has not been validated as one of the genotypes with independent ICD thresholds; standard phenotype-based risk assessment remains appropriate.

Complications include chronic/acute heart failure, atrial and ventricular arrhythmias, sudden cardiac death, functional mitral regurgitation, intracardiac thrombus/systemic embolism, stroke, pulmonary hypertension, and multiorgan dysfunction in advanced failure. Recovery of LVEF is possible with therapy, but inherited susceptibility remains lifelong.

12. Treatment and current applications

Current care

There is no approved ACTC1-directed treatment. Management follows DCM/HFrEF and arrhythmia guidelines:

ARNI or ACE inhibitor/ARB, evidence-based β-blocker, mineralocorticoid-receptor antagonist, and SGLT2 inhibitor for eligible HFrEF patients.
Loop diuretics for congestion; hydralazine/isosorbide dinitrate, ivabradine, digoxin, or intravenous iron in selected patients.
Anticoagulation for atrial fibrillation, intracardiac thrombus, previous embolism, or another standard indication—not for genotype alone.
ICD for secondary prevention and for eligible primary-prevention patients after optimized therapy; CRT for standard electrical/mechanical criteria.
Catheter ablation or antiarrhythmic therapy for selected clinically important arrhythmias.
Mechanical circulatory support and heart transplantation for refractory advanced heart failure. Guideline synthesis supports transplant for refractory NYHA III–IV disease without prohibitive contraindications. (sorella2025diagnosisandmanagement pages 12-13)

Suggested NCIT intervention terms: Pharmacologic Therapy, Angiotensin Receptor-Neprilysin Inhibitor, Beta Blocker, Mineralocorticoid Receptor Antagonist, Sodium-Glucose Cotransporter 2 Inhibitor, Diuretic, Anticoagulant Therapy, Implantable Cardioverter-Defibrillator, Cardiac Resynchronization Therapy, Ventricular Assist Device, and Heart Transplantation; verify current NCIT codes.

A related ACTC1 p.Ala21Val family with HCM/LVNC—not classical CMD1R—was treated with carvedilol, amiodarone, diuretics, ACE inhibition, anticoagulation, and consideration of ICD/transplant, illustrating phenotype-based rather than genotype-specific care. (frustaci2018novelα‐actingene pages 6-7)

Experimental therapy and trials

No ACTC1-specific gene replacement, CRISPR, ASO/siRNA, cell therapy, or molecular thin-filament drug has reached clinical implementation. Challenges include the structural stoichiometry of sarcomeric actin and the likelihood that many missense alleles act through altered/dominant-negative protein function rather than simple deficiency.

Relevant mixed-genotype trials include EARLY-GENE, NCT05321875, a recruiting phase III study of candesartan versus placebo in genetic DCM carriers (planned n=320), and broader familial/genetic DCM precision-medicine studies. These do not establish ACTC1-specific efficacy. No ACTC1-selective interventional trial was identified.

13. Prevention

Primary prevention: inheritance cannot be prevented by lifestyle. Reproductive options after identifying a familial P/LP variant include preconception counseling, natural conception with prenatal diagnosis, IVF with PGT-M, donor gametes, or adoption. Counseling should address variable expressivity and inability to predict severity reliably.

Secondary prevention: targeted cascade testing and longitudinal ECG/echo—plus CMR or ambulatory monitoring when indicated—can detect preclinical disease. The p.Gly247Asp data particularly support long-term surveillance of ACTC1-positive patients initially presenting with ASD. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)

Tertiary prevention: early guideline-directed therapy, rhythm surveillance, blood-pressure control, avoidance of cardiotoxins and heavy alcohol, individualized exercise advice, prompt evaluation of pregnancy-related symptoms, vaccination according to heart-failure guidance, and device/transplant referral when indicated. There is no newborn population screening program, vaccine, or prophylactic drug validated specifically for CMD1R.

14. Other species and natural disease

ACTC1 orthologues are highly conserved across vertebrates. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955). No well-established naturally occurring veterinary syndrome confidently equivalent to human ACTC1-CMD1R was identified, and no breed/VBO association can be recommended. The disorder has no zoonotic potential and is not transmissible between species.

15. Model organisms and experimental systems

Neonatal rat ventricular cardiomyocytes: adenoviral p.Gly247Asp overexpression reproduced sarcomeric disruption, abnormal morphology and apoptosis. Strength: direct cardiomyocyte phenotype. Limitation: overexpression, nonhuman and neonatal context. (frank2019cardiacαactin(actc1) pages 1-2, frank2019cardiacαactin(actc1) pages 4-6)
Purified regulated thin filaments/actomyosin assays: R312 substitutions were tested by in-vitro motility, ATPase, tropomyosin-binding and cMyBP-C-fragment assays. Strength: residue-level mechanistic resolution. Limitation: incomplete cellular architecture and discrepant calcium-sensitivity findings across assays. (jones2023divergenceofdisease pages 68-73)
Molecular dynamics: G247D and 2023 syndromic variants predicted defective polymerization, D-loop interactions and filament mechanics. Strength: structural hypotheses; limitation: computational inference. (frank2019cardiacαactin(actc1) pages 1-2, chong2023variantsinactc1 pages 13-16)
Human myocardial biopsy: highest disease relevance and direct visualization of myofibrillar degeneration/remodeling, but exceptionally scarce and cross-sectional. (frank2019cardiacαactin(actc1) pages 4-6)

No validated ACTC1-CMD1R knock-in mouse, zebrafish natural-history platform, patient-specific iPSC-cardiomyocyte series, cardiac organoid, CRISPR rescue screen, or single-cell/spatial atlas was identified in the retrieved evidence. These are major research opportunities.

Recent developments and expert interpretation

2023 phenotypic expansion: Chong et al. identified five families with heterozygous ACTC1 variants causing distal arthrogryposis with congenital cardiac defects. The abstract states: “Our discovery delineates a new DA condition due to mutations in ACTC1 and suggests that some functions of actin, alpha, cardiac muscle 1 are shared in cardiac and skeletal muscle.” Human Genetics and Genomics Advances, July 2023; DOI 10.1016/j.xhgg.2023.100213. This establishes allelic pleiotropy but should not inflate CMD1R case counts. (chong2023variantsinactc1 pages 1-5, chong2023variantsinactc1 pages 7-10)
2024 severe infant case: Acuña-Ochoa et al. reported ACTC1 p.Ala222Thr plus TTN p.Glu11084Lys in a child dying at age one. Their abstract conclusion states that the findings “suggest a likely pathogenic de novo mutation in ACTC1 in coexpression of a TTN variant as possible causes of an early onset of a severe DCM and premature death.” The cautious words “suggest” and “possible” are important because this is one computationally supported, potentially oligogenic case. (acunaochoa2024adenovo pages 1-2)
Current expert approach: contemporary cardiomyopathy guidance favors deep phenotyping, CMR, genetic counseling, curated testing, and cascade screening, while acknowledging major gaps in genotype-specific trajectory and therapy. For ACTC1, experts should resist deterministic counseling: the same gene spans developmental defects, HCM, LVNC, DCM and skeletal contractures. (jurcut2025keyprioritiesfor pages 6-7, sorella2025diagnosisandmanagement pages 12-13, chong2023variantsinactc1 pages 1-5)

Knowledge gaps and database-ingestion cautions

Verify MONDO:0013261 and the phenotype-specific OMIM disease number directly in current source releases.
Do not treat every rare ACTC1 missense variant as pathogenic or every ACTC1 pathogenic variant as DCM-causing.
Do not assign broad DCM prevalence, prognosis, or treatment-response statistics to CMD1R.
“Fully penetrant” G247D segregation applies to the reported combined familial phenotype, not necessarily age-independent DCM.
p.Ala222Thr remains confounded by a co-occurring TTN variant and lacks direct functional validation.
No CMD1R-specific environmental exposure, protective factor, biomarker, transcriptomic signature, pharmacogenomic rule, treatment, trial, or validated risk calculator is currently established.

References

(OpenTargets Search: dilated cardiomyopathy-ACTC1): Open Targets Query (dilated cardiomyopathy-ACTC1, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(chong2023variantsinactc1 pages 7-10): Jessica X. Chong, Matthew Carter Childers, Colby T. Marvin, Anthony J. Marcello, Hernan Gonorazky, Lili-Naz Hazrati, James J. Dowling, Fatema Al Amrani, Yasemin Alanay, Yolanda Nieto, Miguel Á Marín Gabriel, Arthur S. Aylsworth, Kati J. Buckingham, Kathryn M. Shively, Olivia Sommers, Kailyn Anderson, Michael Regnier, and Michael J. Bamshad. Variants in actc1 underlie distal arthrogryposis accompanied by congenital heart defects. Jul 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100213, doi:10.1016/j.xhgg.2023.100213. This article has 20 citations and is from a peer-reviewed journal.
(frank2019cardiacαactin(actc1) pages 1-2): Derk Frank, Ashraf Yusuf Rangrez, Corinna Friedrich, Sven Dittmann, Birgit Stallmeyer, Pankaj Yadav, Alexander Bernt, Ellen Schulze-Bahr, Ankush Borlepawar, Wolfram-Hubertus Zimmermann, Stefan Peischard, Guiscard Seebohm, Wolfgang A. Linke, Hideo A. Baba, Marcus Krüger, Andreas Unger, Philip Usinger, Norbert Frey, and Eric Schulze-Bahr. Cardiac α-actin (actc1) gene mutation causes atrial-septal defects associated with late-onset dilated cardiomyopathy. Circulation. Genomic and precision medicine, 12 8:e002491, Aug 2019. URL: https://doi.org/10.1161/circgen.119.002491, doi:10.1161/circgen.119.002491. This article has 78 citations and is from a peer-reviewed journal.
(acunaochoa2024adenovo pages 1-2): Jose G. Acuña-Ochoa, Norma A. Balderrábano-Saucedo, Ana C. Cepeda-Nieto, Maria Y. Alvarado-Cervantes, Vianca L. Ibarra-Garcia, Daniel Barr, Matthew J. Gage, Ryan Pfeiffer, Dan Hu, and Hector Barajas-Martinez. A de novo mutation in actc1 and a ttn variant linked to a severe sporadic infant dilated cardiomyopathy case. Case Reports in Genetics, Jan 2024. URL: https://doi.org/10.1155/crig/9517735, doi:10.1155/crig/9517735. This article has 2 citations.
(chong2023variantsinactc1 pages 22-24): Jessica X. Chong, Matthew Carter Childers, Colby T. Marvin, Anthony J. Marcello, Hernan Gonorazky, Lili-Naz Hazrati, James J. Dowling, Fatema Al Amrani, Yasemin Alanay, Yolanda Nieto, Miguel Á Marín Gabriel, Arthur S. Aylsworth, Kati J. Buckingham, Kathryn M. Shively, Olivia Sommers, Kailyn Anderson, Michael Regnier, and Michael J. Bamshad. Variants in actc1 underlie distal arthrogryposis accompanied by congenital heart defects. Jul 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100213, doi:10.1016/j.xhgg.2023.100213. This article has 20 citations and is from a peer-reviewed journal.
(frank2019cardiacαactin(actc1) pages 4-6): Derk Frank, Ashraf Yusuf Rangrez, Corinna Friedrich, Sven Dittmann, Birgit Stallmeyer, Pankaj Yadav, Alexander Bernt, Ellen Schulze-Bahr, Ankush Borlepawar, Wolfram-Hubertus Zimmermann, Stefan Peischard, Guiscard Seebohm, Wolfgang A. Linke, Hideo A. Baba, Marcus Krüger, Andreas Unger, Philip Usinger, Norbert Frey, and Eric Schulze-Bahr. Cardiac α-actin (actc1) gene mutation causes atrial-septal defects associated with late-onset dilated cardiomyopathy. Circulation. Genomic and precision medicine, 12 8:e002491, Aug 2019. URL: https://doi.org/10.1161/circgen.119.002491, doi:10.1161/circgen.119.002491. This article has 78 citations and is from a peer-reviewed journal.
(chong2023variantsinactc1 pages 13-16): Jessica X. Chong, Matthew Carter Childers, Colby T. Marvin, Anthony J. Marcello, Hernan Gonorazky, Lili-Naz Hazrati, James J. Dowling, Fatema Al Amrani, Yasemin Alanay, Yolanda Nieto, Miguel Á Marín Gabriel, Arthur S. Aylsworth, Kati J. Buckingham, Kathryn M. Shively, Olivia Sommers, Kailyn Anderson, Michael Regnier, and Michael J. Bamshad. Variants in actc1 underlie distal arthrogryposis accompanied by congenital heart defects. Jul 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100213, doi:10.1016/j.xhgg.2023.100213. This article has 20 citations and is from a peer-reviewed journal.
(jones2023divergenceofdisease pages 68-73): M Jones. Divergence of disease: a characterization of actin residue r312 and its relation to hypertrophic and dilated cardiomyopathy onset. Unknown journal, 2023.
(jurcut2025keyprioritiesfor pages 6-7): Ruxandra Jurcut, Roberto Barriales-Villa, Elena Biagini, Pablo Garcia-Pavia, Iacopo Olivotto, Alexandros Protonotarios, Eloisa Arbustini, Jens Mogensen, Perry Elliott, Elena Arbelo, Juan Pablo Kaski, Cristina Basso, Connie Bezzina, Nico Blom, Rudolf de Boer, Tim de Winter, Marcus Flather, Pablo García-Pavía, Juan R Gimeno, Sabine Klaassen, Giuseppe Limongelli, Bart Loeys, Antonis Pantazis, Sanjay Sharma, Peter Van Tintelen, and James Ware. Key priorities for the implementation of the 2023 esc guidelines for the management of cardiomyopathies in low-resource settings. Mar 2025. URL: https://doi.org/10.1093/ehjqcco/qcae103, doi:10.1093/ehjqcco/qcae103. This article has 7 citations.
(sorella2025diagnosisandmanagement pages 12-13): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.
(mcnally2017dilatedcardiomyopathygenetic pages 3-4): Elizabeth M. McNally and Luisa Mestroni. Dilated cardiomyopathy: genetic determinants and mechanisms. Circulation Research, 121:731–748, Sep 2017. URL: https://doi.org/10.1161/circresaha.116.309396, doi:10.1161/circresaha.116.309396. This article has 996 citations and is from a highest quality peer-reviewed journal.
(frustaci2018novelα‐actingene pages 6-7): Andrea Frustaci, Alessandro De Luca, Valentina Guida, Tommaso Biagini, Tommaso Mazza, Carlo Gaudio, Claudio Letizia, Matteo Antonio Russo, Nicola Galea, and Cristina Chimenti. Novel α‐actin gene mutation p.(ala21val) causing familial hypertrophic cardiomyopathy, myocardial noncompaction, and transmural crypts. clinical‐pathologic correlation. Feb 2018. URL: https://doi.org/10.1161/jaha.117.008068, doi:10.1161/jaha.117.008068. This article has 31 citations.
(chong2023variantsinactc1 pages 1-5): Jessica X. Chong, Matthew Carter Childers, Colby T. Marvin, Anthony J. Marcello, Hernan Gonorazky, Lili-Naz Hazrati, James J. Dowling, Fatema Al Amrani, Yasemin Alanay, Yolanda Nieto, Miguel Á Marín Gabriel, Arthur S. Aylsworth, Kati J. Buckingham, Kathryn M. Shively, Olivia Sommers, Kailyn Anderson, Michael Regnier, and Michael J. Bamshad. Variants in actc1 underlie distal arthrogryposis accompanied by congenital heart defects. Jul 2023. URL: https://doi.org/10.1016/j.xhgg.2023.100213, doi:10.1016/j.xhgg.2023.100213. This article has 20 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	4
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	38
Resolved	37
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	7
Terms named correctly	0
Terms named as a different term	7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0013261 (4 mentions) - the report calls it "if available"; MONDO calls it dilated cardiomyopathy 1R
HP:0001631 (2 mentions) - the report calls it "About 88% of p.Gly247Asp carriers in the reported families"; HP calls it Atrial septal defect
HP:0001644 (4 mentions) - the report calls it "Core CMD1R phenotype"; HP calls it Dilated cardiomyopathy
HP:0012664 (2 mentions) - the report calls it "Borderline LVEF 52% in one 2023 p.Arg185Trp carrier; severe dysfunction in the infant case"; HP calls it Reduced left ventricular ejection fraction
HP:0001711 (1 mention) - the report calls it "Severe in the 1-year-old 2024 case"; HP calls it Abnormal left ventricle morphology
HP:0001635 (1 mention) - the report calls it "Late onset in p.Gly247Asp carriers; advanced cases required transplant"; HP calls it Congestive heart failure
HP:0030680 (1 mention) - the report calls it "Part of broader ACTC1 allelic spectrum, not obligatory CMD1R"; HP calls it Abnormal cardiovascular system morphology

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Dilated Cardiomyopathy 1R (CMD1R): ACTC1-related dilated cardiomyopathy

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1. Disease information

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2. Etiology, risk, protection, and gene–environment interaction

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