Case#: WPW385, 13 yrs

DiseaseAssertion: LYH, WPW, SVT

FamilyInfo: inherited

CasePresentingHPOs: Wolff-Parkinson-White syndrome, Supraventricular tachycardia, Left ventricular hypertrophy (HP:0001716, HP:0004755, HP:0001712)

CaseHPOFreeText: 0 ARIC, 0 THou, 2.03e-5 gnomAD, 3.3e-5 Exac, 7.7e-5 esp6500, 20.5 CADD_phred, 0 pLI,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: ECG, exome sequencing, gene analysis, burden analysis,

Variant: NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr)

ClinVar: 42901 https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/

CAID: N/A

gnomAD: 0.0001230 African/African American https://gnomad.broadinstitute.org/variant/14-23894525-C-T

Supplementary Material 4

Case M-16: 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.2156G>A (p.Arg719Gln)

ClinVar: 14107, https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: n/a

Supplementary Material 4

Case M-29: 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.2803G>A (p.Glu935Lys)

ClinVar: 14106, https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: n/a

Supplementary Material 4

Case M-20: 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

Supplementary Material 4

Case M-19: 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

Supplementary Material 4

Case M-1: 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 1: NM_000257.3:c.175G>A

CAID: CA029319, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA029319

gnomAD: 0.000007955, https://gnomad.broadinstitute.org/variant/14-23902767-C-T

Variant 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089, https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: n/a

CaseMYH7-35: 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.1324C>T (p.Arg442Cys)

ClinVar: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/

gnomAD: East Asian 5.012e-5, Overall 2.121e-5 https://gnomad.broadinstitute.org/variant/14-23898247-G-A

CaseMYH7-32: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 3 other probands share this genotype

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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: European (Non-Finnish) 1.548e-5, Overall 7.070e-6 https://gnomad.broadinstitute.org/variant/14-23896866-C-T

CaseMYH7-29: 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.2093T>C (p.Val698Ala)

ClinVar: 42878 https://www.ncbi.nlm.nih.gov/clinvar/variation/42878/

gnomAD: Not in gnomAD

CaseC: 13 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Three affected relatives (5 possibly affected), Mother died 44 y with heart failure, Brother SCD 16 y

CasePresentingHPOs: HP:0001639, HP:0005110 (Hypertrophic cardiomyopathy, Atrial fibrillation)

HPOsFreeText: Maximum left ventricular hypertrophy at 20 mm

CaseNotHPOs: N/A

NotHPOsFreeText: Sudden cardiac death event

CaseAddInfo: Heart transplant was required

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.2156G>A (p.Arg719Gln)

ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.818G>A (p.Arg273His)

ClinVar: 161312 https://www.ncbi.nlm.nih.gov/clinvar/variation/161312/

gnomAD: Latino 2.275e-4, Overall 9.182e-5 https://gnomad.broadinstitute.org/variant/11-47369411-C-T

CaseMYH7-41: 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.611G>A (p.Arg204His)

ClinVar: 43095 https://www.ncbi.nlm.nih.gov/clinvar/variation/43095/

gnomAD: East Asian 5.012e-5, Overall 1.767e-5 https://gnomad.broadinstitute.org/variant/14-23900998-C-T

CaseMYH7-17: 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.2609G>A (p.Arg870His)

ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.072e-6 https://gnomad.broadinstitute.org/variant/14-23894048-C-T

CaseMYH7-7: 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.4124A>G (p.Tyr1375Cys)

ClinVar: 164293 https://www.ncbi.nlm.nih.gov/clinvar/variation/164293/

gnomAD: Not in gnomAD

CaseMYH7-14: 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.2770G>A (p.Glu924Lys)

ClinVar: 14092 https://www.ncbi.nlm.nih.gov/clinvar/variation/14092/

gnomAD: Not in gnomAD

CaseMYH7-38: 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.1051A>G (p.Lys351Glu)

ClinVar: 181335 https://www.ncbi.nlm.nih.gov/clinvar/variation/181335/

gnomAD: Not in gnomAD

Case1: 42 year old male

DiseaseAssertion:DCM and LVNC

FamilyInfo: Same mutation in proband found in father, sister, and daughter

CasePreviousTesting: Sanger sequencing of coding exons and flanking intronic regions of the main sarcomeric genes, including MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL2, MYL3 and TNNC.

GenotypingMethod: NGS, Sanger sequencing

Variant: NM_000257.4:c.2146G>A

ClinVar: 14105

CAID: CA011770

gnomAD: not found

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in five HCM probands and one PanCM proband

Variant: NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)

ClinVarID: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/

gnomAD: 0.000008790, http://gnomad.broadinstitute.org/variant/14-23896932-C-G

DiseaseAssertion: None

VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

Variant: NM_000257.4(MYH7):c.2890G>C (p.Val964Leu)

ClinVar: 42938 https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/

gnomAD: 0.0008437, http://gnomad.broadinstitute.org/variant/14-23893148-C-G

DiseaseAssertion: Dilated Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, and VCL were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 74 DCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one DCM proband

Variant: NM_000257.4(MYH7):c.2711G>A (p.Arg904His)

ClinVarID: 42926 https://www.ncbi.nlm.nih.gov/clinvar/variation/42926/

gnomAD: Not in gnomAD

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one HCM probands

Variant: NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

gnomAD: 0.000008792, http://gnomad.broadinstitute.org/variant/14-23900635-A-G

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one HCM proband

Variant: NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)

ClinVarID: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23895023-G-A

CaseMYH7-17: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 3 other probands share this genotype

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.1750G>C (p.Gly584Arg)

ClinVar: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/

gnomAD: European (Non-Finnish) 8.790e-6, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/14-23896932-C-G

CaseMYH7-14: 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A

CaseMYH7-3: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 3 other probands share this genotype

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.2717A>G (p.Asp906Gly)

ClinVar: 14125 https://www.ncbi.nlm.nih.gov/clinvar/variation/14125/

gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23893321-T-C

CaseMYH7-23: 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.1357C>T (p.Arg453Cys)

ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

gnomAD: Not in gnomAD

Supplementary Data, Table 2

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.2087A>G (p.Asn696Ser)

ClinVar: 181173, https://www.ncbi.nlm.nih.gov/clinvar/variation/181173/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.438G>T (p.Lys146Asn)

ClinVar: 43013, https://www.ncbi.nlm.nih.gov/clinvar/variation/43013/

gnomAD: n/a

Supplementary Data, Table 2

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.1370T>C (p.Ile457Thr)

ClinVar: 42840, https://www.ncbi.nlm.nih.gov/clinvar/variation/42840/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23898201-A-G

Supplementary Data, Table 2

Variant noted to be present in 6 individuals

Variant: NM_000257.3(MYH7):c.1988G>A (p.Arg663His)

ClinVar: 42875, https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Case14: Male, 23 yrs onset, Slovakia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Affected family members

CasePresentingHPOs: HP:0001639 (Hypertrophic Cardiomyopathy)

HPOsFreeText: 65% LV ejection fraction

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CasePreviousTesting: ABCC9, ACTC1, ACTN2, ANKRD1, CASQ2, CAV3, CRYAB, CSRP3, CTF1, DES, DSC2, DSG2, DSP, DTNA, EMD, FHL2, GLA, JUP, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PKP2, PLN, PRKAG2, RBM20, RYR2, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL were all tested on NGS panel

CaseGenotypingMethod: Genomic DNA was extracted from whole blood and samples were purified and amplified. The coding exons for the above genes were enriched and sequenced. The resulting variants were analyzed and filtered for predicted pathogenicity.

CaseAddInfo: Variants are confirmed compound heterozygous

Variant1: NM_000257.3:c.1025C>T (p.Thr342Ile)

CAID: CA389051521 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051521

gnomAD: 0.000008791, http://gnomad.broadinstitute.org/variant/14-23899097-G-A

Variant2: NM_000257.4(MYH7):c.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

gnomAD: 0.00003097, http://gnomad.broadinstitute.org/variant/14-23896042-C-T

Supplementary Data: S2 Table

Case 113: Spanish, 40yo, 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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3:c.530C>G

CAID: CA389052613, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052613

gnomAD: n/a

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_001001430.2:c.101C>T

CAID: CA088874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA088874

gnomAD: 0.00001193, https://gnomad.broadinstitute.org/variant/1-201337322-G-A

Supplementary Data: S2 Table

Case 235: Spanish, 28yo, Female

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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3:c.2428T>C

CAID: CA389048429, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048429

gnomAD: n/a

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_001256850.1(TTN):c.57107T>C (p.Ile19036Thr)

ClinVar: 179416, https://www.ncbi.nlm.nih.gov/clinvar/variation/179416/

gnomAD: 0.00004835, https://gnomad.broadinstitute.org/variant/2-179454422-A-G

Supplementary Data: S2 Table

Case 159: Spanish, 65yo, Female

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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)

ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Supplementary Data: S2 Table

Case 178: Spanish, 30yo, Female

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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3:c.920C>G

CAID: CA389051750, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051750

gnomAD: n/a

Supplementary Data: S2 Table

Case 157: Spanish, 71yo, Female

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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.5342G>A (p.Arg1781His)

ClinVar: 43064, https://www.ncbi.nlm.nih.gov/clinvar/variation/43064/

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23884421-C-T

Supplementary Data: S2 Table

Case 5: Spanish, 7yo, 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.2146G>A (p.Gly716Arg)

ClinVar: 14105, https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: n/a

Supplementary Data: S2 Table

Case 232: Spanish, 32yo, Female

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, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

ClinVar: 14104, https://www.ncbi.nlm.nih.gov/clinvar/variation/14104/

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.878G>A (p.Arg293His) listed in paper as c.857G>A (p.Arg286His)

ClinVar: 43677, https://www.ncbi.nlm.nih.gov/clinvar/variation/43677/

gnomAD: 0.00006936, https://gnomad.broadinstitute.org/variant/1-201328348-C-T

(2) ACTN2 Variant:

Variant: NM_001103.3(ACTN2):c.1930G>A (p.Ala644Thr)

ClinVar: 43920, https://www.ncbi.nlm.nih.gov/clinvar/variation/43920/

gnomAD: 0.0001629, https://gnomad.broadinstitute.org/variant/1-236917337-G-A

Supplementary Data: S2 Table

Case 6: Spanish, 54yo, Female

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.2389G>A (p.Ala797Thr)

ClinVar: 42901, https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/

gnomAD: 0.00002386, https://gnomad.broadinstitute.org/variant/14-23894525-C-T

CaseMYH7-3: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.2504A>C (p.Lys835Thr)

CAID: CA389048271 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2504A%3EC

gnomAD: Not in gnomAD

CaseMYH7-10: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.746G>A (p.Arg249Gln)

ClinVar: 14088 https://www.ncbi.nlm.nih.gov/clinvar/variation/14088/

gnomAD: Not in gnomAD

CaseMYH7-2: Japan, Asian

CasePresentingHPOs: HP:0001639, HP:0006685 (Hypertrophic cardiomyopathy, Endomyocardial fibrosis)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each proband. They each had 95 genes associated with DCM, HCM, and other inherited cardiovascular diseases sequenced with a panel, including both the exons and spicing regions. Variants were then filtered for rarity and pathogenicity.

Variant: NM_000257.3:c.2546T>C (p.Met849Thr)

ClinVar: 42914 https://www.ncbi.nlm.nih.gov/clinvar/variation/42914/

gnomAD: Not in gnomAD

Case#: HCM439, male, 15 years,

DiseaseAssertion: HCM

FamilyInfo: Yes, father has HCM

CasePresentingHPOs: N/A

CaseHPOFreeText: inverted T-waves, ST-segment depression, 22mm MLVWT, 64% LVE F, 1.21 E/A ratio, LVOT-PG 14mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: sequencing, physical examination, ECG, 3D modeling, statistical analysis

MultipleGeneVariants:

(1) Variant: absent (MYH7-G407C)

ClinVar: absent

CAID: CA389051099

gnomAD: absent

(2) Variant: NM_000257.4(MYH7):c.4348G>A (p.Asp1450Asn)

ClinVar: 43009 https://www.ncbi.nlm.nih.gov/clinvar/variation/43009/

CAID: N/A

gnomAD: 0.00002891 Latino/Admixed American https://gnomad.broadinstitute.org/variant/14-23886717-C-T

PMID: 23674513

Gene: MYH7

HGNC: 7577

Supplementary Data: Online Table 1a

Case:

CasePresentingHPOs: HP:0001631, HP:0001629 (atrial septal defect, ventricular septal defect)

CaseHPOFreeText: Trisomy 21

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.976G>C (p.Ala326Pro)

ClinVar: 43117, https://www.ncbi.nlm.nih.gov/clinvar/variation/43117/

gnomAD: 0.00008846, https://gnomad.broadinstitute.org/variant/14-23899792-C-G

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.2945T>C (p.Met982Thr)

ClinVar: 42941, https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

gnomAD: 0.0008484, https://gnomad.broadinstitute.org/variant/14-23892910-A-G

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.3113T>C

CAID: CA257817954, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257817954

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.715_717del

CAID: CA913184869, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184869

gnomAD: n/a

Supplementary Data: Online Table 1a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.798T>A

CAID: CA389052023, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052023

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.266A>G

CAID: CA389053299, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389053299

gnomAD: n/a

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.2453T>A

CAID: CA389048376, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048376

gnomAD: n/a

Supplementary Data: Online Table 1a

Case:

CasePresentingHPOs: HP:0010316 (Ebstein anomaly)

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.3113T>C

CAID: CA257817954, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257817954

gnomAD: n/a

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.4377G>T (p.Lys1459Asn)

ClinVar: 43012, https://www.ncbi.nlm.nih.gov/clinvar/variation/43012/

gnomAD: 0.0002937, https://gnomad.broadinstitute.org/variant/14-23886504-C-A

Supplementary Data: Online Table 2a

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.689T>C (p.Phe230Ser)

ClinVar: 236543, https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/

gnomAD: n/a

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3:c.644C>T

CAID: CA389052345, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052345

gnomAD: n/a

PMID: 32394868

Gene: MYH7

HGNC: 7577

FamilyE

DiseaseAssertion: Left ventricular noncompaction (LVNC)

FamilyInfo: Presenting LVNC, Identified rare, protein changing mutations in MYH7, none of which have been previously reported but all of which were predicted to be pathogenic with multiple in silico prediction algorithms

GenotypingMethod: Whole exome sequencing analysis

Variant: NM_000257.4:c.2099A>G

ClinVar: not found

CAID: CA389049130

gnomAD: not found

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)

ClinVarID: 14105, https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: n/a

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys)

ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.728G>A (p.Arg243His)

ClinVar: 14126, https://www.ncbi.nlm.nih.gov/clinvar/variation/14126/

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23900798-C-T

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg)

ClinVar: 14098, https://www.ncbi.nlm.nih.gov/clinvar/variation/14098/

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23894969-C-T

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (TNNC1, CSRP3, TCAP, ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CAV3, CRYAB, CTNNA3, DES, DSC2, DSG2, DSP, EMD, FHL1, GLA, JPH2, JUP, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYOZ2, MYPN, NEXN, PKP2, PLN, PRDM16, PRKAG2, RBM20, SCN5A, TAZ, TMEM43, TNNC1, TTN, TTR, VCL), electrocardiography

CaseGenotypingMethod: direct sequencing of all coding intron-exon boundaries of 12 genes (prior to 2012), next-generation sequencing (post 2012)

Variant: NM_000257.3(MYH7):c.2788G>A (p.Glu930Lys)

ClinVar: 42933, https://www.ncbi.nlm.nih.gov/clinvar/variation/42933/

gnomAD: n/a

Supplementary Data Table S3

Case: 258

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.958G>A (p.Val320Met)

ClinVar: 161328 https://www.ncbi.nlm.nih.gov/clinvar/variation/161328/

gnomAD: 0.00006154, https://gnomad.broadinstitute.org/variant/14-23899810-C-T

MultipleGeneVariants:

(1) FHL2 Variant

Variant: NM_001450.3:c.476C>T (p.Ala159Val)

CAID: CA347999492 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA347999492

gnomAD: Not in gnomAD

(2) NEXN Variant

Variant: NM_144573.3(NEXN):c.995A>C (p.Glu332Ala)

ClinVar: 47915 https://www.ncbi.nlm.nih.gov/clinvar/variation/47915/

gnomAD: 0.01350, https://gnomad.broadinstitute.org/variant/1-78395131-A-C

(3) TMPO Variant

Variant: NM_001032284.2:c.318T>A (p.Asp106Glu)

CAID: CA6732167 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6732167

gnomAD: 0.0005880, https://gnomad.broadinstitute.org/variant/12-98921702-T-A

Supplementary Data Table S3

Case: 109

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) LDB3 Variant

Variant: NM_001171610.1:c.1394C>T (p.Ala465Val)

CAID: CA5585146 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA5585146

gnomAD: 0.001479, https://gnomad.broadinstitute.org/variant/10-88476231-C-T

Supplementary Data Table S3

Case: 320

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) NEXN Variant

Variant: NM_144573.3(NEXN):c.995A>C (p.Glu332Ala)

ClinVar: 47915 https://www.ncbi.nlm.nih.gov/clinvar/variation/47915/

gnomAD: 0.01350, https://gnomad.broadinstitute.org/variant/1-78395131-A-C

Supplementary Data Table S3

Case: 49

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.4353+3G>T

CAID: CA041823, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA041823

gnomAD: 0.0002122, https://gnomad.broadinstitute.org/variant/14-23886709-C-A

MultipleGeneVariants:

(1) DMD Variant

Variant: NM_004006.2(DMD):c.2391T>G (p.Asn797Lys)

ClinVar: 94510, https://www.ncbi.nlm.nih.gov/clinvar/variation/94510/

gnomAD: 0.006548, https://gnomad.broadinstitute.org/variant/X-32509625-A-C

(2) JUP Variant

Variant: NM_002230.4(JUP):c.1942G>A (p.Val648Ile)

ClinVar: 45842, https://www.ncbi.nlm.nih.gov/clinvar/variation/45842/

gnomAD: 0.007385, https://gnomad.broadinstitute.org/variant/17-39913771-C-T

Supplementary Data Table S3

Case: 374

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.3250G>C (p.Asp1084His)

CAID: CA389044579 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389044579

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) ABCC9 Variant

Variant: NM_000256.3(MYBPC3):c.440C>T (p.Pro147Leu)

CAID: CA6481647 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6481647

gnomAD: Not in gnomAD

Supplementary Data Table S3

Case: 100

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) FBN1 Variant

Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)

ClinVar: 199948 https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/

gnomAD: 0.006608, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

Supplementary Data Table S3

Case: 131

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant1: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: 0.00001548, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Variant2: NM_000257.4(MYH7):c.3853+7C>T

ClinVar: 42977 https://www.ncbi.nlm.nih.gov/clinvar/variation/42977/

gnomAD: 0.003956, https://gnomad.broadinstitute.org/variant/14-23888685-G-A

MultipleGeneVariants:

(1) GLA Variant

Variant: NM_000169.2(GLA):c.427G>A (p.Ala143Thr)

ClinVar: 10748 https://www.ncbi.nlm.nih.gov/clinvar/variation/10748/

gnomAD: 0.0009486, https://gnomad.broadinstitute.org/variant/X-100656740-C-T

(2) SCN5A Variant

Variant: NM_001099404.1:c.3440C>A (p.Thr1147Asn)

ClinVar: CA061831 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA061831

gnomAD: 0.0001446, https://gnomad.broadinstitute.org/variant/3-38618223-G-T

Supplementary Data Table S3

Case: 26

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

ClinVar: 155814, https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) FBN1 Variant

Variant: NM_000138.4(FBN1):c.3077T>C (p.Phe1026Ser)

ClinVar: 199948, https://www.ncbi.nlm.nih.gov/clinvar/variation/199948/

gnomAD: 0.0006449, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

(2) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T

No Case Info

MultipleGeneVariant:

Variant2191 NM_000257.4:c.2191C>T

ClinVar: 181176

CAID: CA011922

gnomAD: not found

Variant2606: NM_000257.4:c.2606G>A

ClinVar: 177667

CAID: CA012723

gnomAD: https://gnomad.broadinstitute.org/variant/14-23894051-C-T

0.0001230 African

CaseDCM-19: Male, 5 year diagnosis, Caucasian, Germany

CasePresentingHPOs: HP:0001644, HP:0001635 (Dilated cardiomyopathy, Heart failure)

HPOsFreeText: LVEDD at 74 mm, LV-Ejection Fraction at 20%, Cardiac Index at 2.38

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband treated with VAD and ICD, Sporadic family history of cardiac disease, Proband also has a variant in NEXN, Patient is heterozygous for MYH7 variant

CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.

Variant: NM_000257.3:c.1106G>A (p.Arg369Gln)

ClinVar: 42822 https://www.ncbi.nlm.nih.gov/clinvar/variation/42822/

gnomAD: Not in gnomAD

Multiple Gene Variants

NEXN Variant

Variant: NM_144573.3:c.1955A>G (p.Tyr652Cys)

ClinVar: 326 https://www.ncbi.nlm.nih.gov/clinvar/variation/326/

gnomAD: European (Non-Finnish) 1.407e-4, Overall 7.859e-5 https://gnomad.broadinstitute.org/variant/1-78408441-A-G

Case#: male, 19 yrs

DiseaseAssertion:

FamilyInfo: No apparent history or HCM or SCD

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: testing on rest of genes

CaseGenotypingMethod: MYH7 specific

Variant: NM_000257.4(MYH7):c.2803G>A (p.Glu935Lys)

ClinVar: 14106 https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

CAID: N/A

gnomAD: absent

PMID: 24360430

Gene: MYH7

HGNC: 7577

"we used liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) to identify all of the high molecular weight proteins and their degradation products during post mortem storage, in order to determine the changes of proteins in muscle during post mortem aging and its relationship with meat quality."

Case N40: Tunisia, Female, 56yo at onset, deceased

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0100749, HP:0002094 (chest pain, dyspnea)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 20mm

FamilyInfo: Family history of sudden cardiac death

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (FLNC, TNNC1), electrocardiogram, echocardiography

CaseGenotypingMethod: PCR, Next-generation sequencing, identified variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.2213G>A

CAID: CA389048899, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048899

gnomAD: n/a

Case N29: Tunisia, Female, 60yo at onset, 61yo at study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0100749, HP:0001962 (chest pain, palpitations)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 21mm

FamilyInfo: no family history of HCM or sudden cardiac death

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (FLNC, TNNC1), electrocardiogram, echocardiography

CaseGenotypingMethod: PCR, Next-generation sequencing, identified variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.2792A>C

CAID: CA389047043, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047043

gnomAD: n/a

Case N17: Tunisia, Male, 74yo at onset and study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001962 (palpitations)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 17mm

FamilyInfo: no family history of HCM or sudden cardiac death

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (FLNC, TNNC1), electrocardiogram, echocardiography

CaseGenotypingMethod: PCR, Next-generation sequencing, identified variants confirmed via Sanger Sequencing

Variant: NM_000257.3:c.3016G>A

CAID: CA389045889, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389045889

gnomAD: n/a

CaseST4-89: Sweden

DiseaseAssertion: Idiopathic Dilated Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002140, HP:0000822, HP:0001654, HP:0030955, HP:0000819, HP:0002666, HP:0000845, HP:0000820 (Ischemic stroke, Hypertension, Valvular heart disease, Alcoholism, Diabetes mellitus, Pheochromocytoma, Acromegaly, Thyroid disease)

NotHPOsFreeText: Patients were excluded for significant systemic infection, systemic diseases, previous cancer treatment including irradiation, and tachycardia-induced cardiomyopathy or other primary cardiomyopathy.

CaseAddInfo: N/A

CasePreviousTesting: See Supplemental Table 1

CaseGenotypingMethod: Genomic DNA was extracted from the patients. 41 exons of previously-reported genes that were reported in DCM patients were amplified and directly sequenced. Afterwards, the variants were aligned and sorted for pathogenicity.

Variant: NM_000257.3:c.3286G>T (p.Asp1096Tyr)

ClinVar: 42953 https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/

gnomAD: European (Non-Finnish) 3.097e-4, Overall 1.414e-4 https://gnomad.broadinstitute.org/variant/14-23890217-C-A

Case: Male, 4yo

CasePresentingHPOs: HP:0001324, HP:0001270, HP:0006830, HP:0003458, HP:0000467, HP:0003547, HP:0002650 (muscle weakness, delayed motor development, congenital hypotonia, Myopathic electromyogram, neck muscle weakness, shoulder girdle muscle weakness, scoliosis)

HPOsFreeText: sporadic congenital muscle weakness, decreased cardiac pump function, perinatal encephalopathy, rolled over at 7mo, left ventricular dilation, normal total creatine phosphokinase, unspecified muscle atrophy shown in histological exam, signs of dropped head syndrome, gluteal and quadricep muscle weakness, axial weakness distribution. At 4yo: weight = 14kg, height = 104cm, ejection fraction = 56%, able to walk if head is supported, preserved emotional and intellectual development

CaseNotHPOs: HP:0002098, HP:0002015, HP:0001635 (breathing difficulties, dysphagia, heart failure)

DiseaseEntity: DCM

InheritancePattern: not specified

FamilyInformation: family not consanguineous, no history of progressive muscular disorders or cardiomyopathy, pedigree in Fig. 1

CasePreviousTesting: WES

CaseGenotypingMethod: genomic DNA extracted from white blood cells of proband and parents, WES, confirmed findings in proband, parents and siblings via PCR-based bidirectional Sanger sequencing, abnormal MYH7 transcript confirmed in vivo by RT-PCR, paternity and maternity confirmed by multiplex STR typing of 15 loci

Variant: NM_000257.3:c.5655+5G>C, confirmed de novo by parental testing

No ClinVar or CAID

Case KMP 1: Eastern Slovakia, Female, 39yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification I,

CaseNotHPOFreeText: left ventricular outflow tract obstruction

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

Case KMP 7: Eastern Slovakia, Male, 36yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%

CasePreviousTesting: 12-lead ECG, echocardiography, partial testing (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2)

CaseGenotypingMethod: genomic DNA collected from peripheral blood leukocytes, Sanger sequencing

Variant: NM_000257.3(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093, https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

gnomAD: n/a

PMID: 23861362

Gene: MYH7

HGNC: 7577

CaseCM1855: Male, 14 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, Variant is asserted as novel

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.1617G>A (p.Met539Ile)

CAID: CA389050189 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1617G%3EA

gnomAD: Not in gnomAD

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

CaseCM1852: Male, 6 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, Variant reported as novel

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.2444A>C (p.Gln815Pro)

CAID: CA389048400 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2444A%3EC

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYH6 Variant

Variant: NM_002471.3:c.3249G>T (p.Lys1083Asn)

CAID: CA389007516 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002471.3%3Ac.3249G%3ET

gnomAD: Not in gnomAD

CaseCM1414: Male, 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: No 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.1358G>A (p.Arg453His)

ClinVar: 42838 https://www.ncbi.nlm.nih.gov/clinvar/variation/42838/

gnomAD: Not in gnomAD

PMID: 23700792

Gene: MYH7

HGNC: 7577

Case22: 14 year old male, gen III

DiseaseAssertion: HCM

FamilyInfo: Chinese, 4 additional family members present MYH7 mutation

CasePresentingHPOs: HP:0012378, HP:0002094

"Fatigue, Dyspnea"

CasePreviousTesting: exom sequencing MYH7, ACTC, CSRP3, TNNC1, MYH6, VCL, MYOZ2, JPH2, PLN, CALR2, and NEXN

GenotypingMethod: whole exome sequencing

Variant: NM_000257.4:c.1219G>T

ClinVar: not found

CAID: CA389051099

gnomAD: not found

Case#: HCM490, female, 41 yrs, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 44mm LAD, 15mm LVST, 39mm LVEDD, 58% LVEF, 21mm Maxi LVWT, 63mmHg Maxi LVOTG, 109178274 raw RNA-seq reads, 102325212 HQ reads (93.72%), 96.79% mapping rate, 728218 total variant, 33873 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

Variant: NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met)

ClinVar: 42992 https://www.ncbi.nlm.nih.gov/clinvar/variation/42992/

CAID: N/A

gnomAD: 0.000008791 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23887458-G-A

Case#: HCM562, female, 36 yrs, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 36mm LAD, 0mm LVST, 36mm LVEDD, 66% LVEF, 21mm Maxi LVWT, 70mmHg Maxi LVOTG, 119176332 raw RNA-seq reads, 113518840 HQ reads (95.25%), 96.63% mapping rate, 782848 total variant, 34382 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: RNA-seq, read mapping, variant calling, identify functional variants, differential expression analysis, miRWalk miRNA target prediction, LncRNA annotation, Co-expression network analysis, PPI network analysis, gene over-representation analysis,

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

Case390: Male, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169 (Left ventricular noncompaction, Left ventricular systolic dysfunction)

HPOsFreeText: Left Ventricular Ejection Fraction at 43.5%, LVDD-Z score at 3.3833

CaseNotHPOs: HP:0011675, HP:0001635 (Arrhythmia, Heart failure)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.

Variant: NM_000257.3:c.5740G>A (p.Glu1914Lys)

ClinVar: 43088 https://www.ncbi.nlm.nih.gov/clinvar/variation/43088/

gnomAD: Not in gnomAD

Case3: Male, 37 years report, Netherlands

CasePresentingHPOs: HP:0011663, HP:0011675, HP:0001279, HP:0005135, HP:0001707, HP:0004308 (Right ventricular cardiomyopathy, Arrhythmia, Syncope, Abnormal T-wave, Abnormality of the right ventricle, Ventricular arrhythmia)

HPOsFreeText: Positive EPS inducibility

CaseNotHPOs: HP:0001639, HP:0001635, HP:0001711 (Hypertrophic cardiomyopathy, Congestive heart failure, Abnormality of the left ventricle)

NotHPOsFreeText: ECG Depolarization abnormality, Cardiac transplant

CaseAddInfo:

CasePreviousTesting: No variants were in any of DSP, PKP2, DSG2, DSC2, and JUP. Patients were tested for variants in ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1.

CaseGenotypingMethod: 92 patients underwent panel sequencing of the specific genes listed above, and 45 were subject to Whole Exome Sequencing to locate variants. Afterwards, all variants were verified by PCR amplification and Sanger sequencing and filtered for pathogenicity.

Variant: NM_000257.3:c.5536C>T (p.Arg1846Cys)

ClinVar: 161321 https://www.ncbi.nlm.nih.gov/clinvar/variation/161321/

gnomAD: East Asian 5.441e-5, Overall 1.208e-5 https://gnomad.broadinstitute.org/variant/14-23884227-G-A

PMID:28491642

Gene:ACTC1

HGNC ID:143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

CasePT-57: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.1231G>A (p.Val411Ile)

ClinVar: 181339 https://www.ncbi.nlm.nih.gov/clinvar/variation/181339/

gnomAD: Latino 5.643e-5, Overall 2.121e-5 https://gnomad.broadinstitute.org/variant/14-23898464-C-T

CasePT-31: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo: 1 other patient has the same genotype

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.2761G>A (p.Glu921Lys)

ClinVar: 181205 https://www.ncbi.nlm.nih.gov/clinvar/variation/181205/

gnomAD: Not in gnomAD

CaseHCM047: 59 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of hypertrophic cardiomyopathy, Has a sister with MYBPC3 mutation with asymptomatic HCM (did not mention MYH7 mutation)

CasePresentingHPOs: HP:0002875, HP:0001712 (Exertional dyspnea, Left ventricular hypertrophy)

HPOsFreeText: Maximal LV thickness 20 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.1322C>T (p.Thr441Met)

ClinVar: 14122 https://www.ncbi.nlm.nih.gov/clinvar/variation/14122/

gnomAD: 0.002556, http://gnomad.broadinstitute.org/variant/14-23898249-G-A

Multiple Gene Variants

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.2308G>A (p.Asp770Asn)

ClinVar: 36604 https://www.ncbi.nlm.nih.gov/clinvar/variation/36604/

gnomAD: 0.00008693, http://gnomad.broadinstitute.org/variant/11-47360071-C-T

CaseHCM033: 30 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of Sudden Cardiac Death and Hypertrophic Cardiomyopathy, Has a 7 year old son with the same variant but no symptoms

CasePresentingHPOs: HP:0001712, HP:0100749, HP:0002875, HP:0011103, HP:0031295 (Left ventricular hypertrophy, Chest pain, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 27 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.1063G>A (p.Ala355Thr)

ClinVar: 42820 https://www.ncbi.nlm.nih.gov/clinvar/variation/42820/

gnomAD: Not in gnomAD

PMID: 31790337

Gene: MYH7

HGNC: 7577

Evidence: no proband info

"We suggest that a different mRNA lifetime of the alleles may cause the allelic drift in R723G patients."

PMID: 32380161

Gene: MYH7

HGNC: 7577

PMID: 23852727

Gene: MYH7

HGNC: 7577

"So, how do we stop a genetic heartbreaker like R453C? The identification of a biochemical and biophysical phenotype is the first step. Now that we know that this mutation causes a subtle decrease in ATPase cycling and an increase in force production by changing the stiffness of the myosin motor domain, we can investigate how these changes affect heart function and development."

Case I-2: Female, 66yo, suspected to be the founder of the variant

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001635 (heart failure)

CaseHPOFreeText: suspected double-chambered left ventricle

CasePreviousTesting: same as proband

CaseGenotypingMethod: segregation analysis using the results from Sanger sequencing

Variant: NM_000257.3:c.998A>T

CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586

gnomAD: n/a

Case II-5: Female, 35yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0003388, HP:0001712 (fatigability, left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, normal thickness of septum and left ventricular wall, 2 chamber of left ventricle have 14.2mm diameter of communication and they both contract normally, left ventricle ventricle end-diastolic diameter = 59.9mm, left ventricular ejection fraction = 50%

CasePreviousTesting: same as proband

CaseGenotypingMethod: WES, segregation analysis using the results from Sanger sequencing

Variant: NM_000257.3:c.998A>T

CAID: CA389051586, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051586

gnomAD: n/a

PMID: 23956225

Gene: MYH7

HGNC: 7577

CaseBII-1: Female, 64 years diagnosis, Italy, Caucasian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: See Figure 1

CasePresentingHPOs: HP:0005110, HP:0001639, HP:0004756, HP:0001712, HP:0005135, HP:0002094, HP:0001962, HP:0006682, HP:0001279, HP:0000821 (Atrial fibrillation, Hypertrophic cardiomyopathy, Ventricular tachycardia, Left ventricular hypertrophy, Abnormal T-wave, Dyspnea, Palpitations, Premature ventricular contractions, Syncope, Hypothyroidism)

HPOsFreeText: Widespread septal and apical late gadolinium enhancement, Max Left ventricular wall thickness of 20 mm, Left atrium diameter of 54 mm, Left ventricular ejection fraction of 56%, Apical aneurism, Latent tuberculosis

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The ACM proband from Family B was genotyped for PKP2, DSP, DSC2, DSG2, JUP and CTNNA3; the HCM patient from Family B was genotyped for MYBPC3, MYH7, TNNI3 and TNNT2.

CaseGenotypingMethod: All patients in Family B were directly sequenced according to the found variants in CTNNA3 and MYH7. These variants were filtered for pathogenicity and prevalence and classified accordingly.

Variant: NM_000257.3:c.2631G>T (p.Met877Ile)

ClinVar: 417718 https://www.ncbi.nlm.nih.gov/clinvar/variation/417718/

gnomAD: Not in gnomAD