Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Case: Pedigree 1 proband, male, 11yo at diagnosis, Iraqi‐Jewish

CasePresentingHPOs: HP:0001639, HP:0004756, HP:0005110, HP:0002094, HP:0001712 (hypertrophic cardiomyopathy, ventricular tachycardia, atrial fibrillation, dyspnea, left ventricular hypertrophy)

HPOsFreeText: clinical severity: moderate to asymptomatic, systolic murmur, NYHA Class II, maximal wall thickness at the anterior septum = 30 mm, resting LVOT gradient of 35 mmHg, increasing to 48 mmHg, normal LV systolic function, estimated ejection fraction (EF) of 65%, Grade II (moderate) LV diastolic dysfunction, ECH showed sinus rhythm, LV strain, inverted T waves, eptal wall thickness of 31 mm, extensive late gadolinium enhancement involving 45% of the left ventricle

CaseNotHPOs: HP:0001279 (syncope)

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: Fifty‐six genes known to cause HCM were sequenced in parallel

Variant: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

FamilyInfo: mother was heterozygous for variant, she was asymptomatic, had mild nonobstructive hypertrophy, hypertension, and anterior septal thickness of 13 mm

Case: Pedigree 3 proband, female, 3mo at diagnosis, North African and Jewish

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

HPOsFreeText: clinical severity: severe (fatal)

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: DCM CardioChip, included 19 genes known to cause DCM

Variant 1: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Variant 2: NM_000257.4(MYH7):c.4588C>T (p.Arg1530Ter)

ClinVar: 43029, https://www.ncbi.nlm.nih.gov/clinvar/variation/43029/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23886133-G-A

FamilyInfo: mother is of North African and Iraqi‐Jewish descent, while the father is of North African and Balkan Jewish descent, probands brother died at 3.5mo and also carried both variants, maternal cousin died of RCM in early childhood, maternal aunt carried p.R143W

Case: Pedigree 2 proband, male, 37yo at diagnosis, Iraqi‐Jewish

CasePresentingHPOs: HP:0001639, HP:0005110, HP:0001708, HP:0005180 (hypertrophic cardiomyopathy, atrial fibrillation, right heart failure, tricuspid regurgitation)

HPOsFreeText: clinical severity: moderate to asymptomatic

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: Fifty‐six genes known to cause HCM were sequenced in parallel

Variant: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

FamilyInfo: older brother had sudden death at 33yo with postmortem diagnosis of HCM, patient's siblings, aged 67 and 70, were also found to be heterozygous for this variant, though they are both clinically asymptomatic with no echocardiographic evidence of HCM

Supplementary Data: S2 Table

Case 1: Spanish, 42yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401, https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: 0.00002784, https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Case#: Consequence 9 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)

ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

CAID: n/a

gnomAD: 0.0001087 East Asian https://gnomad.broadinstitute.org/variant/14-23901923-G-A

CaseMYH7-8: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.

Variant: NM_000257.3:c.427C>T (p.Arg143Trp)

ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

gnomAD: East Asian 1.087e-4, Overall 2.784e-5 https://gnomad.broadinstitute.org/variant/14-23901923-G-A