PMID: 42569619

Gene: MYBPC3

HGNC ID: 7551

Case1: 42 year old Male

DiseaseAssertion: History of acromegaly

FamilyInfo: N/A

ParentalTesting: No parental testing done

CasePresentingHPOs: “elevated levels of growth hormone, and IGF-1”

CaseHPOFreeText: Genetic analysis revealed a heterozygous nonsense variant in MYBPC3

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac MRI revealed normal dimensions of thoracic aorta, no evidence of stenosis or aneurysms

CasePreviousTesting: An oral glucose tolerance test was performed, growth hormone failed to suppress below 0.88

Genotyping Method: Echocardiography used to confirm enlarged left atrium, increased septal thickness, mild mitral and tricuspid regurgitation

Variant: NM_000256.3 c.3408C>G MANE select

ClinVar: 851340

CAID: CA380313523

gnomAD: chr11-47332896

https://www.ncbi.nlm.nih.gov/clinvar/variation/851340/?term=%22c.3408C%3EG%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

Case3: Male, 44,57,17, 2 Native American, European, Guaranda, Zaruma, Ibarra

DiseaseAssertion: asymmetric septal hypertrophy, dynamic left ventricular outflow tract obstruction, HCM, fatigue and presyncope

FamilyInfo: family history included parental hypertension and cancer, Relatives had cardiovascular conditions, including a paternal uncle with myocardial infarction at 58, another with a heart murmur, and a grandmother with hypertension

ParentalTesting: Family history of first degree relatives with myocardial infarction

CasePresentingHPOs: HP: 000256.3, HP: 033118.3, HP:000540.2 “Gene encodes the cardiac isoform of myosin-binding, Gene encodes an enzyme that is expressed in adult skeletal muscle, gene encodes a ryanodine receptor found in skeletal muscle”

CaseHPOFreeText: N/A

CaseNotHPOs: HP: 004168.3, HP: 000384.2, HP: 020433.4

CaseNotHPOFreeText: “Mutations in gene are linked to Leigh syndrome, mutations to gene are linked to diseases affecting plasma cholesterol, gene encodes a protein to mediate cross talk between cell surface and intracellular ion channels”

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Next-generation sequencing (NGS)

FunctionalAnalysis: N/A

Variant: NM_000256.3 c.772G>A MANE select

ClinVar: 42792

CAID: CA015823

gnomAD: 0.00003

https://www.ncbi.nlm.nih.gov/clinvar/variation/42792/?term=%22p.Glu258Lys%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

PMID: 41647802

Gene: MYBPC3

HGNC ID: 7551

Case2: 12 year old Male, 9 month old Female

Disease Assertion:Double atrial and right ventricular hypertrophy, intermittent chest pain and left ventricular hypertrophy

FamilyInfo: No family history of sudden cardiac death, HCM, or coronary artery disease, granduncle had HCM history and died at 67

ParentalTesting: Heterozygous mutation myosin binding protein C gene(MYBPC3) is confirmed in mother

CasePresentingHPOs: “enlarged left and right atria, double ventricular hypertrophy, interventricular septal thickness”

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Sanger sequencing

FunctionalAnalysis: N/A

Variant: TNN c.50171G>T, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA012326&

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

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.

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

PMID: 42112275

Gene: MYBPC3

HGNC ID: 7551

Case2: 40 year old Male, 37 year old Female

DiseaseAssertion: HCM, basal septal hypertrophy, dilated phase HCM

FamilyInfo: Family was notable for end stage HCM in father and in younger brother, family history was notable for HCM in grandmother and sudden cardiac death(SDC) due to HCM in mother

ParentalTesting: No parental testing done

CasePresentingHPOs: “Inguinal Hernia surgery, exertional dyspnea”

CaseHPOFreeText: Transthoracic echocardiography unveiled hypertrophy of the interventricular septum and left ventricular anterior wall, systolic anterior motion of the mitral valve

CaseNotHPOs: N/A

CaseNotHPOFreeText: ECG demonstrated a sinus rhythm at 58 bpm with complete right bundle branch block, heart failure progressively worsened

CasePreviousTesting: Cardiac magnetic resonance reveals ring like late gadolinium enhancement(LGE) as a imaging phenotype

Genotyping Method: Cardiac magnetic resonance

FunctionalAnalysis: N/A

Variant: NM_000257.4 c.2302G>A, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA012326

Case1: 48 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

Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction

FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.⁠

ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.

CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678

CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.

CaseNotHPOs: HP:0000822; HP:0000819

CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.

CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.

Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.

FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.

Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)

ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!

CAID: N/A

gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.

AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

case1: male, 40 weeks,

DiseaseAssertion: sudden-onset acute heart failure

FamilyInfo: Both parents suspected of being heterozygous carriers of a pathogenic MYBPC3 variant

ParentalTesting: Both parents were identified as heterozygous carriers of a pathogenic MYBPC3 variant

CasePresentingHPOs: HP: 0001639, HP: 0001631, HP: 0001635

“Hypertrophic cardiomyopathy, atrial septal defect, acute heart failure”

CaseHPOFreeText: Absence of significant interstitial fibrosis, extensive myocardial disarray and contraction band necrosis

CaseNotHPOs: N/A

CaseNotHPOFreeText: normal fetal growth and anatomy reported

CasePreviousTesting: Targeted gene panel for pathogenic variants in MYBPC3

Genotyping Method: Whole-exome sequencing (WES)

FunctionalAnalysis: N/A

Variant: NM_000256.3:c.2905+1G>A

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

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

Case1:19 Year-old male

DiseaseAssertion:HCM

FamilyInfo:None documented

ParentalTesting:

CasePresentingHPOs:HP:0001639

CaseHPOFreeText:Hypertrophic Cardiomyopathy

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

Genotyping Method:Next Generation Sequencing

FunctionalAnalysis:

Variant:c.442G>A, (p.Gly148Arg)

ClinVar:42752

CAID: CA015105

gnomAD:

AdditionalInfo:

PMID: 31293105

Gene: MYBPC3

HGNC ID: HGNC: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

Case#: 51-year-old Spanish man

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Familial HCM

ParentalTesting:

CasePresentingHPOs: Hypertrophic cardiomyopathy

CaseHPOFreeText: not reported

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: not reported

Genotyping Method: Genetic testing/sequencing

FunctionalAnalysis:

Variant: g.47363647G>A, p.Ala562Val

ClinVar: not found

CAID: CA078267

gnomAD: not found

AdditionalInfo: not reported

PMID: 28265379

Gene: MYBPC3

HGNC ID: 7551

Case:Female, 35. DiseaseAssertion:Hypertrophic cardiomyopathy (HCM) with left ventricular noncompaction (LVNC) and conduction abnormalities. Familyinfo:The patient's father had hypertrophic cardiomyopathy and carried a heterozygous MYBPC3 p.(Pro1066Arg) variant. The patient's mother was also heterozygous for the MYBPC3 variant. The patient had one sister who did not have reported cardiac abnormalities and was heterozygous for the MYBPC3 variant. The family was initially considered non-consanguineous. Genetic analysis identified a 26 Mb region of homozygosity, suggesting distant parental relatedness. ParentalTesting:Both parents were tested. The father and mother were heterozygous for MYBPC3 c.3197C>G (p.Pro1066Arg). The affected daughter inherited the variant from both parents and was homozygous. CasePresentingHPOs:HP:0031992, HP:0001685, HP:0005157, HP:0031295, HP:0001667, HP:0001670, HP:0001712, HP:0005144, HP: 0031195, HP:0030682, HP:0005135, HP: 0006682, HP: 0004763 CaseHPOFreeText:The patient developed severe cardiac manifestations associated with homozygous MYBPC3 p.(Pro1066Arg). Cardiac MRI showed ventricular hypertrophy, myocardial fibrosis, and features of left ventricular noncompaction. At follow-up, imaging showed asymmetric ventricular wall thickness, with a maximum diastolic thickness of 20 mm in the mid-lateral segment. She also had apical hypokinesia and left atrial enlargement. Electrocardiography and Holter monitoring showed premature ventricular complexes and a 20-beat episode of nonsustained ventricular tachycardia. CaseNotHPOs:No specific negative HPO findings were established for the affected daughter in the reported HPO table. CaseNOTHPOFreeText:not reported CasePreviousTesting:Cardiac MRI, echocardiography, electrocardiography, and 24-hour Holter monitoring were performed. Genetic evaluation was also conducted to identify the MYBPC3 and MYH7 variants. GenotypingMethod:Whole-exome sequencing (WES) trio analysis was performed using DNA from the affected daughter and both parents. Family segregation analysis was performed by Sanger sequencing using an Applied Biosystems 3130 sequencer. FunctionalAnalysis:No direct functional analysis of the MYBPC3 variant was reported. Variant:NM_000256.3 (MYBPC3): c.3197C>G; p.(Pro1066Arg). ClinVar:1171602. CAID:not reported gnomAD:not reported AdditionalInfo:The patient was homozygous for the MYBPC3 p.(Pro1066Arg) variant. Both parents carried the variant in the heterozygous state. A 26 Mb region of homozygosity was identified on chromosome 11, supporting the possibility of distant parental relatedness. The variant was initially classified as a variant of uncertain significance and was subsequently reclassified as likely pathogenic following family segregation analysis.

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#: IV-2; female; age 51; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: IV-2 is the mother of V-1

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Atypical hypertrophy with a septal thickness of 23 mm; exertional angina for 10 years.

Genotyping Method: Sanger sequencing and targeted next-generation sequencing

Variant: c.3624delC, frameshift

ClinVar: 42727

CAID: CA014493

AdditionalInfo: Also carried CACNB2 p.Ser533Leu and DSP p.Arg1308Gln.

Case#: V-1; male; age 28; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: V-1 is part of a large consanguineous HCM pedigree. Family segregation information was reported for the MYBPC3 variant. V-1 died suddenly at age 29

CasePresentingHPOs: HP:0001712 HP:0005144 HP:0032092

CaseHPOFreeText: Left ventricular hypertrophy; increased interventricular septal thickness; left ventricular outflow tract obstruction

Genotyping Method: Sanger sequencing and next-generation sequencing

Variant: c.3624delC, missense

ClinVar: 42727

CAID: CA014493

Case#: IV-6; female; age 64; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: IV-6 is a member of the MYBPC3-positive HCM pedigree

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Moderately affected, asymmetrical hypertrophy with a maximum wall thickness of 15 mm; normal left ventricular dimensions and systolic function.

CaseNotHPOFreeText: No cardiac symptoms or cardiac events were reported.

Genotyping Method: Sanger sequencing and targeted next-generation sequencing

Variant: c.3624delC, frameshift

ClinVar: 42727

CAID: CA014493

AdditionalInfo: No additional CACNB2 variant was reported.

PMID: 36555486

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#: Pedigree C, C.6, age 38, Female

FamilyInfo: C.6 is the daughter of C.4 in Pedigree C. C.6 carries the MYBPC3 P910T variant only and does not carry the TNNC1 D145E variant. Normal cardiac screening was reported at age 38.

ParentalTesting: Mother, C.4, carries MYBPC3 P910T and TNNC1 D145E

GenotypingMethod: DNA was isolated from a peripheral blood sample of the patient and was screened for mutations by direct sequencing

FunctionalAnalysis: NR

Variant: NM_000256.3: c.2728C>A (p.Pro910Thr; P910T)

ClinVar: 42656

CAID: CA012881

Case1: Male, 12, China

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: parents where not consanguineous, both carried variants.

ParentalTesting: sanger sequencing showed c.1789C>T variant in patients paternal grandmother, and c.3033delG from maternal grandmother

CasePresentingHPOs: HP:0001962 HP:0002094 HP:0001279 HP:0001712 “Palpitations, Dyspnea, Syncope, Left ventricular hypertrophy”

CaseHPOFreeText: symptoms lasted about a year, ECG showed sinus arrhythmia, high left ventricle voltage

CaseNotHPOs: “the patient had no skeletal muscle disease or mental retardation. The diagnosis of glycogen storage disease was also excluded.”

CaseNotHPOFreeText: no other family members diagnosed with heart disease

CasePreviousTesting: diagnosed 3 months before presentation with HCM, no prior genetic testing, but there was echocardiogram and ecg testing.

Genotyping Method: Sanger and NGS

FunctionalAnalysis: no functional analysis preformed

Variant: c.1789C>T (p.Arg597Trp), c.3033delG (p.Gln1012Serfs*8)

ClinVar: NM_000256.3(MYBPC3):c.1789C>T (p.Arg597Trp),

CAID: no results

gnomAD: no results

AdditionalInfo: treated with metoprolol, at 3 moth follow up lvot decreased

PMID: 30896616

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#: cohort annotation with 8 probands and 25 relatives that are carriers.

DiseaseAssertion: Pathogenic MYBPC3 c.2149–1G>A variant associated with hypertrophic cardiomyopathy

FamilyInfo: Eight unrelated probands, all male, with 45 relatives, 25 where carriers of the variant, 12 had HCM and 13 where unaffected

ParentalTesting: not reported

CasePresentingHPOs: HP:0001712 HP:0002094 HP:0001279 HP:0100749 HP:0001962 HP:0001649 “Left ventricular hypertrophy, Dyspnea, syncope, Chest pain, Palpitations, Tachycardia CaseHPOFreeText:HCM with variable expression with men diagnosed younger then women

CaseNotHPOs:not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: not reported

Genotyping Method: Sanger sequencing

FunctionalAnalysis: rna analysis shows abnormal transcript, suggesting founder effect.

Variant: MYBPC3 NM_000256.3:c.2149–1G>A

ClinVar: 177814

CAID: not reported

gnomAD:not reported

AdditionalInfo: HCM penetrance increased with age and was highest in males over 30

PMID: 34588271

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#: A94, male, age 57; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: positive family history of cardiomyopathy

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Interventricular septal thickness was 16.3 mm

Genotyping Method: Targeted sequencing using the Ion Torrent PGM system with Sanger sequencing confirmation.

Variant: MYBPC3 c.706A>G (p.Ser236Gly), missense

ClinVar: 42786

CAID: CA015725

gnomAD: 0.09513

PMID: : 37929589

Gene: MYBPC3 ,MYH7 ,TNNT2 ,TNNI3,MYL2, MYL3 TPM1, CSRP3 Multiple genes associated with hypertrophic cardiomyopathy (HCM)

HGNC ID: MYBPC3: HGNC:7551, MYH7: HGNC:7577, TNNT2: HGNC:11949, TNNI3: HGNC:11947, MYL2: HGNC:7576 ,MYL3: HGNC:7584, TPM1: HGNC:12010 CSRP3: HGNC:1430

Case#:: no individual case number

DiseaseAssertion:: Hypertrophic cardiomyopathy (HCM)

FamilyInfo::Familial HCM cohorts and at-risk relatives carrying pathogenic or likely pathogenic sarcomeric variants were investigated. Pooled penetrance among non-proband variant-carrying relatives was 57%

ParentalTesting:: No individual parental segregation or parental testing information reported.

CasePresentingHPOs:: Left ventricular hypertrophy

CaseHPOFreeText:: Hypertrophic cardiomyopathy characterized by unexplained left ventricular hypertrophy.

CaseNotHPOs:: N/A

CaseNotHPOFreeText:; N/A

CasePreviousTesting::N/A

Genotyping Method::N/A

FunctionalAnalysis::N/A

Variant:: No specific nucleotide or protein-level variant reported as the subject of an individual case.

ClinVar:: N/A

CAID:: N/A

gnomAD:: N/A

AdditionalInfo:

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.⁠

Case#:1 Male, 27, no reported ethnicity

DiseaseAssertion: sinus tachycardia, signs of hypertrophy of both atria and ventricles

FamilyInfo: proband had a sister who died at 15 days of age due to a congenital heart disease (transposition of the great arteries). No other relative was diagnosed with cardiomyopathy of other cardiac disease before 50 years of age

ParentalTesting: family history was unremarkable. Parents were not consanguineous.

CasePresentingHPOs: HP:0001639, HP:0001644, HP:0200128, HP:0004308 "Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Biventricular hypertrophy, Ventricular arrhythmia <br /> CaseHPOFreeText: Dilated cardiomyopathy recorded at age of 4, Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis"

CaseNotHPOs: none reported

CaseNotHPOFreeText: no evidence of myeloproliferative disease was found when bone marrow trepanobiopsy was preformed.

CasePreviousTesting: dcm diagnosis at age 4, Whole exome sequencing (WES)

Genotyping Method: WES, NGS, & Sanger

FunctionalAnalysis: none reported

Variant: chr11:g.47357432_47357458del, ENST00000545968.1: c.2711_2737del, p.2711_2737del

ClinVar: VCV000978729.2

gnomAD: ENSG00000134571.12

33101033

MyBPC3

HGNCID:7551

PMID: 30009132

Gene: MYBPC3, multiple genes, cohort study

HGNC ID: HGNC:7551

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

PMID: 39160446 Gene: MYBPC3 HGNC: HGNC:7551

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

CaseV-1: Male, 27 yrs onset, China, Asian

CasePresentingHPOs: HP:0002875, HP:0001639, HP:0002027, HP:0001712, HP:0001671, HP:0032092, HP:0001645 (Exertional dyspnea, Hypertrophic cardiomyopathy, Abdominal pain, Left ventricular hypertrophy, Abnormal cardiac septum morphology, Left ventricular outflow tract obstruction, Sudden cardiac death)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Family is consanguineous, The MYPBC3 variant was the only one to segregate with the disease, with the CACNB2 variant also being present in individuals with "severe" forms of the disease. CACNB2+ MYH7- individuals showed no symptoms of cardiomyopathy, supporting a modifying effect leading to the clinical heterogeneity of this family, MYBPC3 variant leads to a premature termination and a loss of 49 amino acids which is predicted to undergo NMD but is also associated with incomplete penetrance

CasePreviousTesting: Marked hypertrophic septum (27  mm) and a left-ventricular outflow obstruction (LVOTO) of 32  mmHg, Clinical features in Table 1, No members showed Brugada syndrome phenotypes, Proband also has polymorphisms in TGFB1 and AKAP9 but no other affected family member contains them suggesting a benign pathogenicity

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. PCR amplification was performed and sanger sequencing was performed for MYH7 and MYPBC3 mutations. After positive confirmation of the MYBPC3 mutation, RAAS genes were genotyped for a possible modifying effect. Negative findings led to a targeted NGS for the index patient using all known 104 causing/closely related genes of cardiomyopathy and chanelopathy. These variants were then filtered and analyzed for pathogenicity and confirmed in family members via Sanger sequencing.

Variant: NM_201597.3:c.1598C>T (p.Ser533Leu)

ClinVar: 190730 https://www.ncbi.nlm.nih.gov/clinvar/variation/190730/

gnomAD: 0.01004, https://gnomad.broadinstitute.org/variant/10-18828340-C-T

MultipleGeneVariants

MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs)

ClinVar: 42727 https://www.ncbi.nlm.nih.gov/clinvar/variation/42727/

gnomAD: 0.00005140, https://gnomad.broadinstitute.org/variant/11-47354119-TG-T

DSP Variant

Variant: NM_004415.4(DSP):c.3923G>A (p.Arg1308Gln)

ClinVar: 178028 https://www.ncbi.nlm.nih.gov/clinvar/variation/178028/

gnomAD: 0.01680, https://gnomad.broadinstitute.org/variant/6-7580346-G-A

Case1: 21, Male

DiseaseAssertion: To be found

FamilyInfo: No remarkable family history.

CasePresentingHPOs: HP:0003401, HP:0410173, HP:0001688

CaseHPOFreeText: "arietal ischemic lesions, elevated high-sensitivity I troponin, left ventricle (LV) dilation, apical hypokinesia, apical thrombus, and multifocal nonischemic late gadolinium enhancement with edema" " elevated N-terminal pro–B-type natriuretic peptide and low c-reactive protein"

CaseNotHPOs: HP:0001297, HP:0012819

CaseNotHPOFreeText: "A cardioembolic stroke due to myocarditis with an LV thrombus was assumed" “Ischemic heart disease was considered unlikely at presentation” “Cardiac sarcoidosis was considered but was not supported” “Autoimmune myocarditis and other systemic inflammatory causes were also considered” “Giant cell myocarditis was considered to be unlikely”

CasePreviousTesting:

Genotyping Method: Whole genome sequencing

Variant: c.1484G>A; p.Arg495Gln

ClinVar: CA010464

gnomAD: To be found

PMID: 42460955

Gene: MYBPC3

HGNC ID: 7551

PMID: 41550885 Gene: MYBPC3 HGNC: 7551

Case1: Male, 65, Chinese DiseaseAssertion: Non‐obstructive HCM, heart failure, and atrial fibrillation FamilyInfo:Family history of HCM and sudden cardiac death CasePresentingHPOs: HP:0031295, HP:0001685, HP:0001712, HP:0012664, HP:0025169, HP:0005110, HP:0001658, HP:0001635 CaseHPOFreeText: Presented with stenosis in the circumflex artery and has a history of non‐obstructive HCM, heart failure NYHA class III, AF, myocardial infarction, and coronary atherosclerosis CasePreviousTesting: Exercise stress echocardiography test, transthoracic echocardiography, electrocardiogram, cardiovascular magnetic resonance (CMR), computerized tomography coronary angiogram, and peripheral blood draw Genotyping Method: Genomic DNA for whole-exome sequencing (WES) by NovaSeq 6000 platform from the peripheral blood draw of proband. FunctionalAnalysis:C to T transition at nucleotide 1522 in coding exon 16 of MYBPC3 replaces the glutamine residue with a premature translational stop signal (p.Gln508Ter) Variant: NM_000256.3:c.1522C>T MANE Select <br /> ClinVar:180941

PMID: 37271167

Gene: MYBPC3

HGNC ID: 7551

PMID: 21832052

Gene: MYBPC3

HGNC: 7551

PMID: 35888124 Gene: MYBPC3 HCNC ID: 7551

PMID: 41488457

Gene: MYBPC3

HGNC ID: 7551

PMID: 35717150 Gene: MYBPC3 HGNC ID: 7551

CaseCM1827: Female, 0 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother tested negative for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.2608C>T (p.Arg870Cys)

ClinVar: 161326 https://www.ncbi.nlm.nih.gov/clinvar/variation/161326/

gnomAD: Ashkenazi Jewish 9.923e-5, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894049-G-A

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3:c.2285T>A (p.Val762Asp)

CAID: CA380320183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000256.3%3Ac.2285T%3EA

gnomAD: Not in gnomAD