Supplementary Material 4

Case M-12: 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.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

Supplementary Material 4

Case M-31: 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.4721G>A (p.Arg1574Gln)

ClinVar: 228912, https://www.ncbi.nlm.nih.gov/clinvar/variation/228912/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23885445-C-T

Supplementary Material 4

Case M-11: 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.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

Supplementary Material 4

Case M-27: 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.2770G>A (p.Glu924Lys)

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

gnomAD: n/a

Supplementary Material 4

Case M-3: 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.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Supplementary Material 4

Case M-5: 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.1012G>A (p.Val338Met)

Clinvar: 164381, https://www.ncbi.nlm.nih.gov/clinvar/variation/164381/

gnomAD: n/a

Supplementary Material 4

Case M-17: 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.2207T>C (p.Ile736Thr)

ClinVar: 164342, https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: n/a

Supplementary Material 4

Case M-13: 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.2011C>T (p.Arg671Cys)

ClinVar: 164350, https://www.ncbi.nlm.nih.gov/clinvar/variation/164350/

gnomAD: n/a

Supplementary Material 4

Case M-7: 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 2: NM_000257.3(MYH7):c.1357C>T (p.Arg453Cys)

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

gnomAD: n/a

Supplementary Material 4

Case M-24: 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.2546T>C (p.Met849Thr)

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

gnomAD: n/a

Supplementary Material 4

Case M-4: 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.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Table V

Case 898: Italian, 1yo at onset

DiseaseAssertion: HCM

FamilyInfo: family history of HCM

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: LVWT = 11mm, LV ejection fraction = 70%

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.5302G>A (p.Glu1768Lys)

ClinVar: 43059, https://www.ncbi.nlm.nih.gov/clinvar/variation/43059/

gnomAD: n/a

Table III

Case 748: Italian, Female, 16yo

DiseaseAssertion: HCM

FamilyInfo: Family history of HCM and sudden cardiac death

CasePresentingHPOs: HP:0001712, HP:0004756, HP:0005110, HP:0001716 (left ventricular hypertrophy, ventricular tachycardia, atrial fibrillation, Wolff-Parkinson-White syndrome)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, LVWT = 17mm, automatic implantable cardioverter defibrillator, LV ejection fraction = 60%

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.5287G>A (p.Ala1763Thr)

ClinVar: 177846, https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/

gnomAD: 0.00007423, https://gnomad.broadinstitute.org/variant/14-23884476-C-T

MultipleGeneVariants:

(1) LAMP2 Variant:

Variant: NM_002294.2(LAMP2):c.928G>A (p.Val310Ile)

ClinVar: 9982, https://www.ncbi.nlm.nih.gov/clinvar/variation/9982/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)

ClinVar: 42874, https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

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:c.2306T>C

CAID: CA389048688, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048688

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 3 individuals

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 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.1532T>C (p.Ile511Thr)

ClinVar: 42848, https://www.ncbi.nlm.nih.gov/clinvar/variation/42848/

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.727C>T (p.Arg243Cys)

ClinVar: 43101, https://www.ncbi.nlm.nih.gov/clinvar/variation/43101/

gnomAD: 0.00003184, https://gnomad.broadinstitute.org/variant/14-23900799-G-A

PMID: 24298987

Gene: MYH7

HGNC: 7577

CaseMYH7-40: 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.937A>T (p.Ile313Phe)

CAID: CA389051713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.937A%3ET

gnomAD: Not in gnomAD

CaseMYH7-20: 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.2420G>A (p.Arg807His)

ClinVar: 391904 https://www.ncbi.nlm.nih.gov/clinvar/variation/391904/

gnomAD: Latino 5.644e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23894494-C-T

CaseMYH7-9: 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.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

gnomAD: Not in gnomAD

CaseMYH7-23: 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.2225C>A (p.Ala742Glu)

ClinVar: 192310 https://www.ncbi.nlm.nih.gov/clinvar/variation/192310/

gnomAD: Not in gnomAD

CaseWJ: 30 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One affected relative Brother (index case) died suddenly aged 34 y (MYH7 p.Asp778Val only)

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 18 mm

CaseNotHPOs: N/A

NotHPOsFreeText: Sudden cardiac death event

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.

Variant1: NM_000257.3:c.2333A>T (p.Asp778Val)

ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/

gnomAD: Not in gnomAD

Variant2: NM_000257.3:c.5452C>T (p.Arg1818Trp)

ClinVar: 217826 https://www.ncbi.nlm.nih.gov/clinvar/variation/217826/

gnomAD: Latino 5.782e-5, Overall 7.956e-6 https://gnomad.broadinstitute.org/variant/14-23884311-G-A

CaseMYH7-33: 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.1727A>G (p.His576Arg)

ClinVar: 177625 https://www.ncbi.nlm.nih.gov/clinvar/variation/177625/

gnomAD: African 4.008e-5, Overall 1.768e-5 https://gnomad.broadinstitute.org/variant/14-23896955-T-C

CaseMYH7-27: 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.2156G>A (p.Arg719Gln)

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

gnomAD: Not in gnomAD

CaseMYH7-12: 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.3236G>A (p.Arg1079Gln)

ClinVar: 177826 https://www.ncbi.nlm.nih.gov/clinvar/variation/177826/

gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.073e-6 https://gnomad.broadinstitute.org/variant/14-23891398-C-T

CaseDW: 16 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One affected relative, Father, died suddenly

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 21 mm

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.937A>T (p.Ile313Phe)

CAID: CA389051713 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.937A%3ET

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2372_2373insG (p.Trp792Valfs)

ClinVar: 42619 https://www.ncbi.nlm.nih.gov/clinvar/variation/42619/

gnomAD: European (Non-Finnish) 4.277e-5, Overall 1.744e-5 https://gnomad.broadinstitute.org/variant/11-47359280-A-AC

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.2713T>C

CAID: CA389047302, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047302

gnomAD: n/a

Supplementary Data: Online Table 1a

Case:

CasePresentingHPOs: HP:0001629 (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(MYH7):c.689T>C (p.Phe230Ser)

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

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.1208G>C

CAID: CA389051121, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051121

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.345C>T (p.Tyr115=)

ClinVar: 42962, https://www.ncbi.nlm.nih.gov/clinvar/variation/42962/

gnomAD: 0.0001061, https://gnomad.broadinstitute.org/variant/14-23902293-G-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.698C>T (p.Ala233Val)

ClinVar: 177858, https://www.ncbi.nlm.nih.gov/clinvar/variation/177858/

gnomAD: n/a

Supplementary Data Table S3

Case: 18

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.2770G>A (p.Glu924Lys)

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

gnomAD: absent

MultipleGeneVariants:

(1) LMNA Variant

Variant: NM_170707.4(LMNA):c.357C>T (p.Arg119=)

ClinVar: 48062, https://www.ncbi.nlm.nih.gov/clinvar/variation/48062/

gnomAD: 0.00424

(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

(2) TTN Variant

Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)

ClinVar: 165840, https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/

gnomAD: 0.001152, https://gnomad.broadinstitute.org/variant/2-179436256-ATTG-A

Supplementary Data Table S3

Case: 8

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) LAMA4 Variant

Variant: NM_001105206.3(LAMA4):c.2614C>G (p.Pro872Ala)

ClinVar: 180391, https://www.ncbi.nlm.nih.gov/clinvar/variation/180391/

gnomAD: 0.0004032, https://gnomad.broadinstitute.org/variant/6-112463374-G-C

Supplementary Data Table S3

Case: 110

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.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

Variant2: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)

ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/

gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C

MultipleGeneVariants:

(1) CRYAB Variant

Variant as listed does not exist on any transcript

Variant: c.331G>A (p.Gly111Ser)

ClinVar: N/A

gnomAD: N/A

(2) DSP Variant

Variant: NM_004415.4(DSP):c.4588G>T (p.Val1530Phe)

ClinVar: 137171 https://www.ncbi.nlm.nih.gov/clinvar/variation/137171/

gnomAD: 0.01477, https://gnomad.broadinstitute.org/variant/6-7581011-G-T

(3) SDHA Variant

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

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

gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

(4) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

(5) TTN Variant

Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)

ClinVar: 165840 https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/

gnomAD: 0.003324, https://gnomad.broadinstitute.org/variant/2-179436256-ATTG-A

Supplementary Data Table S3

Case: 118

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) CSRP3 Variant

Variant: NM_003476.4:c.529G>A (p.Gly177Ser)

CAID: CA5916512 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA5916512

gnomAD: 0.00004619, https://gnomad.broadinstitute.org/variant/11-19204273-C-T

Supplementary Data Table S3

Case: 21

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) LDB3 Variant

Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)

ClinVar: 178059, https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/

gnomAD: 0.0009830, https://gnomad.broadinstitute.org/variant/10-88439888-C-T

Supplementary Data Table S3

Case: 216

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

Supplementary Data Table S3

Case: 2

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) MYBPC3 Variant

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

ClinVar: 181035, https://www.ncbi.nlm.nih.gov/clinvar/variation/181035/

gnomAD: 0.0005896, https://gnomad.broadinstitute.org/variant/11-47371630-G-A

(2) MYOZ2 Variant

Variant: NM_016599.4(MYOZ2):c.738A>G (p.Ile246Met)

ClinVar: 30509, https://www.ncbi.nlm.nih.gov/clinvar/variation/30509/

gnomAD: 0.002300, https://gnomad.broadinstitute.org/variant/4-120107298-A-G

(3) PSEN2 Variant

Variant: NM_000447.3(PSEN2):c.211C>T (p.Arg71Trp)

ClinVar: 192130, https://www.ncbi.nlm.nih.gov/clinvar/variation/192130/

gnomAD: 0.003711, https://gnomad.broadinstitute.org/variant/1-227071475-C-T

(4) SCN5A Variant

Variant: NM_000335.4(SCN5A):c.1715C>A (p.Ala572Asp)

ClinVar: 67683, https://www.ncbi.nlm.nih.gov/clinvar/variation/67683/

gnomAD: 0.005175, https://gnomad.broadinstitute.org/variant/3-38645378-G-T

Supplementary Data Table S3

Case: 231

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.4472C>G (p.Ser1491Cys)

ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/

gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C

MultipleGeneVariants:

(1) LDB3 Variant

Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)

ClinVar: 178059 https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/

gnomAD: 0.009200, https://gnomad.broadinstitute.org/variant/10-88439888-C-T

Supplementary Data Table S3

Case: 129

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.1987C>T (p.Arg663Cys)

ClinVar: 42874 https://www.ncbi.nlm.nih.gov/clinvar/variation/42874/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) LAMA4 Variant

Variant: NM_001105206.3(LAMA4):c.3239G>A (p.Arg1080Gln)

ClinVar: 44374 https://www.ncbi.nlm.nih.gov/clinvar/variation/44374/

gnomAD: 0.02400, https://gnomad.broadinstitute.org/variant/6-112460365-C-T

Supplementary Data Table S3

Case: 13

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) PLB1 Variant

Variant: NM_153021.4:c.3967C>A

CAID: CA1588921, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1588921

gnomAD: 0.01507, https://gnomad.broadinstitute.org/variant/2-28854972-C-A

(2) TTN Variant

Variant: c.33510_33512dupAGA, p.Glu11171dup Unregistered Variant

Supplementary Data Table S3

Case: 152

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) CRYAB Variant

Variant as listed does not exist on any transcript

Variant: c.331G>A (p.Gly111Ser)

ClinVar: N/A

gnomAD: N/A

(2) DSP Variant

Variant: NM_004415.4(DSP):c.4372C>G (p.Arg1458Gly)

ClinVar: 44906 https://www.ncbi.nlm.nih.gov/clinvar/variation/44906/

gnomAD: 0.003556, https://gnomad.broadinstitute.org/variant/6-7580795-C-G

Supplementary Data Table S3

Case: 138

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.2162G>A (p.Arg721Lys)

CAID: CA389049002 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049002

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) CRYAB Variant

Variant as listed does not exist on any transcript

Variant: c.331G>A (p.Gly111Ser)

ClinVar: N/A

gnomAD: N/A

(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: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

(3) TCAP Variant

Variant: NM_003673.3(TCAP):c.458G>A (p.Arg153His)

ClinVar: 44710 https://www.ncbi.nlm.nih.gov/clinvar/variation/44710/

gnomAD: 0.002296, https://gnomad.broadinstitute.org/variant/17-37822316-G-A

Supplementary Data: S2 Table

Case 156: Spanish, 82yo, 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.5135G>A (p.Arg1712Gln)

ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Supplementary Data: S2 Table

Case 9: Spanish, 13yo, 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.4124A>G (p.Tyr1375Cys)

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

gnomAD: n/a

Supplementary Data: S2 Table

Case 65: Spanish, 35yo, 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(MYH7):c.715G>A (p.Asp239Asn)

ClinVar: 43100, https://www.ncbi.nlm.nih.gov/clinvar/variation/43100/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23900811-C-T

MultipleGeneVariants:

(1) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.3676C>T (p.Arg1226Cys)

ClinVar: 42731, https://www.ncbi.nlm.nih.gov/clinvar/variation/42731/

gnomAD: 0.00004815, https://gnomad.broadinstitute.org/variant/11-47353761-G-A

(2) TTN Variant:

Variant: NM_001267550.2(TTN):c.49175C>A (p.Ala16392Glu)

ClinVar: 405004, https://www.ncbi.nlm.nih.gov/clinvar/variation/405004/

gnomAD: 0.000004042, https://gnomad.broadinstitute.org/variant/2-179478949-G-T

Supplementary Data: S2 Table

Case 100: Spanish, 81yo, 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.1580C>T

CAID: CA389050265, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389050265

gnomAD: n/a

Supplementary Data: S2 Table

Case 7: Spanish, 23yo, 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:c.2596T>C

CAID: CA389048059, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048059

gnomAD: n/a

Supplementary Data: S2 Table

Case 234: Spanish, 50yo, 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.2312G>C

CAID: CA032230, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA032230

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23894602-C-G

Supplementary Data: S2 Table

Case 251: Spanish, 55yo, 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.3610G>C (p.Gly1204Arg)

ClinVar: 42966, https://www.ncbi.nlm.nih.gov/clinvar/variation/42966/

gnomAD: 0.000004008, https://gnomad.broadinstitute.org/variant/14-23889170-C-G

Supplementary Data: S2 Table

Case 10: Spanish, 69yo, 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.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: S2 Table

Case 130: Spanish, 14yo, 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(MYH7):c.2167C>G (p.Arg723Gly)

ClinVar: 42885, https://www.ncbi.nlm.nih.gov/clinvar/variation/42885/

gnomAD: n/a

MultipleGeneVariants:

(1) TCAP Variant:

Variant: NM_003673.3(TCAP):c.97C>T (p.Arg33Trp)

ClinVar: 282451, https://www.ncbi.nlm.nih.gov/clinvar/variation/282451/

gnomAD: 0.00007092, https://gnomad.broadinstitute.org/variant/17-37821709-C-T

Supplementary Data: S2 Table

Case 67: 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(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

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_133378.4(TTN):c.4396T>C (p.Phe1466Leu)

ClinVar: 166320, https://www.ncbi.nlm.nih.gov/clinvar/variation/166320/

gnomAD: 0.0006871, https://gnomad.broadinstitute.org/variant/2-179642515-A-G

Case III-3: Male, 27yo, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0005135 (exertional dyspnea, chest pain, ST segment depression, abnormal T wave)

CaseHPOFreeText: abnormal Q wave, interventricular septum = 20mm, posterior wall of left ventricle = 7mm

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

Case II-9: Female, 46yo, diagnosed at 14yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0005135, HP:0011713 (exertional dyspnea, chest pain, ST segment depression, abnormal T wave, left bundle branch block)

CaseHPOFreeText: abnormal Q wave, Wide QRS, interventricular septum = 13mm, posterior wall of left ventricule = 9mm

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

PMID: 23676496

Gene: MYH7

HGNC: 7577

Case#: father, diagnosis as child,

DiseaseAssertion: HCM

FamilyInfo: daughter and 2 sons also diagnosed, G6P2 30 yr mother had normal pregnancy

CasePresentingHPOs: N/A

CaseHPOFreeText: heart transplantation at 33 yr

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.1969A>C (p.Lys657Gln)

ClinVar: 164351 https://www.ncbi.nlm.nih.gov/clinvar/variation/164351/

CAID: N/A

gnomAD: N/A

Case1: 49 year old male

DiseaseAssertion: LVNC

FamilyInfo: parent to child transmission affecting both sexes in ≥2 successive generations

CasePresentingHPOs: HP:0001650

"Aortic valve stenosis"

CaseHPOFreeText: bicuspid aortic valve (BAV) and mild-to-moderate aortic valvular stenosis, grade III/VI harsh crescendo-decrescendo murmur at right upper sternal border radiating to both carotids, prominent trabeculations, left ventricular apical recesses in continuation with the ventricular cavity, reduced LV systolic function with concomitant LV dilation

GenotypingMethod: next-generation sequencing using an Illumina Solexa platform for the coding regions including the splice sites of 27 genes known to be associated with familial dilated cardiomyopathy

Variant: NM_000257.4:c.1316T>G

ClinVar: 181406

CAID: CA010528

gnomAD: not found

PMID: 27082122

Gene: MYH7

HGNC ID: 7577

Gene: PRKAG2

HGNC ID: 9386

Table 1 and 4

Case A13: Male, 10yo, proband (III-2)

DiseaseAssertion: malignant HCM

FamilyInfo: positive family history (fig 1), grandfather died at 42yo from heart disease, father died at 40yo due to sudden cardiac death, mother (A11, II-1) had no clinical symptoms, sister (A12, III-1) diagnosed at 21yo with severe HCM

CasePresentingHPOs: HP:0100749, HP:0001279 (chest pain, syncope)

CaseHPOFreeText: interventricular septum thickness = 21.0mm, left ventricular posterior wall thickness = 12.0mm, left atrium = 40.0mm, left ventricular ejection fraction = 48%, septal asymmetry, decreased left ventricular systolic and diastolic function

CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)

CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing

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) PRKAG2 Variant:

Variant: NM_016203.3(PRKAG2):c.298G>A (p.Gly100Ser)

ClinVar: 36697, https://www.ncbi.nlm.nih.gov/clinvar/variation/36697/

gnomAD: 0.006770, https://gnomad.broadinstitute.org/variant/7-151478406-C-T

Case KMP 22: Eastern Slovakia, Male, 21yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: negative family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, implantable cardioverter defibrillator

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 15: Eastern Slovakia, Female, 82yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: positive family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%, New York Heart Association Classification = III, implantable cardioverter defibrillator

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.2734A>G (p.Lys912Glu)

ClinVar: 520267, https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/

gnomAD: n/a

Case KMP 8: Eastern Slovakia, Male, 62yo

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

Case: Patient 19, female, 33yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0008959, HP:0009053, HP:0008997, HP:0008994, HP:0002650, HP:0003458 (foot drop, Distal upper limb muscle weakness, Distal lower limb muscle weakness, Proximal muscle weakness in upper limbs, Proximal muscle weakness in lower limbs, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: respiratory involvement - restrictive from 25yo, normal CK levels, minicores present on muscle biopsy

CaseNotHPOs: no cardiac involvement

FamilyInfo: family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Case: 6, femaly, 16yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0008959, HP:0009053, HP:0002650 (axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, scoliosis)

HPOsFreeText: normal CK

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: family history, pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4807G>C (p.Ala1603Pro)

ClinVar: 190407, https://www.ncbi.nlm.nih.gov/clinvar/variation/190407/

gnomAD: absent

Case: Patient 17, male, 36yo, symptom onset in childhood

CasePresentingHPOs: HP:0003327, HP:0008959, HP:0009053 (axial muscle weakness, Distal upper limb muscle weakness, Distal lower limb muscle weakness)

HPOsFreeText: normal CK levels

CaseNotHPOs: HP:0002650 (scoliosis)

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: 0.00004598, https://gnomad.broadinstitute.org/variant/14-23882979-T-A?dataset=gnomad_r2_1

Case: Patient 4, male, 22yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0008959, HP:0009053, HP:0001701, HP:0030682 (foot drop, axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, pericarditis, left ventricular noncompaction)

CaseNotHPOs: HP:0003306 (rigid spine)

HPOsFreeText: restrictive respiratory involvement from age 16, CK = 711U/l, minicores present on muscle biopsy, hypertrophy of gastrocnemii

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below; variants in SEPN1 and LMNA rules out

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

PMID: 23816408

Gene: MYH7

HGNC: 7577

4 mutations in MYH7 reported but no case information

(R204H, M493V, R719W, and R870H)

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias

PMID: 28491642

Gene:ACTC1

HGNC ID:143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID:28491642

Gene:ACTC1

HGNC ID:143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

CasePresentingHPOs: HP:0004756

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

Case11:

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: 1 family member tested, 0 tested positive for cardiomyopathy

CasePresentingHPOs: HP:0001644

"Dilated cardiomyopathy"

CasePreviousTesting: If there was a normal heart at autopsy, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were sequenced. If death occurred during exertion, CPVT was considered and RYR2 sequenced. If these tests were negative and there was a family history of sudden death, PKP2, DSC2, DSG and DSP2 were sequenced. If dilated cardiomyopathy (DCM) was suspected, the six sarcomere genes were sequenced along with LMNA and SCN5A.

GenotypingMethod: Sanger sequencing

Variant: NM_000257.4:c.3726G>A

CAID: CA485766621

Case N16: Tunisia, Female, 72yo at onset, 76yo at study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0100749 (chest pain)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 18mm

FamilyInfo: family history 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(MYH7):c.4909G>A (p.Ala1637Thr)

ClinVar: 43044, https://www.ncbi.nlm.nih.gov/clinvar/variation/43044/

gnomAD: 0.00008840, https://gnomad.broadinstitute.org/variant/14-23885257-C-T

Case N22: Tunisia, Male, 36yo at onset, 37yo at study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001962 (palpitations)

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

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(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: 0.00004598, https://gnomad.broadinstitute.org/variant/14-23882979-T-A

CaseII2: 19 year old male, Chinese

DiseaseAssertion: LVNC

FamilyInfo: Mother met diagnostic criteria for LVNC but was asymptomatic, cardiopath diagnosed brother suffered sudden death at age 13

CasePresentingHPOs: HP:0001962

"Palpitations"

CasePreviousTesting: Echocardiography

GenotypingMethod: Whole Exome Sequencing and mutation screening, SPRING used to prioritize the disease-causing nonsynonymous single nucleotide variants (SNVs) in exome sequencing, Sanger sequencing confirmed cosegregation of the mutations in pedigree

Variant: NM_000257.3:c.1492C>G

identified 13 SNVs with P < 0.05 (Table 1). MYH7 (c.C1492G), DSP (c.A2360G), RICTOR (c.C629T) and PRMT3 (c.T500C) all show P < 0.01 but only MYH7 (c.C1492G) reach significant criterion with P of 3.45E− 05 and q-value of 4.65E− 03.

ClinVar: not found

CAID: CA389050478

gnomAD: not found

Case8: Female, 58 years report, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: No family history

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Interventricular septal thickness at 17.3 mm, Left ventricular posterior wall thickness at 15.9 mm, Left ventricular end-diastolic diameter at 60.7 mm, Left ventricular septal thickness at 45.3 mm, Left ventricular ejection fraction at 50%

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See list of sequenced genes

CaseGenotypingMethod: Genomic DNA was isolated from whole blood of all patients and controls. Whole coding exons and exon-intron boundaries of the 19 HCM-related genes listed above were amplified and sequenced on Ion Torrent PGM. These variants were then filtered for pathogenicity and compared to the controls. Any mutations found were confirmed by conventional dideoxy sequencing and Sanger sequencing.

Variant: NM_000257.3:c.730T>C (p.Phe244Leu)

ClinVar: 181319 https://www.ncbi.nlm.nih.gov/clinvar/variation/181319/

gnomAD: Not in gnomAD

CaseMYH7-4: 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.2221G>C (p.Gly741Arg)

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

gnomAD: Not in gnomAD

CaseMYH7-6: 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.1511A>G (p.Glu504Gly)

CAID: CA257822944 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1511A%3EG

gnomAD: Not in gnomAD

PMID: 31164718

Gene: MYH7

AnimalModel: detection of feline orthologue of NM_000257.2(MYH7):c.5647G>A (p.Glu1883Lys) (ClinVarID: 14121), which was determined to cause HCM in domestic short hair cat

ClinVar: 14121, https://www.ncbi.nlm.nih.gov/clinvar/variation/14121/

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23883224-C-T

CaseII.1: 25 year old female

DiseaseAssertion: moderate left ventricular hypertrophy

FamilyInfo: All the members of the family were studied, four affected individuals aged 10–52 years presenting with restrictive phenotype but with minimal or no LVH

CasePresentingHPOs: HP:0002875

"Exertional dyspnea"

CaseHPOFreeText: exertional dyspnoea and oedema in lower extremities

GenotypingMethod: genetic analysis of all family members

Variant: NM_000257.4:c.755T>C

ClinVar: 179894

CAID: CA016801

gnomAD: not found

CaseMYH7-12: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 1 other proband shares 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.1358G>A (p.Arg453His)

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

gnomAD: Not in gnomAD

CaseMYH7-15: 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.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: European (Non-Finnish) 4.657e-5, Overall 2.125e-5 https://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseMYH7-10: 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.2779G>A (p.Glu927Lys)

ClinVar: 42932 https://www.ncbi.nlm.nih.gov/clinvar/variation/42932/

gnomAD: Not in gnomAD

CaseMYH7-21: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 5 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.2722C>G (p.Leu908Val)

ClinVar: 14097 https://www.ncbi.nlm.nih.gov/clinvar/variation/14097/

gnomAD: European (Non-Finnish) 6.482e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23893316-G-C

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.2539A>G (p.Lys847Glu)

ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

gnomAD: Not in gnomAD

CaseMYH7-4: 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.2156G>A (p.Arg719Gln)

ClinVar: 140107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: Not in gnomAD

CaseMYH7-19: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 2 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.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

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.1207C>T (p.Arg403Trp)

ClinVar: 14102, https://www.ncbi.nlm.nih.gov/clinvar/variation/14102/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 5 individuals

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 2

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr)

ClinVar: 164342, https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 2 individuals

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

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

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.1954A>G (p.Arg652Gly)

ClinVar: 177626, https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: 0.000003978, https://gnomad.broadinstitute.org/variant/14-23896451-T-C

Case143: Male, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0001635, HP:0025169 (Left ventricular noncompaction, Heart failure, Left ventricular systolic dysfunction)

HPOsFreeText: Left Ventricular Ejection Fraction at 42%, LVDD-Z score at 1

CaseNotHPOs: HP:0011675 (Arrhythmia)

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.262G>A (p.Glu88Lys)

CAID: CA389053315 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.262G%3EA

gnomAD: Not in gnomAD

Case339: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635, HP:0011675 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure, Arrhythmia)

HPOsFreeText: Left Ventricular Ejection Fraction at 48%, LVDD-Z score at 1

CaseNotHPOs: N/A

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.

There are two possible mutations that result in the below variant, CA389050168 and CA389050167. It is not clear which one is correct here.

Variant: NP_000248.2:p.Lys542Asn

CAID: N/A

gnomAD: N/A

Case377: Female, 0.0833 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)

HPOsFreeText: Left Ventricular Ejection Fraction at 30%, LVDD-Z score at 1.3333

CaseNotHPOs: HP:0011675 (Arrhythmia)

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.2078T>G (p.Leu693Arg)

CAID: CA389049168 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2078T%3EG

gnomAD: Not in gnomAD

Case391: Female, 0.83 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)

HPOsFreeText: Left Ventricular Ejection Fraction at 38%, LVDD-Z score at 2.6785

CaseNotHPOs: HP:0011675 (Arrhythmia)

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.5401G>A (p.Glu1801Lys)

ClinVar: 43069 https://www.ncbi.nlm.nih.gov/clinvar/variation/43069/

gnomAD: Not in gnomAD

Case362: Female, 0.0833 years 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 40%, LVDD-Z score at -0.823

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.689T>C (p.Phe230Ser)

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

gnomAD: Not in gnomAD

Case3: Female, 57 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0005110, HP:0004756, HP:0001279 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Atrial fibrillation, Ventricular tachycardia, Syncope)

HPOsFreeText: 2 SCD risk factors, NYHA class is III, Right ventricular wall thickness 11.5 mm

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

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: NM_000257.3:c.1955G>C (p.Arg652Thr)

CAID: CA389049460 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1955G%3EC

gnomAD: Not in gnomAD

MultipleGeneVariants:

MYH6 Variant:

Variant: NM_002471.3:c.35C>T (p.Ala12Val)

ClinVar: 537952 https://www.ncbi.nlm.nih.gov/clinvar/variation/537952/

gnomAD: African 6.152e-5, Overall 7.954e-6 https://gnomad.broadinstitute.org/variant/14-23876398-G-A

Variant1: NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607 https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.00001759, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

Variant2: NM_000257.4(MYH7):c.2678C>T (p.Ala893Val)

ClinVar: 177763 https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/

gnomAD: Not in gnomAD

Variant3: NM_000257.3:c.2713T>C (p.Cys905Arg)

CAID: CA389047302 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.2713T%3EC

gnomAD: Not in gnomAD

Variant4: NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608 https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: Not in gnomAD

Variant5: NM_000257.3:c.415G>T (p.Val139Leu)

CAID: CA389052864 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.415G%3ET

gnomAD: Not in gnomAD

Variant6: NM_000257.4(MYH7):c.495G>A (p.Met165Ile)

ClinVar: 524948 https://www.ncbi.nlm.nih.gov/clinvar/variation/524948/

gnomAD: Not in gnomAD

Variant7: NM_000257.3:c.547G>A (p.Gly183Arg)

CAID: CA389052574 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.547G%3EA

gnomAD: Not in gnomAD

Variant8: NM_000257.3:c.5754C>G (p.Asn1918Lys)

CAID: CA389034544 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5754C%3EG

gnomAD: Not in gnomAD

Variant9: NM_000257.3:c.5773C>G (p.Arg1925Gly)

CAID: CA257807342 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5773C%3EG

gnomAD: Not in gnomAD

Variant10: NM_000257.4(MYH7):c.689T>C (p.Phe230Ser)

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

gnomAD: Not in gnomAD

Variant11: NM_000257.3:c.715_717del (p.Asp239del)

CAID: CA913184869 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.715_717del

gnomAD: Not in gnomAD

Variant12: NM_000257.4(MYH7):c.732+1G>A

ClinVar: 14127 https://www.ncbi.nlm.nih.gov/clinvar/variation/14127/

gnomAD: 0.00005437, https://gnomad.broadinstitute.org/variant/14-23900793-C-T

Variant13: NM_000257.3:c.798T>A (p.Tyr266Ter)

CAID: CA389052023 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.798T%3EA

gnomAD: Not in gnomAD

Variant14: NM_000257.4(MYH7):c.847T>G (p.Tyr283Asp)

ClinVar: 66081 https://www.ncbi.nlm.nih.gov/clinvar/variation/66081/

gnomAD: Not in gnomAD

Variant15: NM_000257.3:c.902T>A (p.Leu301Gln)

CAID: CA389051788 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.902T%3EA

gnomAD: Not in gnomAD

PMID: 21832052

Gene: MYBPC3

HGNC: 7551

PMID: 35888124 Gene: MYBPC3 HCNC ID: 7551

Case#: An El-Salvadoran 22-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with sarcomeric gene variants in MYL3 and MYL2

FamilyInfo: The patient’s mother was the only family member available for evaluation (Fig 2). On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age

ParentalTesting: Patients mother

CasePresentingHPOs: HP:0002099, HP:0012378, HP:0012764, HP:0001962, HP:0034807, HP:0001541, HP:0001410, HP:0031667, HP:0004749,

CaseHPOFreeText: diagnosed with RCM and advanced heart failure requiring heart transplantation. A prior diagnosis of childhood asthma presented with worsening fatigue and dyspnea on exertion over the course of 12 months. She reported having frequent episodes of shortness of breath as a child, also reported orthopnea, paroxysmal nocturnal dyspnea, and palpitations; her heart failure symptoms were classified as NYHA Class III–IV. did have ascites suggestive of congestive hepatopathy. Her cardiovascular examination revealed a nondisplaced, nonsustained point of maximal impulse, with a mild parasternal lift without a pulmonary artery tap.She had a normal S1, but P2>A2. She had an S3, but no S4. She had a soft I/IV holosystolic murmur over the apex; no knock or rub. Her electrocardiogram demonstrated atrial flutter with an atrial rate of 250–300 and a ventricular rate of 85.

CaseNotHPOs: HP:0002321, HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied dizziness, syncope, and lower extremity edema.

CasePreviousTesting: The patient's mother was also tested to assess inheritance.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: MYL2 p.Gly57Glu variant using sequence conservation and computational splice-site prediction

Variant: NM_000432.4:c.170G>A

ClinVar:43458

CAID: CA009910

gnomAD: gnomAD v2 12:111352094 C / T https://gnomad.broadinstitute.org/variant/12-111352094-C-T?dataset=gnomad_r2_1 gnomAD v3 12:110914290 C / T https://gnomad.broadinstitute.org/variant/12-110914290-C-T?dataset=gnomad_r3 , gnomAD v4 chr12-110914290-C-T https://gnomad.broadinstitute.org/variant/chr12-110914290-C-T?dataset=gnomad_r4

PMID: 24085031

Gene: MYH7

HGNC: 7577

"Defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure"

FamilyB

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.1943C>T

ClinVar: not found

CAID: CA389049480

gnomAD: not found