Case: Bottillo Patient 17, Female, 50 yrs at diagnosis

CasePresentingHPOs: copy from group

CasePresentingHPOsFreeText: NYHA functional class 2, maximal wall thickness=14mm, left ventricular mass (at CMRI)=91(mg/m2), LVEF=52%, maximal oxygen uptake=78%, diastolic dysfunction grade=3, QT interval corrected for heart rate=0.4ms, thoracic pains, met ECG hypertrophy criteria, left bundle branch block, heart failure, mild intramyocardial CMRI

CaseNOTHPOs:

CaseNOTHPOSFreeText: family history of HCM or SCD

CasePreviousTesting: copy from group

CaseGenotypingMethod: copy from group

Variant: c.4485-6T>C

ClinVarID: or CAID: CA2573331909

gnomAD: This proband has an intronic missense variant that is not present in gnomAD. Pt also has variants in TNNT2 (p.R84S), RBM20 (p.D20G), CAV3 (p.T78M), and MYPN (p.A135A) which are either not present in or have conflicting interpretations of pathogenicity in ClinVar. This proband is scored reduced points.

AddCaseInfo:

PreviouslyPublished: no

VariantEvidence: Predicted branch-point splice site broken.

Table V

Case 905: Italian, Male, 30yo at onset

DiseaseAssertion: HCM

FamilyInfo: family history of HCM

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, automatic implantable cardioverter defibrillator, heart transplantation

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2), additional genes added with NGS: (TNNC1, MYH6, MYOM1, MYOZ2, ANKRD1, VCL, CALR3, CAV3)

CaseGenotypingMethod: Genomic DNA extracted from peripheral leukocytes, Sanger sequencing (73 samples), Next-gen sequencing (19 samples)

Variant: NM_000257.3(MYH7):c.2302G>A (p.Gly768Arg)

ClinVar: 164337, https://www.ncbi.nlm.nih.gov/clinvar/variation/164337/

gnomAD: n/a

MultipleGeneVariants:

(1) MYOM1 Variant:

Variant: NM_003803.3:c.1655G>A

CAID: CA401714383, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA401714383

gnomAD: n/a

Case: Cecconi_Patient#905, male, 30 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm (not provided for this proband); the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM. LVEF is not provided. Family history of HCM.

CaseNOTHPOs:

CaseNOTHPOSFreeText: no family history of SCD

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.1655G>A p.(Gly552Asp)

ClinVarID: or CAID: CA401714383

gnomAD: This proband has a missense variant, Gly552Asp. Not present in gnomAD. Proband has a variant in another HCM gene-MYH7.

AddCaseInfo: history of heart transplant, automatic implantable cardioverter defibrillator

PreviouslyPublished: no

VariantEvidence: none

Case: Cecconi_Patient#907, male, 37 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm (<15mm for this proband-diagnosis of borderline HCM); the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM. LVEF of 60%

CaseNOTHPOs:

CaseNOTHPOSFreeText: family history of HCM

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.432-1G>T

ClinVarID: or CAID: CA401717111

gnomAD: This proband has a splice site variant, c.432-1G>T. MAF=0.00001597 in European (non-Finnish) (2/125212 alleles), total allele frequency=0.000007246. No homozygotes. gnomAD v2.1.1.

AddCaseInfo: history of ECG abnormalities

PreviouslyPublished: no

VariantEvidence: none

Case7: Female, 13 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0001279 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Syncope)

HPOsFreeText: 2 SCD risk factors, NYHA class is II, Right ventricular wall thickness 12 mm

CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680, HP:0011675 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease, Arrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.

Variant reported as below, but no SNP corresponds to the variant.

Variant: NP_000248.2:p.R719E

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

MYOM1 Variant:

Variant: NM_003803.3:c.2507G>T (p.Gly836Val)

CAID: CA8874590 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_003803.3:c.2507G%3ET

gnomAD: East Asian 5.044e-4, Overall 3.707e-5 https://gnomad.broadinstitute.org/variant/18-3129517-C-A

AKAP9 Variant:

Variant: NM_005751.4:c.11590T>C (p.Cys3864Arg)

CAID: CA368165252 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_005751.4:c.11590T%3EC

gnomAD: Not in gnomAD