Supplementary Material 4

Case M-18: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)

ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: n/a

CaseCM1839: Female, 12 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: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2

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.2221G>T (p.Gly741Trp)

ClinVar: 177665 https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) BAG3 Variant Variant: NM_004281.3:c.1015A>G (p.Ile339Val)

ClinVar: 228453 https://www.ncbi.nlm.nih.gov/clinvar/variation/228453/

gnomAD: East Asian 5.437e-5, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/10-121436081-A-G

Supplementary Data, Table 2

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)

ClinVar: 177665, https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: n/a

CaseMYH7-24: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.2221G>T (p.Gly741Trp)

ClinVar: 177665 https://www.ncbi.nlm.nih.gov/clinvar/variation/177665/

gnomAD: Not in gnomAD