PMID: 31524317

Gene: MYBPC3, MYPN

HGNC ID: 7551, 23246

Case1: 50‐year‐old woman

DiseaseAssertion: Ankles swelling and shortness of breath.

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs:

CaseHPOFreeText: dilated cardiomyopathy with end‐diastolic diameter of the left ventricle (LV) of 62 mm, severely depressed left ventricle ejection fraction (LVEF), 20%, mild hypertrophic septum (13.5 mm), trabecular aspect of lateral and inferior LV wall, thrombus in the apex, and severe tricuspid regurgitation with inferior vena cava reflow

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: next‐generation sequencing

FunctionalAnalysis: NR

Variant: NM_000256.3(MYBPC3):c.2459G>A (p.Arg820Gln), NM_032578.4(MYPN):c.3335C>T (p.Pro1112Leu)

ClinVar: 8617, 31791

CAID: CA012326, CA143763

gnomAD: 11-47359085-C-T, 10-69959174-C-T

AdditionalInfo: NR

Case#: 29 year old female; diagnosed with DCM 8 years before death; died suddenly at home on 22 February 2017; forensic autopsy case

DiseaseAssertion: Dilated cardiomyopathy (DCM) with sudden cardiac death; MYBPC3-related

FamilyInfo: Family from Central-South China with a history of SCD. Father (I:1) reportedly died of a heart attack at 37, not genetically tested. Mother (I:2) and sister (II:2) are unaffected and do not carry the variant. No other affected relatives reported.

ParentalTesting: Not performed, both parents were not genotyped for the variant; the father was deceased before the study. Maternal non-carriage confirmed by Sanger, so the variant is either paternal or de novo; phase not established.

CasePresentingHPOs: HP:0001644; HP:0001645

CaseHPOFreeText: Diagnosed with DCM 8 years before death, with no other abnormalities. Found unresponsive at home at noon and expired; no prodromal symptoms documented. Autopsy: enlarged heart with valve thickening, myocardial fibrosis, and multi-organ congestion; no other fatal injury or disease. HE staining of left ventricle showed no hypertrophy or other anomalies. Toxicological screening for ethanol, benzodiazepines, barbiturates, amphetamine, methamphetamine, ketamine, morphine, MDMA, and THC-acid was negative; serum IgE normal (27 IU/ml); eosinophils 4.7% with no mast-cell degranulation.

CaseNotHPOs: HP:0001639; HP:0001634; HP:0003124

CaseNotHPOFreeText: No cardiomyocyte hypertrophy on histology, distinguishing this from HCM. No coronary, valvular, or congenital structural disease identified. No toxicological cause of death.

CasePreviousTesting: Whole-exome sequencing on postmortem blood, retaining synonymous variants; filtering against gnomAD and CMDB; in silico prediction with MutationTaster, PolyPhen-2, and SIFT; NetGene2-2.42 used to predict splice effects. Five variants in cardiomyopathy-related genes were found; only the MYBPC3 variant was classified likely pathogenic.

Genotyping Method: WES with Sanger confirmation on ABI 3100; family members genotyped by Sanger.

FunctionalAnalysis: Minigene assay pcDNA3.1-MYBPC3 construct spanning exon 1-intron 1-exon 2, transfected into HEK293 cells: wild-type and the c.10G>A negative control both produced a ~1,500 bp full-length band and a ~300 bp spliceosome band; the c.24A>C construct produced no spliceosome band, indicating abnormal splicing with intron 1 retention and frameshift. Immunohistochemistry showed decreased MYBPC3 protein in the proband's left ventricle versus a control heart.

Variant: MYBPC3 NM_000256.3:c.24A>C (p.Pro8Pro); heterozygous synonymous variant at the penultimate base of exon 1; disrupts the splice donor site; novel

ClinVar: 164098

CAID: CA11138

gnomAD: 0.00001541

AdditionalInfo: Classified likely pathogenic with PS3, PM2, PP1, PP3; note the paper's Discussion relabels the prediction code as PP4, an internal inconsistency. The authors describe it as the first reported deleterious synonymous MYBPC3 variant, acting by intron retention and reduced protein. The same splice site is affected by the known HCM variants c.24+1G>A and c.24+3A>C. Four other variants were found and classified likely benign or VUS: LDB3 c.2131T>C (VUS), BBS2 c.422A>G, EVC2 c.2643G>C, and BBS4 c.1548_1549del.

PMID: : 42824042

Gene: MYBPC3

HGNC ID: :7551

Case#: Patient 1; 89-year-old female; identical twin (Patient 2) with mild HCM

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the pathogenic MYBPC3 nonsense variant NM_000256.3.787G>T (p.Gly263Ter). Patient 1 is an 89-year-old female with severe symptomatic obstructive HCM, previously requiring septal ablation. Her maximum reported left ventricular wall thickness was 29 mm by echocardiography in 2015.

FamilyInfo: Patient 1 belongs to a family with hereditary hypertrophic cardiomyopathy associated with the MYBPC3 p.Gly263Ter founder variant. Her monozygotic twin sister (Patient 2) carries the same pathogenic variant but has a substantially milder HCM phenotype, with a maximum left ventricular wall thickness of 13 mm and no reported symptoms at an advanced age. The twin pair belongs to the extended family that also includes Patients 3 and 4, another pair of monozygotic twins carrying the same variant. The pedigree documents additional affected relatives and a history of sudden death, although not all family members have confirmed genetic testing.

ParentalTesting: NR – The family pedigree supports familial occurrence of hypertrophic cardiomyopathy, but the specific parent from whom Patient 1 inherited the MYBPC3 p.Gly263Ter variant cannot be conclusively determined from the available genetic testing data. Her monozygotic twin sister (Patient 2) was confirmed to carry the same variant.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001712 (Left ventricular hypertrophy); HP:0032092 (Left ventricular outflow tract obstruction)

CaseHPOFreeText: Echocardiography documented a maximum left ventricular wall thickness of 29 mm in 2015. She previously experienced significant dyspnea, with symptoms classified as NYHA III/IV, associated with severe left ventricular outflow tract obstruction. She underwent septal ablation, which improved her clinical symptoms. At the time of the study, she remained minimally symptomatic.

CaseNotHPOs: HP:0000822 (Hypertension)

CaseNotHPOFreeText: Explicitly reported that Patient 1 did not have hypertension. No additional negative phenotypic findings were specifically documented for this patient.

CasePreviousTesting: Previous cardiac evaluations included echocardiography demonstrating severe left ventricular hypertrophy, with a maximum wall thickness of 29 mm in 2015, and clinical identification of severe left ventricular outflow tract obstruction. The patient underwent septal ablation for symptomatic obstructive hypertrophic cardiomyopathy. Electrocardiographic findings were also evaluated following the procedure. The article does not provide a detailed history of genetic testing performed before the reported familial MYBPC3 investigation.

Genotyping Method: Genetic testing of index cases was performed using targeted next-generation sequencing (NGS) with Ion Torrent technology. The earlier index cases were evaluated using a nine-gene sarcomeric panel, including MYBPC3. Familial screening for the MYBPC3 NM_000256.3.787G>T (p.Gly263Ter) variant was performed using Sanger sequencing on an ABI3130XL sequencer. Monozygosity of the twin pairs was independently confirmed using the PowerPlex 16 HS System, which analyzes 16 microsatellite markers. Article does not specify whether Patient 1's individual MYBPC3 genotype was initially established through NGS or other targeted Sanger sequencing.

FunctionalAnalysis: The MYBPC3 NM_000256.3.787G>T (p.Gly263Ter) variant is a nonsense mutation that introduces a premature termination codon. The authors classified this founder variant as pathogenic based on its predicted loss-of-function effect, absence from the population reference databases examined, and segregation among affected family members. Computational evidence supported a deleterious effect. However, no patient-specific functional assays measuring MYBPC3 RNA expression, protein abundance, or protein function were reported in this study. The molecular consequences were inferred from the variant type and existing evidence rather than directly demonstrated experimentally in Patient 1.

Variant: MYBPC3 NM_000256.3:c.787G>T p.Gly263Ter; Nonsense; Autosomal dominant; Clinical significance: Pathogenic (1 submission). Review status: 1 out of 4 stars (criteria provided, single submitter).

ClinVar: 1460339

CAID: CA380333920

gnomAD: GRCh38 variant 11-47347891-C-A. African/African American population: AC = 0; AF = 0.0000.

AdditionalInfo: Patient’s monozygotic twin sister (Patient 2) carries the same variant but exhibits a substantially milder clinical phenotype. Patient 1 had a maximum left ventricular wall thickness of 29 mm in 2015, severe left ventricular outflow tract obstruction, and symptomatic dyspnea requiring septal ablation. In contrast, Patient 2 had a maximum wall thickness of 13 mm and was asymptomatic. This illustrates variable expressivity of MYBPC3-associated hypertrophic cardiomyopathy, even among genetically identical individuals. The authors discuss environmental and epigenetic factors as possible contributors to phenotypic variability, although no specific modifying mechanism was experimentally demonstrated in these patients.

Case#: Patient 5; 47-year-old male; identical twin (Patient 6) with less severe hypertrophy

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Patient has a monozygotic twin brother (Patient 6), who is also affected by HCM. Both individuals carry the same pathogenic MYBPC3 nonsense variant, NM_000256.3.787G>T (p.Gly263Ter). However, Patient 5 demonstrates more pronounced left ventricular hypertrophy than Patient 6. Cardiac magnetic resonance imaging (CMR) revealed maximum left ventricular wall thicknesses of 28 mm and 19 mm, respectively.

ParentalTesting: NR – Parental genetic testing results were not explicitly reported for Patient 5 or his monozygotic twin brother (Patient 6)

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Patient diagnosed with hypertrophic cardiomyopathy (HCM), characterized by substantial left ventricular hypertrophy. Echocardiography performed in 2022 demonstrated a maximum left ventricular wall thickness of 18 mm, while cardiac magnetic resonance imaging (CMR) showed a maximum thickness of 28 mm.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction); HP:0000822 (Hypertension)

CaseNotHPOFreeText: Patient 5 did not exhibit left ventricular outflow tract obstruction (LVOTO), even though having substantial left ventricular hypertrophy (max wall thickness of 28 mm). The study also explicitly reports that none of the six patients, including Patient 5, had hypertension.

CasePreviousTesting: Patient 5 underwent clinical cardiac evaluation, including echocardiography, cardiac magnetic resonance imaging (CMR), and electrocardiography (ECG).

Genotyping Method: Genetic analysis was performed using next-generation sequencing (NGS) with Ion Torrent technology for index patients and targeted Sanger sequencing for familial screening. The study reports that recent index cases associated with Patients 5–6 were evaluated using an expanded 195-gene NGS panel, as described in Supplementary Table S2. The pathogenic MYBPC3 variant NM_000256.3.787G>T (p.Gly263Ter) was identified in both monozygotic twins. However, the article does not explicitly specify whether Patient 5 underwent the full NGS panel or targeted familial testing. Monozygosity was independently confirmed using the PowerPlex 16 HS System.

FunctionalAnalysis: NR – No patient-specific functional assays were reported for Patient 5 (computational evidence supporting a deleterious effect, absence from the ESP, 1000 Genomes, and ExAC population databases, and segregation of the variant among affected family members).

Variant: MYBPC3 NM_000256.3:c.787G>T p.Gly263Ter; Premature termination codon; Nonsense; Autosomal dominant; Clinical significance: Pathogenic (1 submission). Review status: 1 out of 4 stars (criteria provided, single submitter).

ClinVar: 1460339

CAID: CA380333920

gnomAD: gnomAD: GRCh38 variant 11-47347891-C-A. African/African American population: AC = 0; AF = 0.0000.

AdditionalInfo: Patient’s monozygotic twin brother (Patient 6) carries the same pathogenic variant but exhibits less pronounced left ventricular hypertrophy. The authors suggest that additional environmental or epigenetic modifiers may influence disease severity, although no specific modifying mechanism was experimentally established.

PMID: 36143383

Gene: MYBPC3

HGNC ID: 7551

Case1: 45 year old man, Chinese Han descent

DiseaseAssertion: Symptoms of congestive heart failure for 10 years and then developed ascites

FamilyInfo: No obvious family history.

ParentalTesting: NR

CasePresentingHPOs: HP:0031295, HP:0030718, HP:0001639

CaseHPOFreeText: typical RCM phenotype with biatrial enlargement, normal LV volume and wall thickness, mildly depressed LV ejection fraction (52%), and significantly impaired LV diastolic function

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: high-throughput NGS

FunctionalAnalysis: NR

Variant: NM_000256.3(MYBPC3):c.1000G>A (p.Glu334Lys)

ClinVar: 177902

CAID: CA009667

gnomAD: 11-47367848-C-T

AdditionalInfo: NR

PMID: 26163040

Gene: MYBPC3

HGNC ID: 7551

Case1: 5 week old female

DiseaseAssertion: Feeding problems and cyanosis. X-thorax showed a grossly enlarged heart

FamilyInfo: Family history of both parents was positive for HCM and sudden death

ParentalTesting: Initial echocardiography revealed no abnormalities in the 32-year-old mother, who was heterozygous for c.2373dup, nor in the 31-year-old father, heterozygous for c.2827C>T. ECG in the father showed mild repolarization abnormalities (ST elevation of 0.5 mm in V1, followed by a negative T in V1–V4). Re-evaluation after 7 years revealed moderate septal hypertrophy (HCM) with an interventricular septum of 14 mm in the mother, and interventricular septal measurements at the upper limit of the normal range (12 mm) in the father.

CasePresentingHPOs: HP:0001640, HP:0001639,

CaseHPOFreeText: Severe cardiomegaly and dilatation with a total weight of 115  g (normal weight at this age, 30  g). Right ventricular thickening was noted, especially of the posterior wall. The anterior wall of the left ventricle was severely thickened and showed abnormal trabeculation and multiple intertrabecular recesses as seen in noncompaction cardiomyopathy. Secundum ASD was confirmed. No other congenital malformations were found. Microscopic examination of cardiac tissue (Figure 1a) showed myofibrillar disarray in both the ventricular septum and the left ventricular wall. Hypertrophic myocytes with a diameter of 20–30 μm (normal 12  μm) and multiple vacuoles on electron microscopy suggested glycogenosis

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: Microscopic postmortem examination of heart muscle from patient 1. Hypertrophic myocytes with myofibrillar disarray typical of HCM due to sarcomeric protein variations were present, albeit without a significant amount of interstitial fibrosis (hematoxylin and eosin staining, magnification × 100). (b) Electron micrograph showing a large, irregular vacuole.

Variant: NC_000011.10:g.47337730dup, NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039, 42619

CAID: CA013001, CA012139

gnomAD: 11-47356671-G-A, 11-47359280-A-AC

AdditionalInfo: NR

Case4: 6 week old female

DiseaseAssertion: dyspnea, hypotension, feeding difficulties, and failure to thrive

FamilyInfo: Her mother was diagnosed with postpartum HCM with diastolic dysfunction, confirmed by cardiac MRI, at age 26. Echocardiography of the father was normal; ECG showed a right bundle branch block. A paternal uncle of patient 4 had died aged 3 months of unknown cause

ParentalTesting: Both parents were heterozygous for c.2827C>T p.(Arg943*) nonsense mutation in MYBPC3

CasePresentingHPOs: HP:0001639

CaseHPOFreeText: Severe HCM with features of noncompaction, and severe diastolic and systolic left ventricular dysfunction (IVSd 11 mm, Z+10; LVPWd 10 mm, Z+10, FS 13% (LVID 17/20) and left ventricular mass 255 g/m2). A secundum ASD with a left–right shunt was also observed.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039

CAID: CA013001

gnomAD: 11-47356671-G-A

AdditionalInfo: NR

PMID: 25335496

Gene: MYBPC3

HGNC ID: 7551

Case3: 7 week old female

DiseaseAssertion:

FamilyInfo: A cousin of the father presented with cardiac arrest due to HCM. He had a heterozygous pathogenic c.2373dup p.(Trp792fs) mutation in MYBPC3. We subsequently confirmed homozygosity for the c.2373dup variant in DNA isolated from stored fibroblasts from the deceased proband. Both parents of the proband were heterozygous for this truncating variant (Figure 2b). Cardiac re-evaluation showed only slightly reduced ECG voltages in the father (age 38) and borderline hypertrophy (septal thickness 11 mm) in the mother (age 41).

ParentalTesting:

CasePresentingHPOs: HP:0001640, HP:0002119

CaseHPOFreeText: Cardiomegaly was seen on chest X-ray, and echocardiography showed HCM with dilated ventricles. M-Mode measurements were unavailable. Noncompaction was not a clear feature, but could not be excluded. There was a small foramen ovale and mitral valve insufficiency

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: DNA isolated from stored fibroblasts from the deceased proband.

Variant: NC_000011.10:g.47337730dup

ClinVar: 42619

CAID: CA012139

gnomAD: 11-47359280-A-AC

AdditionalInfo: NR

Case2: 4 week old male

DiseaseAssertion: Feeding problems in the first weeks of life and dyspnea and mild hypotonia were noticed at age 4 weeks.

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0001640

CaseHPOFreeText: A grossly enlarged heart was observed on the X-thorax (heart–thorax ratio 0.8%) and low oxygen saturation blood levels were found. Echocardiography revealed moderately dilated ventricles with severe diastolic and systolic dysfunction. Hypertrabeculation with flow perfused intertrabecular recesses was present in both ventricles, including the apical walls (Figure 3). An apical muscular ventricular septal defect (VSD) was visualized, although deep recessal flow complicated interpretation of the images

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NC_000011.10:g.47337730dup, NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039, 42619

CAID: CA013001, CA012139

gnomAD: 11-47356671-G-A, 11-47359280-A-AC

AdditionalInfo: NR

Case 1: One proband; (53-year-old woman)

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) with fasciculoventricular bypass tract (FVBT)

FamilyInfo: Autosomal dominant family with HCM and pre-excitation. Mother has an ICD for nonischemic cardiomyopathy and progressed from HCM to DCM; sister (49) carries the variant with HCM and NSVT; younger daughter (25) carries the variant with pre-excitation but no HCM. Maternal aunt died suddenly at 42; maternal uncle had a sudden cardiac arrest at 40 with subsequent ICD.

CasePresentingHPOs: HP:0001962; HP:0001639; HP:0004756; HP:0001677; HP:0001671; HP:0004308

CaseHPOFreeText: Palpitations prompted workup. ECG showed pre-excitation; Holter documented NSVT; echo showed HCM without significant outflow obstruction; EP study demonstrated an FVBT with inducible AF; CMR showed midventricular septal thickness of 22 mm with patchy enhancement involving 25% of myocardial mass.

CaseNotHPOs: HP:0001635; HP:0001279; HP:0001645

CaseNotHPOFreeText: No heart failure reported; no syncope; alive at publication.

CasePreviousTesting: ECG (pre-excitation), Holter (NSVT), echo (HCM without significant outflow obstruction), EP study (FVBT with inducible AF), CMR (midventricular septum 22 mm, patchy enhancement 25% of mass).

GenotypingMethod: HCMNext panel (Ambry Genetics); heterozygous c.655G>C (p.Val219Leu) in MYBPC3, reported pathogenic.

FunctionalAnalysis: None performed.

Variant: MYBPC3 NM_000256.3:c.655G>C (p.Val219Leu); heterozygous missense

ClinVar: 42784

CAID: CA015670

gnomAD: 0.00002

AdditionalInfo:N/A

Case1: Pedigree mother; affected carrier; HCM progressing to DCM; clinical case

DiseaseAssertion: Hypertrophic cardiomyopathy progressing to dilated cardiomyopathy, with pre-excitation; MYBPC3-related

FamilyInfo: Carries the familial MYBPC3 variant. ICD in place for nonischemic cardiomyopathy despite optimal medical therapy; never received a shock. Mother of the proband and the sister.

ParentalTesting: Not applicable, this is the transmitting generation.

CasePresentingHPOs: HP:0001639; HP:0001644; HP:0004308

CaseHPOFreeText: Serial echocardiography over 11 years documented progression from hypertrophic to dilated phenotype. ECG showed pre-excitation. ICD implanted; no appropriate or inappropriate therapy to date.

CaseNotHPOs: HP:0001279 ; HP:0001645

CaseNotHPOFreeText: No syncope reported; alive at publication.

CasePreviousTesting: Serial echocardiography; ECG; ICD interrogation.

Genotyping Method: Family screening; carrier status reported.

FunctionalAnalysis: None performed.

Variant: MYBPC3 NM_000256.3:c.655G>C (p.Val219Leu); heterozygous missense

ClinVar: 42784

CAID: CA015670

gnomAD: 0.00002

AdditionalInfo:N/A

Case#:reports one patient with this variant

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: N/A

ParentalTesting:N/A

CasePresentingHPOs: HP:0001639 "Hypertrophic cardiomyopathy"

CaseHPOFreeText: The study cohort consisted of 23 patients diagnosed with HCM.

CaseNotHPOs: N/A

CaseNotHPOFreeText:N/A

CasePreviousTesting:N/A

Genotyping Method: Sanger sequencing

FunctionalAnalysis: none preformed

Variant: MYBPC3 c.1037G>C, p.Arg346Pro

ClinVar: No exact match, closest is MYBPC3 c.1037G>A

CAID: N/A

gnomAD:N/A

AdditionalInfo: variant is suspected to be novel and potentially pathenogenic

PMID: 28815794

Gene: MYBPC3

HGNC ID: HGNC:7551

Case1: 38 year old male

DiseaseAssertion: . Two missense variants in MYBPC3 (NM_000256.3): c.2533C>G in exon 26 (C6 domain) were identified and, classified as a variant of uncertain significance (VUS, score 2), and c.1696T>A in exon 18 (C4 domain), a VUS with a score of 5.

FamilyInfo: There was no family history of cardiomyopathy or SCD.

ParentalTesting: NR

CasePresentingHPOs: HP:0004751, HP:0006682, HP:0001712

CaseHPOFreeText: 38 year old man, suffering from contractions, and one short run of non-sustained ventricular tachycardia lasting four beats. Asymmetric septal hypertrophy with a maximum thickness of 19 mm. In addition, marked biatrial enlargement was evident, with a left atrial volume index of 79 mL/m² and right atrial area of 25 cm². Importantly, extensive diffuse late gadolinium enhancement (LGE) was detected in the basal and mid-septal and anterior segments, involving 17% of the myocardial mass

CaseNotHPOs: NR

CasePreviousTesting: genetic testing was performed using the Health in Code HCM panel, which includes the following 18 genes: ACTC1, DES, FHL1, FHOD3, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, TRIM63, and TTR.

Genotyping Method: Health in Code HCM panel

FunctionalAnalysis:

Variant: NM_000256.3:c.2533C>G, NM_000256.3:c.1696T>A

ClinVarID:180973, 915724

CAID:CA380324353, CA012504

gnomAD:

AdditionalInfo:NR

Case1: Female, 85 at diagnosis, ethnicity not stated

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: An index patient’s brother (II.6) was reported with moderate HCM and another brother (II.7) with sudden cardiac death at the age of 40 years. The clinical screening led to the diagnosis of HCM in two of the index patient’s descendants, a daughter and a son. Daughter (III.4, age 59) with septal hypertrophy of 16 mm confirmed by cardiac MRI, son (III.8, age 47) with septal hypertrophy of 15 mm. Daughter (III.6, age 50) is an unaffected carrier. Five other relatives (III.1, III.5, III.6, III.7, IV.1) were healthy with normal cardiac evaluation. Pedigree shown in Figure 1.

ParentalTesting: Not preformed.

CasePresentingHPOs: HP:0001639, HP:0001279

CaseHPOFreeText: Admitted to the emergency unit with chest pain after a pre-syncopal episode at the age of 85. Electrocardiogram showed sinus rhythm, negative T waves in V1-V3 and signs of ventricular hypertrophy. Transthoracic echocardiography detected asymmetric septal hypertrophy of 25 mm with preserved ejection fraction, moderate diastolic dysfunction and mild left atrial enlargement. Twenty-four-hour Holter monitoring documented episodes of non-sustained ventricular tachycardia defined as ≥ 3 beats at a rate of ≥ 120 bpm

CaseNotHPOs: NR

CaseNotHPOFreeText: Coronary artery disease was ruled out

CasePreviousTesting: NR

Genotyping Method: The index patient’s genomic DNA was subjected to massively parallel sequencing to identify the genetic origin of the disease using a 251-gene cardiomyopathy diagnostic panel. Targeted massively parallel sequencing of the index patient’s genomic DNA was performed with an Agilent SureSelect custom library covering 251 genes. For the MYBPC3 gene: all exons including the complete sequence of introns. Sequencing performed on NovaSeq 6000 (Illumina), bioinformatics pipeline using BWA alignment and GATK variant calling, reference genome GRCh37/hg19. Sanger sequencing confirmed both variants

FunctionalAnalysis: Minigene and patient blood RNA splicing assays performed. Both the minigene and patients’ RNA splicing assays revealed that the MYBPC3 c.3331−26T>G variant promoted complete intron 30 retention in the mRNA, and also partial retention of the second half of intron 30. Normal MYBPC3 mRNA was not detected in the MUT lanes. The corresponding normal MYBPC3 fusion protein was not detected with either of the two antibodies in cells transfected with the MUT plasmid.

Variant: NM_000256.3:c.3331−26T>G

ClinVar: 1320039

CAID: CA2573146361

gnomAD: chr11-47332999-A-C

AdditionalInfo: This paper also identified two additional unrelated HCM probands carrying c.3331−26T>G in a large cohort of 9,611 HCM probands

PMID: 35513690

Gene: MYBPC3

HGNC ID: 7551

Case#: a male in the age range of 36-40

DiseaseAssertion: Dilated cardiomyopathy and generated hiPSC-CMS

FamilyInfo: not reported

ParentalTesting: not reported

CasePresentingHPOs: HP:0002875, HP:0031352 Exertional dyspnea and chest tightness

CaseHPOFreeText: nocturnal dyspnea and reduced exercise tolerance

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: echocardiogram and electrocardiograms

Genotyping Method: peripheral blood was extracted and use to sequence the entire genome

FunctionalAnalysis: hiPSCs were looked at in this case

Variant: NM_000256.3: c.194 C > T (p.Thr65Met)

ClinVar:407324

CAID: CA047700

gnomAD: 11-47372888-G-A

AdditionalInfo:F

PMID:41703309

Gene: MYBPC3

HGNC ID: 7551

Case#: Female with DCM symptoms beginning at age 30

DiseaseAssertion: Dilated cardiomyopathy (DCM) associated with a heterozygous missense variant in MYBPC3, c.3373G>A (p.Val1125Met). The authors propose autosomal dominant inheritance in this DCM case.

FamilyInfo: NR – Detailed family relationships, segregation testing, and individual relatives' phenotypes are not described for the current DCM proband.

ParentalTesting: NR

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0002094 (Dyspnea); HP:0001962 (Palpitations); HP:0004756 (Ventricular tachycardia)

CaseHPOFreeText: The patient experienced symptoms beginning at age 30, including frequent palpitations and dyspnea. ECG monitoring revealed multiple premature ventricular contractions and nonsustained ventricular tachycardia. Echocardiography demonstrated severe spherical left ventricular enlargement, severe systolic and diastolic dysfunction, LVEF of 10%, and mild pulmonary hypertension. She was classified as NYHA functional class II–III and received medical therapy and an implantable cardioverter-defibrillator.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR – Article describes patient's clinical evaluation, including ECG monitoring and echocardiography, before genetic analysis.

Genotyping Method: Genomic DNA was extracted from peripheral blood. Targeted next-generation sequencing was performed using a custom NimbleGen panel covering the coding regions and exon–intron boundaries of 23 genes associated with DCM. Sequencing was conducted on an Illumina HiSeq 2000 platform. Reads were aligned to the hg19 reference genome using BWA, and SAMtools was used for variant analysis. MYBPC3 variant confirmed using Sanger sequencing.

FunctionalAnalysis: In silico analyses were performed to investigate the potential functional consequences of MYBPC3 p.Val1125Met. SIFT, PolyPhen-2, and MutationTaster predicted potentially damaging effects, while CADD produced a score of 33. Multiple-sequence alignment demonstrated that Val1125 is highly conserved across species. Protein modeling using I-TASSER and Phyre2 predicted structural differences involving the region surrounding residue 1125, located within the C9 fibronectin type III domain of cardiac myosin-binding protein C (cMyBP-C). The authors proposed that the substitution could affect protein structure and function. No direct experimental functional validation of this variant was reported.

Variant: MYBPC3 NM_000256.3:c. 3373G>A (p.Val1125Met); rsID: rs121909378; missense; heterozygous

ClinVar: 8604

CAID: CA014038

gnomAD: MYBPC3 c.3373G>A (p.Val1125Met), GRCh38: 11-47332931-C-T. In gnomAD v4, the reported allele frequencies are 0.00001920 (exomes), 0.00003943 (genomes), and 0.00002111 (total). The highest ancestry-specific allele frequency identified was in the Ashkenazi Jewish population (AC = 5; AF = 0.0001695).

AdditionalInfo: Authors propose variant dosage, interactions with other variants, and genetic modifiers may contribute to differences in disease phenotype. However, the proposed autosomal dominant association with DCM was not supported by documented segregation testing in the current proband's family, and the functional analyses were computational rather than experimental.

PMID: 29493010

Gene: MYBPC3

HGNC ID: 7551

Case#: 80-year-old male (I-1) diagnosed with HCM at approximately 50–55 years of age; familial case with his 3 adult offspring (II-2, II-3, and II-4)

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with a heterozygous frameshift variant in MYBPC3.

FamilyInfo: The proband (I-1) is an elderly male with familial hypertrophic cardiomyopathy. Three adult offspring (II-2, II-3, and II-4) were evaluated and diagnosed with HCM based on interventricular septal hypertrophy. All four individuals carried the heterozygous MYBPC3 c.1042_1043insCGGCA variant. Individual II-2 experienced chest discomfort and palpitations, whereas II-3 and II-4 were asymptomatic at evaluation. These findings demonstrate segregation of the variant with HCM in the examined family members and are consistent with autosomal dominant inheritance.

ParentalTesting: NR – Genetic testing of the proband's parents was not reported but the variant was identified in his three adult offspring, supporting familial segregation.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001635 (Congestive heart failure)

CaseHPOFreeText: The proband experienced chest tightness, dyspnea, and recurrent heart failure. Echocardiography demonstrated marked interventricular septal hypertrophy (39 mm during diastole and 41 mm during systole), a left atrial diameter of 44 mm, and a left ventricular ejection fraction of 60%. Additional findings included premature atrial beats, intraventricular conduction block, and NYHA functional class II. A history of hypertension was reported.

CaseNotHPOs: HP:0001279 (Syncope); HP:0001681 (Angina pectoris); HP:0001695 (Cardiac arrest)

CaseNotHPOFreeText: The proband had no reported history of syncope, angina pectoris, or cardiac arrest. No surgical myectomy was reported.

CasePreviousTesting: NR – Previous genetic testing was not reported but the proband underwent clinical cardiovascular evaluation, including electrocardiography, echocardiography, and BNP measurement.

Genotyping Method: Whole-genome sequencing (WGS) was performed using peripheral blood DNA on an Illumina NovaSeq 6000 platform with 150-bp paired-end reads and approximately 30× sequencing depth. Reads were aligned to the hs37d5 reference genome using BWA, and variants were annotated using ANNOVAR.

FunctionalAnalysis: Cardiac tissue from the proband was analyzed using RT-qPCR and Western blotting. MYBPC3 mRNA expression and cardiac myosin-binding protein C (cMyBP-C) abundance were significantly reduced (P < 0.05), supporting a haploinsufficiency mechanism. These findings do not independently establish the functional effect of the specific variant, and the Western blot analysis lacked biological replicates.

Variant: MYBPC3 NM_000256.3.1038_1042dup (p.Met348ThrfsTer4). Five-base-pair duplication resulting in a frameshift and premature termination codon. Reported in Zhang et al. (2025) as c.1042_1043insCGGCA.

ClinVar: No exact match identified for MYBPC3 c.1042_1043insCGGCA using the reported HGVS notation. ClinVar Variation ID not established.

CAID: CA273429

gnomAD: No exact matching entry identified in gnomAD v4 for MYBPC3 NM_000256.3:c.1038_1042dup (CA273429). Population allele frequency could not be established.

AdditionalInfo: The variant was identified in the proband and three adult offspring with interventricular septal thickening. The study proposed MYBPC3 haploinsufficiency as a disease mechanism based on reduced transcript and protein abundance. The available familial and functional evidence supports an association with HCM, although the specific variant's pathogenicity requires interpretation alongside the limitations of the study.

PMID: 41134850

Gene: MYBPC3

HGNC ID: 7551

Case#: Patient 3; male; 60 years old at first observation; 14 mm LV wall thickness; family history of HCM

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the heterozygous MYBPC3 intronic splice-altering variant c.1224-80G>A, classified as likely pathogenic by the study authors.

FamilyInfo: Patient was reported to have positive family history of HCM. Echocardiography demonstrated a maximum left ventricular wall thickness of 14 mm without left ventricular outflow tract obstruction. The study did not identify specific affected relatives or provide a family pedigree.

ParentalTesting: NR – Patient had a positive family history of HCM but parental genotypes and variant segregation were not documented.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Echocardiography demonstrated a maximum left ventricular wall thickness of 14 mm without left ventricular outflow tract (LVOT) obstruction. NYHA functional classification was not reported.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction)

CaseNotHPOFreeText: Echocardiographic evaluation showed no left ventricular outflow tract (LVOT) obstruction.

CasePreviousTesting: Patient 3 previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel, which included 174 genes associated with inherited cardiac conditions. The initial genetic analysis was negative. Subsequent reanalysis of existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA obtained from peripheral blood was analyzed using the Illumina TruSight Cardio targeted next-generation sequencing panel on an Illumina MiniSeq platform. Previously generated sequencing data were reexamined using an intronic hotspot analysis approach, with variant visualization in Integrative Genomics Viewer (IGV). The MYBPC3 c.1224-80G>A variant was subsequently confirmed by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a cryptic splice acceptor site within intron 13, resulting in retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons. Previous functional studies demonstrated altered RNA splicing and an approximately 50% reduction in MYBPC3 transcript abundance. SpliceAI predicted a strong splice-altering effect (Δscore = 0.94). The current study did not perform patient-specific RNA functional experiments. Instead, researchers identified the variant through reanalysis of existing next-generation sequencing data and confirmed its presence using Sanger sequencing.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: Although Patient 3 carried the same variant as Patient 2, their reported cardiac phenotypes differed. Patient 2 exhibited a maximum left ventricular wall thickness of 27 mm and LVOT obstruction with a gradient of 50 mmHg. These differences are consistent with variable clinical expression of MYBPC3-associated HCM, although the study did not determine their underlying causes.

Case#: Patient 1; female; 56 years old at first observation with diagnosis of HCM; 13 mm LV wall thickness

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the heterozygous MYBPC3 intronic splice-altering variant c.1224-80G>A, classified as likely pathogenic by the study authors.

FamilyInfo: The study reports a negative family history of HCM. No family pedigree or detailed clinical information about relatives was provided.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy); HP:0031656 (Systolic anterior motion of the mitral valve)

CaseHPOFreeText: Hypertrophic cardiomyopathy and a maximum left ventricular wall thickness of 13 mm. Echocardiography demonstrated systolic anterior motion (SAM) of the mitral valve without left ventricular outflow tract (LVOT) obstruction. The patient had no reported family history of hypertrophic cardiomyopathy. NYHA functional classification was NR.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction)

CaseNotHPOFreeText: No left ventricular outflow tract (LVOT) obstruction was reported despite the presence of systolic anterior motion of the mitral valve.

CasePreviousTesting: Patient 1 previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel covering 174 genes associated with inherited cardiac conditions. Initial genetic analysis was negative. Subsequent reanalysis of existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA from peripheral blood was analyzed using the Illumina TruSight Cardio targeted next-generation sequencing panel on an Illumina MiniSeq platform. Existing sequencing data were reexamined using an intronic hotspot analysis approach and Integrative Genomics Viewer (IGV). The MYBPC3 c.1224-80G>A variant was subsequently confirmed by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a cryptic splice acceptor site within intron 13, resulting in the retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons in the resulting transcript. Previous functional studies demonstrated abnormal RNA splicing and approximately 50% reduction in MYBPC3 transcript abundance. SpliceAI predicted a strong splice-altering effect (Δscore = 0.94). The current study did not perform patient-specific RNA functional experiments. Instead, the researchers identified the variant through reanalysis of existing next-generation sequencing data and confirmed its presence using Sanger sequencing.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: Unlike Patients 2 and 3, Patient 1 had no reported family history of HCM. Echocardiography demonstrated systolic anterior motion of the mitral valve without left ventricular outflow tract obstruction, and maximum left ventricular wall thickness was 13 mm. Although all three patients carried the same splice-altering variant, their reported cardiac phenotypes differed. This observation is consistent with variable clinical expression of MYBPC3-associated HCM, although the study did not establish the underlying causes of these differences.

PMID: 39355877

Gene: MYBPC3

HGNC ID: 7551

Case#: Patient 2; male; 74 years old at first observation; 27 mm LV wall thickness; family history of HCM

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the MYBPC3 intronic splice-altering variant c.1224-80G>A (authors classify as likely pathogenic).

FamilyInfo: Reported family history of hypertrophic cardiomyopathy. Echocardiographic evaluation demonstrated a maximum left ventricular wall thickness of 27 mm and left ventricular outflow tract (LVOT) obstruction, with a gradient of 50 mmHg. The patient was classified as NYHA functional class II.

ParentalTesting: NR – Patient had a positive family history of HCM but parental genotypes and variant segregation were not documented.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0032092 (Left ventricular outflow tract obstruction); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Echocardiography demonstrated a maximum left ventricular wall thickness of 27 mm and left ventricular outflow tract (LVOT) obstruction with a measured gradient of 50 mmHg. The patient was classified as New York Heart Association (NYHA) functional class II, indicating mild limitation of physical activity.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: The patient previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel covering 174 genes associated with hereditary cardiac diseases. The initial analysis produced a negative molecular result. Subsequent reanalysis of the existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA was extracted from peripheral blood and sequenced using the Illumina TruSight Cardio panel on a MiniSeq platform. Initial bioinformatics analysis was performed using Illumina BaseSpace software. Raw sequencing data were subsequently reanalyzed using an intronic-variant hotspot approach, with variant visualization in Integrative Genomics Viewer (IGV). The identified MYBPC3 variant was validated by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a novel splice acceptor site within intron 13, resulting in the retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons and is associated with approximately 50% reduction in MYBPC3 transcript abundance. Previous studies demonstrated the splice-altering effect through functional analyses, while SpliceAI predicted a strong effect on splicing (Δscore = 0.94). The current study identified the variant through reanalysis of existing NGS data and confirmed its presence using Sanger sequencing; it did not perform new patient-specific RNA functional experiments.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: The variant was detected by expanding the analysis to include previously characterized intronic splice-altering regions and was subsequently confirmed by Sanger sequencing. Functional evidence for altered splicing was obtained from previously published research rather than new patient-specific RNA experiments.

Case#: Jenni a 7 year-old female

DiseaseAssertion: Dilated cardiomyopathy with LVNC

FamilyInfo: MYH7 maternally inherited and MYBPC3 paternally inherited

ParentalTesting: Mother has PPCM

CasePresentingHPOs: HP:0004755

heart failure and supraventicular tachycardia

CaseHPOFreeText: Intermittent Wolff-Parkinson- White

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Echocardiogram and MRI

Genotyping Method: Segregation analysis, targeted next generation sequencing

FunctionalAnalysis: electrophysiology, transplant evaluation, CT angiography

Variant: NM_000256.3(MYBPC3):c.2672G>A (p.Arg891Gln)

ClinVar:177884

CAID: CA012826

gnomAD: 11-47357493-C-T

AdditionalInfo:

PMID:41728227

Gene: MYBPC3

HGNC ID: 7551

Case4: 47 year old male

DiseaseAssertion: Carried the MYBPC3 R326Q mutation

FamilyInfo:His father had onset of symptoms at 77 years of age and is stable on medication. Two asymptomatic young children (M21, III:1 and :2) had no signs of hypertrophy or dilatation on echocardiography and normal ECG.

ParentalTesting: NR

CasePresentingHPOs: HP:0011713, HP:0034307, HP:0012665, HP:0001635

CaseHPOFreeText: Had onset of symptoms at 42 years, LBBB on ECG and required cardiac resynchronization therapy. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2) of 81 mm and 3.6 cm/m2. A left ventricular ejection fraction as 20%. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal. As well with cardiac resynchronization therapy.

CaseNotHPOs: HP:0011675

CaseNotHPOFreeText: No arrhythmia

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis: It results in the replacement of a conserved charged arginine with neutral glutamine at residue 326 in the phosphorylatable MyBPC motif of cMyBPC. This charge change is likely to cause functional impairment.

Variant:NM_000256.3:c.977G>A

ClinVar:42813

CAID:CA016212

gnomAD: gnomAD v2: 11:47367871 C / T gnomAD v3: 11:47346320 C / T gnomAD v4: chr11-47346320-C-T

AdditionalInfo:NR

Case8: 56 year old male

DiseaseAssertion: A double heterozygous for the known MYBPC3 R326Q mutation.

FamilyInfo: His father died due to IDC in his fourth decade, whereas his brother developed IDC. DNA was not available from either of these individuals.

ParentalTesting:NR

CasePresentingHPOs:HP:0005110, HP:0034307,HP:0012666, HP:0011675, HP:0005110, HP:0100651

CaseHPOFreeText: He also developed atrial fibrillation, well regulated on medication. Had onset conditions at age 36. He had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)); as a value of 65mm and 3.2 cm/m2. A LVEF, left ventricular ejection fraction as 15%. Arrhythmia level as atrial fibrillation. Clinical status as heart transplantation. He also has type 1 diabetes mellitus

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

Variant:NM_000256.3:c.977G>A

ClinVar:42813

CAID:CA016212

gnomAD:gnomAD v2: 11:47367871 C / T gnomAD v3: 11:47346320 C / T gnomAD v4: chr11-47346320-C-T

AdditionalInfo:NR

Case6: 48 year old male

DiseaseAssertion: Carried the MYBPC3 E619K mutation

FamilyInfo:Three unaffected children were examined (IV:1, IV:2 and IV:3), all with normal echocardiography without signs of hypertrophy or dilatation. Both affected individuals as well as a 26-year-old unaffected daughter (M29, IV:3) carried the MYBPC3 E619K mutation

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:0011713, HP:0001635

CaseHPOFreeText: Onset of symptoms in their third decade; the index case required heart transplantation 3 years after the onset of symptoms. Has onset at the age of 37. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with the value of 79 mm and 3.2 cm/m2. They have a 20% of left ventricular ejection fraction. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1855G>A

ClinVar:161303

CAID:CA011336

gnomAD: gnomAD v2: 11:47362731 C / T gnomAD v3: 11:47341180 C / T gnomAD v4: chr11-47341180-C-T

AdditionalInfo:NR

PMID: 41561115

Gene: MYBPC3

HGNC ID: 7551

Case1: 40-year-old Chinese male

DiseaseAssertion: exertional dyspnea for one year and substernal chest pain for one week.

FamilyInfo: Father experienced sudden cardiac death (SCD) at the age of 41. Targeted region capture and second-generation high throughput sequencing were performed on the proband’s cousin, cousin sister, and sister. Results demonstrated that all family members carried the MYBPC3 c.1827dupC variant. Pedigree in Fig. 3

ParentalTesting: NR

CasePresentingHPOs: HP:0025169, HP:0025168, HP:0031675, HP:0001714,

CaseHPOFreeText: harsh systolic ejection murmur at the left sternal border (3rd–4th intercostal spaces), accentuated by Valsalva maneuver. Echocardiography revealed the following key findings: severe asymmetric septal hypertrophy, characterized by an interventricular septal thickness (IVsd) at end-diastole of 25–30 mm and a left ventricular posterior wall dimensions (LVPWd) of 21 mm, with a preserved left ventricular ejection fraction (LVEF) of 59%

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: target-region capture sequencing and second-generation high throughput sequencing were performed to analyze all exons and their Flanking regions. Rare and known variants were validated using Sanger sequencing and cascade screening was carried out for all available relatives

Genotyping Method: target-region capture sequencing and second-generation high throughput sequencing, Sanger sequencing and cascade screening.

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1827dupC, NM_004415.4:c.1324T>C

ClinVar:NR

CAID:UnregisteredVariant

gnomAD:NR

Case3: 39-year-old man

DiseaseAssertion: seronegative rheumatoid arthritis

FamilyInfo: Father was diagnosed with hypertrophic cardiomyopathy

ParentalTesting: Genetic testing revealed a pathogenic MYBPC3 variant in the patient and his father (c.655G>C [p.Val219Leu])

CasePresentingHPOs: HP:5210340, HP:0006682, HP:0031971

CaseHPOFreeText: Rccentric septal hypertrophy with a maximal wall thickness of 1.7 cm, no evidence of outflow tract obstruction, and an LV EF of 65% to 70%. Rare premature ventricular complexes. Mild mediastinal lymphadenopathy, pulmonary sarcoidosis

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NM_006252.4(PRKAA2):c.148_151del (p.Gln50fs)

ClinVar:4891957

CAID:NR

gnomAD:NR

AdditionalInfo:NR

PMID:42233912

Gene:MYBPC3, FLNC, PKP2

HGNC ID:7551, 9024, 3756

Case#: Pedigree I-1; 74-year-old Korean male; admitted for dyspnea (NYHA III), palpitations, and bilateral pitting leg edema over several months

DiseaseAssertion: Idiopathic restrictive cardiomyopathy (RCM) with biatrial enlargement, in a family with MYBPC3-related cardiomyopathy

FamilyInfo: Family history of heart disease with two affected daughters (II-2 and II-4), both heterozygous for the same variant and both diagnosed with HCM. Unaffected granddaughter (III-3) tested negative. Both daughters showed asymmetric septal hypertrophy on TTE (18 mm and 17 mm) with mildly dilated LA; daughter II-2 had grade I diastolic dysfunction and mild exertional chest discomfort. CMR confirmed reverse septal curvature hypertrophy consistent with HCM in both daughters, with no LGE in either.⁠

ParentalTesting: Not performed; the proband is the index case in generation I; his parents were not evaluated. Phase established only through the daughters and granddaughter.

CasePresentingHPOs:HP:0002094; HP:0001962; HP:0001677; HP:0001635; HP:0001639; HP:0001698

CaseHPOFreeText: Exertional dyspnea NYHA class III, palpitations, and bilateral leg pitting edema for several months; dyspnea refractory to heart failure medication, with pulmonary venous congestion. ECG and Holter: atrial fibrillation with rare premature ventricular complexes. TTE: RCM with biatrial enlargement and small pericardial effusion. CMR: normal LV chamber size, borderline diffuse LV hypertrophy, very large atria, extensive transmural LGE in the apical wall and mid-myocardial patchy LGE in the ventricular septum. Coronary angiogram normal; no secondary cause of RCM found.⁠

CaseNotHPOs: HP:0000822; HP:0000819; HP:0001658; HP:0001678

CaseNotHPOFreeText: Coronary angiogram normal, so no obstructive coronary disease. No secondary cause of RCM identified; no inflammatory, infiltrative, or systemic disease found. No AV block; the rhythm disturbance was atrial fibrillation.

CasePreviousTesting: Whole exome sequencing (Agilent SureSelect XT Human All Exon v5, Illumina HiSeq2500, GATK. Sanger sequencing of family members showed only the MYBPC3 variant tracked with disease; the other four (KALRN c.1702C>T, KCNH2 c.442C>T, SKI c.30T>G, TTN c.54293T>C) did not correlate with phenotype.⁠

Genotyping Method: WES in the proband, with annotation via dbNSFP and Ensembl VEP; Sanger sequencing confirmed the MYBPC3 frameshift in the proband (I-1), daughters II-2 and II-4, and its absence in granddaughter III-3 (Fig. 3B).⁠

FunctionalAnalysis: None performed. CMR showed extensive LGE in the apical LV, and the authors propose that advanced myocardial fibrosis in end-stage HCM can provoke myocardial atrophy, explaining the relatively normal LV chamber size with a predominantly restrictive phenotype hypothesis.⁠

Variant: MYBPC3 NM_000256.3:c.3313_3314insGG (p.Ala1105Glyfs*85); heterozygous frameshift insertion; absent from gnomAD and the Korean Reference Genome Database.

ClinVar: 1473634

CAID: Not reported.

Gene:MYBPC3

HGNC: HGNC: 7551

PMID: 33803538

gnomAD: Absent per the authors' check of gnomAD as of 8 November 2020, and absent from KRGDB.

AdditionalInfo: Authors conclude the MYBPC3 frameshift is the pathogenic variant, with the same allele producing RCM in the proband and HCM in both daughters; an example of pleiotropy and variable expressivity within one family. The frameshift has previously been reported in Korean HCM. Poor-prognosis features in RCM cited by the authors: male sex, age over 70, high NYHA class, and LA dimension >60 mm.

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

Case#: 64-year-old male, non-smoker, first admitted June 2014; Russian family; died 2019 at age 69

DiseaseAssertion: MYBPC3-related cardiomyopathy with a predominantly restrictive phenotype in combination with left ventricular noncompaction (LVNC) and cardiac sarcoidosis

FamilyInfo: Son (39) and daughter (35) both heterozygous for the same variant and both have non-obstructive asymmetric HCM, with no LVNC on cardiac CT; both essentially asymptomatic on beta-blocker monotherapy. Five-year SCD risk 4.82% (son) and 2.07% (daughter); ICD implanted in the son, no shocks in three years. Authors mention another family of theirs with a father who died suddenly young and children with HCM and LVNC.

ParentalTesting: Not performed; the proband is the index case; his parents were not evaluated. Transmission to both children confirmed by Sanger.

CasePresentingHPOs:HP:0001639

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Genotyping Method: Next-generation sequencing panel; variants confirmed by Sanger.

FunctionalAnalysis: N/A

Variant 1: MYBPC3 NM_000256.3:c.278delA; heterozygous frameshift

Variant 2: KCNJ5 c.464G>A; heterozygous missense

ClinVar: N/A

CAID:N/A

gnomAD: N/A

Gene:MYBPC3

PMID:36011256

Case1: gestational age 40 weeks female

DiseaseAssertion: Poor feeding, cyanosis, and difficulty with breathing.

FamilyInfo: Healthy non‐consanguineous parents. Echocardiographic in the mother and sister were normal. Father had mild dilatation of the left atrium with an abnormal flow pattern in the mitral valve, otherwise healthy.

ParentalTesting: c.2373_2374insG mutation found in the mother

CasePresentingHPOs:HP:0025169,

CaseHPOFreeText: hypertrophic non‐obstructive cardiomyopathy with poor left and right ventricular systolic function. The left ventricular end diastolic diameter measured 17.3 mm (99% of normal), end systolic diameter 12.9 mm (116% of normal), and left ventricular posterior wall 3.6 mm (111% of normal). The intraventricular septum measured 11.8 mm (288% of normal). The shortening fraction of the left ventricle was decreased to 25%. Multiple abnormal small communications with a minimal flow between a coronary artery and the right ventricle were observed in the apical portion of the interventricular septum. There were no structural congenital heart defects.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method:

FunctionalAnalysis: NR

Variant: NM_006073.4(TRDN):c.1624+1G>A

ClinVar:2152664

CAID: CA147231745

gnomAD:NR

AdditionalInfo:NR

PMID: 16679492

Gene: MYBPC3

HGNC ID:7551

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

PMID: 38586174 Gene: MYBPC3 HGNC ID: 7551

Case2: 12-year-old boy (Patient 2) DiseaseAssertion: DCM FamilyInfo: Family history unremarkable. ParentalTesting: The MYBPC3 variant was inherited from his father. The father’s cardiac phenotype is not reported. CasePresentingHPOs: HP:0001644, HP:0003546 CaseHPOFreeText: Severely depressed biventricular function; heart transplantation for decompensated heart failure. CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Previous WES was negative; the variant’s intronic region was not adequately covered. Genotyping Method: Whole-genome sequencing (WGS; Illumina NovaSeq 6000; aligned to hg19/GRCh37). FunctionalAnalysis: SpliceAI predicted a potential splicing effect; no functional assay in this patient is reported. Variant: NM_000256.3:c.1224-80G>A (heterozygous intronic variant) ClinVar: 693982 CAID: CA221697326 gnomAD: 0.0000637 AdditionalInfo: The authors classified the variant as a VUS in this DCM case because evidence for a MYBPC3–DCM relationship is limited. ClinVar currently reports a pathogenic/likely pathogenic aggregate classification, primarily in relation to HCM. Reanalysis found no second MYBPC3 variant.

PMID: 22194935

Gene: MYBPC3

HGNC ID: HGNC:7551

Case1: HCM patient-derived cell line UKEi070-A (demographics not reported in this paper) DiseaseAssertion: HCM

ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Genotyping Method: Not reported in this paper; it references a previously established patient-derived cell line. FunctionalAnalysis: The variant is reported to cause MYBPC3 protein haploinsufficiency in cardiomyocytes. In this study, TTL overexpression normalized cell hypertrophy in the HCM cell model. Variant: NM_000256.3:c.2308G>A (heterozygous; the paper reports the splice consequence as p.Asp770Serfs98X) ClinVar: 36604 CAID: gnomAD: NR AdditionalInfo: The paper uses patient-derived induced pluripotent stem cell cardiomyocytes; it does not provide the patient’s age, sex, or pedigree.

Chronic Activation of Tubulin Tyrosination Improves Heart Function

PMID: 39279670 Gene: MYBPC3 HGNC ID: 7551

Novel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes

PMID: 31361967

Gene: MYBPC3

HGNC ID: 7551

Case1: 50 year old male DiseaseAssertion: HCM; hydroxychloroquine cardiotoxicity FamilyInfo: Six children undergoing predictive testing for the familial MYBPC3 variant; family history not reported ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: Monomorphic ventricular tachycardia, dyspnea, nausea, vomiting, biventricular hypertrophy, systolic dysfunction, cardiogenic shock CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Prior CMR showed nonobstructive HCM; cardiomyopathy gene panel identified the variant Genotyping Method: Cardiomyopathy gene panel FunctionalAnalysis: Altered splicing with exon 30 skipping; authors describe a nonfunctional protein or premature stop codon Variant: c.3330+5G>C ClinVar: 42706 CAID: gnomAD: 0.03% (as reported in the article) AdditionalInfo: Long-term hydroxychloroquine exposure for malaria prophylaxis; biopsy findings were consistent with both HCM and hydroxychloroquine cardiotoxicity

Hydroxychloroquine Cardiotoxicity and Sarcomeric Hypertrophic Cardiomyopathy.”

PMID: 40514126 Gene: MYBPC3 HGNC ID: 7551

PMID: 31293105

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#: Deceased child, female; age 5.5 months

DiseaseAssertion: Hypertrophic cardiomyopathy with endomyocardial fibroelastosis

FamilyInfo: The mother carried c.2373dup, and the father carried c.592G>T.

ParentalTesting: The mother carried c.2373dup, and the father carried c.592G>T.

CasePresentingHPOs: HP:0001706 HP:0200128 HP:0012664 HP:0002094 HP:0000961

CaseHPOFreeText: Acute heart failure; massive biventricular cardiac enlargement; biventricular dysfunction; progressive dyspnea; blue lips; pale appearance; endocardial fibrosis; cardiopulmonary arrest.

CaseNotHPOFreeText: No congenital heart disease or valve abnormalities were found at autopsy

Genotyping Method: Postmortem molecular testing

Variant: MYBPC3 c.592G>T (p.Asp198Tyr); missense

MYBPC3 c.2373dup, p.Trp792Valfs*41); frameshift duplication

ClinVar: c.592G>T: NR; c.2373dup: 42619

CAID: c.592G>T: NR; c.2373dup: CA012139

gnomAD: c.592G>T was not observed in more than 123,000 individuals; c.2373dup: 0.0017% overall

AdditionalInfo: The child died from severe early-onset cardiac disease at 5.5 months. Autopsy showed endomyocardial fibroelastosis and severe biventricular involvement.

Case#: Single proband ; 63-year-old female; palpitations at presentation July 2025; HCM diagnosis established at age 63

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) complicated by apical left ventricular aneurysm and mid-ventricular obstruction⁠

FamilyInfo: No family history of cardiac disease or sudden cardiac death at a young age reported. Both parents deceased (one of cancer, one of natural causes at age 92), neither with reported cardiovascular disease; proband has no siblings. Only first-degree relative is her son, who carries the KCNJ5 c.464G>A variant but not the MYBPC3 c.278delA variant, and has a normal echocardiogram with no myocardial hypertrophy. No pedigree beyond the son (Fig. 3B).⁠

ParentalTesting: Not performed; both parents deceased, no DNA available; authors state a valid familial segregation analysis could not be performed. Only one family member (son) was available for cascade Sanger screening.⁠

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001649 (Tachycardia), palpitations; HP:0001712 (Left ventricular hypertrophy).

CaseNotHPOFreeText: No history of hypertension, diabetes, or hyperlipidemia. Phenocopies excluded: no extra-cardiac manifestations of Fabry disease and GLA testing negative; cardiac amyloidosis excluded (no apical sparing, normal serum free light chains, negative serum protein electrophoresis and immunofixation); no significant coronary stenosis on coronary CT angiography. No QT prolongation or features of Andersen–Tawil syndrome on ECG.

CasePreviousTesting: Whole exome sequencing identified both variants; all rare and known variants validated by Sanger sequencing, with cascade Sanger screening in available one family member. No prior genetic testing reported before this episode.

Genotyping Method: Targeted region capture with next-generation high-throughput sequencing (whole exome, exonic plus flanking regions); variants confirmed by bidirectional Sanger sequencing. Cascade screening by Sanger in the son. MYBPC3 variant absent from 1000 Genomes, ESP6500, ExAC, and the Besuper local database. KCNJ5 variant absent from 1000 Genomes and ESP6500, ExAC frequency, absent from local Basenhall controls.⁠

FunctionalAnalysis: None performed; authors list absence of functional studies and lack of mRNA-level validation as limitations. MYBPC3 frameshift predicted to trigger nonsense-mediated decay.⁠

Variant: MYBPC3 NM_000256.3:c.278delA (p.Lys93ArgfsTer3); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified Likely Pathogenic by ACMG (PVS1, PM2). Second variant: KCNJ5 NM_000256.3:c.464G>A (p.Arg155Gln); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified VUS (PM2, PP3). Note the paper's KCNJ5 accession is written as NM_000256.3, which is the MYBPC3 transcript, most likely a typo in the article Pepper please conform for me the correct KCNJ5 accession

ClinVar: No ClinVar record for either variant; nearby KCNJ5 missense variants c.451G>A, c.452G>A, c.470T>G, and c.473C>G are documented as pathogenic/likely pathogenic for long QT syndrome or aldosteronism, and downstream frameshift/nonsense variants at the MYBPC3 locus are classified pathogenic or likely pathogenic.

CAID:Not found.

gnomAD: No allele frequency available, so no MAF to report.

PMID: 42428486

Gene: MYBPC3

HGNC: HGNC:7551

AdditionalInfo:Single-case report, no case numbering system used. Treated with dapagliflozin, metoprolol, rivaroxaban, and recombinant human BNP for 13 days, discharged on the first three; mexiletine added at 1-week follow-up for persistent palpitations. ICD recommended but declined due to financial constraints; 3-month follow-up showed good adherence with occasional palpitations and no serious arrhythmic events. Authors conclude MYBPC3 c.278delA is likely pathogenic for HCM, while the KCNJ5 variant shows no clinical phenotype in the proband or her son and may be incidental or a modifier.⁠

PMID: 34588271

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID: 30009132

Gene: MYBPC3, multiple genes, cohort study

HGNC ID: HGNC:7551

PMID: 30896616

Gene: MYBPC3

HGNC ID: HGNC:7551

33101033

MyBPC3

HGNCID:7551

Table 1 identifies individual Slovenian probands carrying MYBPC3:c.913_914del and compares genetic markers used for haplotype analysis

Table 3 compares heart measurements between probands with MYBPC3:c.913_914del and those with other MYBPC3 variants. These measurements help evaluate how the variants relate to heart structure and function

Table 2 compares clinical symptoms and characteristics between 18 probands with MYBPC3:c.913_914del and 21 probands with other likely pathogenic or pathogenic MYBPC3 variants. The differences shown were not statistically significant.

Case2: A 49 year old woman

DiseaseAssertion: Carried a novel MYBPC3 T494I mutation

FamilyInfo: Both parents were older than 80 years, had no cardiovascular symptoms and declined participation in the study

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:6000091

CaseHPOFreeText: Had onset of symptoms a few days after giving birth to her first child. She had a short, aggressive disease period, which resulted in HTX within 3 months of onset. Age 35 at onset. Has left ventricular end-diastolic diameter (in mm and indexed by body surface area (cm/m2)) 62 mm and 3.2 cm/m2. A left ventricular ejection fraction of 20%. An ECG at normal. New York Heart Association (NYHA) as 4, Clinical status as heart transplantation (HTX), CAG as normal. HTX, 36 years, postpartum.

CaseNotHPOs:HP:0011675

CaseNotHPOFreeText:No Arrhythmia.

CasePreviousTesting:NR

Genotyping Method:genetically screened, also using GenBank with PCR by amplifying the coding region.

FunctionalAnalysis:NR

Variant:NM_000256.3:c.1481C>T

ClinVar:NR

CAID:CA380325267

gnomAD:NR

AdditionalInfo:This index case carried a novel MYBPC3 T494I mutation, which replaces a conserved hydrophilic side chain with a branched neutral side chain in domain C3 of cardiac myosin-binding protein C (cMyBPC); such an alteration may interfere with the secondary structure of the C3 domain. The missense mutations G490R, R495Q and R502W, all located in the proximity of the 494 residue, have all been described as associated with HCM.

PMID: 33849460

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID: 28614222

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID: 41550885 Gene: MYBPC3 HGNC: 7551

PMID: 42460955

Gene: MYBPC3

HGNC ID: 7551

PMID: 21832052

Gene: MYBPC3

HGNC: 7551

PMID: 37271167

Gene: MYBPC3

HGNC ID: 7551