Case 3: A 64 year old female

DiseaseAssertion: The case carried the novel MYH7 K637E mutation

FamilyInfo: Her mother died of a suspected but unconfirmed cardiac cause; thus, this was regarded as a non-FDC case. Two healthy sisters declined participation in the study.

ParentalTesting:NR

CasePresentingHPOs: HP:0003674, HP:0034307, HP:0002372, HP:0011675, HP:0005110

CaseHPOFreeText: Slowly from onset of symptoms at the age of 42 years, and received HTX in her sixth decade. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)), 81mm and then 4.2m2. LVEF as 15%, ECG as normal. Arrhythmia as atrial fibrillation. NYHA as 4. Clinical status as heart transplantation. CAG has a normal level.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method: Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis: NR

Variant:NM_000257.4:c.1909A>G

ClinVar:1329402

CAID:CA389049558

gnomAD:NR

AdditionalInfo:NR

Case1: A 68-year-old female

DiseaseAssertion: dilated cardiomyopathy (DCM), with the MYH7 p.Lys637Glu (K637E) variant identified in the affected patient. The study investigated sarcomeric gene variants associated with DCM

FamilyInfo: The proband's father (M1, II:3) died suddenly at 36 years of age, 2 years after being diagnosed with DCM.

ParentalTesting: Yes from father

CasePresentingHPOs: HP:0011664, HP:0011713, HP:0003677, HP:0001635,

CaseHPOFreeText: was diagnosed as having left ventricular non-compaction (LVNC) based on echocardiography. A left bundle branch block on her ECG. Echocardiography revealed LVNC and she has had a slow progression towards heart failure and an increasing dilatation of her left ventricle. Age 48 at onset, left ventricular end diastolic diameter 59 mm, left ventricular ejection fraction 25%, ventricular extrasystoles for arrhythmia.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method: genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis:NR

Variant: NM_000257.4:c.1909A>G

ClinVar: 1329402

CAID:CA389049558

gnomAD: NR

AdditionalInfo: NR

PMID: 19293840

Gene: MYH7

HGNC ID: 7577

CasePT-104: 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.4399C>G (p.Leu1467Val)

ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C

CasePT-111: 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.563C>A (p.Thr188Asn)

CAID: CA016314 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.563C%3EA

gnomAD: Not in gnomAD

CasePT-45: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo: 2 others in the study have the same MYH7 variant, one sibling has the same multiple variants 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.1988G>A (p.Arg663His)

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

gnomAD: European (non-Finnish) 3.097e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Multiple Gene Variants:

PRKAG2 Variant:

Variant: NM_016203.3:c.1304A>G (p.Asn435Ser)

ClinVar: 167533 https://www.ncbi.nlm.nih.gov/clinvar/variation/167533/

gnomAD: Latino 3.104e-4, Overall 1.025e-4 https://gnomad.broadinstitute.org/variant/7-151262901-T-C

CasePT-80: 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.2546T>C (p.Met849Thr)

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

gnomAD: Not in gnomAD

Supplementary Data, Table 2

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.2609G>A (p.Arg870His)

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

gnomAD: 0.000007072, https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

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

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

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

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

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

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.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

Case#: 12 yr, female,

DiseaseAssertion: HCM

FamilyInfo: Father and younger brother also diagnosed, same mutation, brother asymptomatic,

CasePresentingHPOs: Syncope, Left bundle branch block, third degree atrioventricular block, amaurosis fugax, vertigo, ventricular septal hypertrophy, mitral regurgitation (HP:0001279, HP:0011713, HP:0001709, HP:0100576, HP:0002321, HP:0005144, HP:0001653)

CaseHPOFreeText: bilateral atrial enlargement to 44mm for left and 40 mm for right, interventricular septum thickened to 23mm, posterior left ventricle thickened to 10 mm, left ventricular ejection fraction of 51.8%, elevated plasma level B-type Natriuretic peptic 1165 pg/ml

CaseNotHPOs: heart murmur (HP:0030148)

CaseNotHPOFreeText: normal liver and spleen size, no edema, pericardial abnormality, no obstruction of left ventricular outflow tract, normal pasma amino acids and urine organic acids

CasePreviousTesting: whole exome sequencing

CaseGenotypingMethod: heart rate of 102/min; respiratory rate of 25/min; blood pressure of 127/74 mmHg; ECG; 175 QRS complex; Holter monitor; MRI; Etiologic investigations; Bioinformatic analysis based on Polymorphism Phenotyping v2, Sorting Intolerant From Tolerant;

Variant: NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)

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

CAID: N/A

gnomAD: 0.00006481 https://gnomad.broadinstitute.org/variant/14-23895180-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: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 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.2710C>T (p.Arg904Cys)

ClinVar: 164316, https://www.ncbi.nlm.nih.gov/clinvar/variation/164316/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23893328-G-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.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:c.2384T>C

CAID: CA389048531, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048531

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.541G>A

CAID: CA046725, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA046725

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23901068-C-T

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.5773C>G

CAID: CA257807342, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257807342

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

CasePresentingHPOs: HP:0010316, HP:0001645 (Ebstein anomaly, sudden cardiac death)

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.5754C>G

CAID: CA389034544, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389034544

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

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

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23900793-C-T

Four MYH7 variants mentioned using reference transcript NM_000257.2

c.464_466delTCT

c.745C>G

c.1106G>A

c.2785G>A

CaseIII-3: female

DiseaseAssertion: LVNC, Ebstin anomaly, congenital heart disease

FamilyInfo: all mutation carriers have LVNC, with some having Ebstein anomaly and/or other CHD

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod:

Variant: NM_000257.4:c.847T>G

ClinVar: 66081

CAID: CA016893

gnomAD:

Supplementary Data Table S3

Case: 140

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: 349

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) MYH6 Variant

Variant: NM_002471.3(MYH6):c.1763A>C (p.Asp588Ala)

ClinVar: 155811 https://www.ncbi.nlm.nih.gov/clinvar/variation/155811/

gnomAD: 0.003074, https://gnomad.broadinstitute.org/variant/14-23868065-T-G

(2) MYH6 Variant

Variant: NM_002471.3(MYH6):c.5491G>A (p.Glu1831Lys)

ClinVar: 196975 https://www.ncbi.nlm.nih.gov/clinvar/variation/196975/

gnomAD: 0.0003008, https://gnomad.broadinstitute.org/variant/14-23853725-C-T

(3) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.1958C>T (p.Thr653Ile)

ClinVar: 180045 https://www.ncbi.nlm.nih.gov/clinvar/variation/180045/

gnomAD: 0.0007430, https://gnomad.broadinstitute.org/variant/10-112572113-C-T

(4) TMPO Variant

Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)

ClinVar: 44673 https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/

gnomAD: 0.005407, https://gnomad.broadinstitute.org/variant/12-98926856-G-A

Supplementary Data Table S3

Case: 179

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.2185G>C (p.Ala729Pro)

CAID: CA389048952 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048952

gnomAD: Not in gnomAD

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: 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: 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 Table S3

Case: 155

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) 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

Supplementary Data Table S3

Case: 48

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

Supplementary Data Table S3

Case: 17

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) NEBL Variant

Variant: NM_006393.2(NEBL):c.2054C>T (p.Ala685Val)

ClinVar: 227732, https://www.ncbi.nlm.nih.gov/clinvar/variation/227732/

gnomAD: 0.0003290, https://gnomad.broadinstitute.org/variant/10-21108354-G-A

(2) RBM20 Variant

Variant: NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)

ClinVar: 43995, https://www.ncbi.nlm.nih.gov/clinvar/variation/43995/

gnomAD: 0.004046, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

Supplementary Material 4

Case M-28: 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-21: 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:c.2302_2310del

CAID: CA913184893, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184893

gnomAD: n/a

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-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

Case#: 45 yr, female, diagnosed at 13 from heart murmur

DiseaseAssertion: HCM

FamilyInfo: sibling with HCM, family history of symptoms and same mutation

CasePresentingHPOs: left ventricular hypertrophy (HP:0001712)

CaseHPOFreeText: abnormal coaptation of the mitral valve, systolic anterior motion of the mitral valve,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: stem cell derivation and cardiomyocyte differentiation; hiPSC-cardiomyocyte shRNA silencing experiments; qPCR analysis of MYH7 alleles; ECG; Micropatterning; ASO silencing

Variant: NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln)

ClinVar: 14087 https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/

CAID: N/A

gnomAD: absent

CaseR858C: 44 year old (text states male, pedigree states female)

DiseaseAssertion: HCM

FamilyInfo: No family members manifested sudden death, lethal arrhythmia, LVOT obstruction, or severe heart failure.

One family member also carried double mutations

CaseHPOFreeText: greater LV hypertrophy than his family members who carried a single mutation

CasePreviousTesting: systematic mutation screening of eight sarcomeric genes: (MYH7), (MYBPC3), (TNNT2), (TNNI3), (MYL2), (MYL3), (TPM1), and (ACTC), using direct DNA sequencing

GenotypingMethod: Genomic DNA was isolated from the leukocytes of the peripheral blood. Polymerase chain reaction was used to amplify the exons and flanking intronic bases of the eight genes, including MYH7, MYBPC3, TNNT2, TNNI3, MYL2, and MYL3. When no mutation was found, analysis of the TPM1 and ACTC genes was performed

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.2572C>T

ClinVar: 164324

CAID: CA012656

gnomAD: https://gnomad.broadinstitute.org/variant/14-23894085-G-A

0.00006152 African

VariantTNNT2: NM_001001430.3:c.857G>A

ClinVar: 43677

CAID: CA005304

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

0.0008699 East Asian

CaseR147S: 52 year old male

DiseaseAssertion: HCM

FamilyInfo: son was also diagnosed with HCM, but his younger daughter and granddaughter were genotype positive–phenotype negative.

CaseHPOFreeText: asymmetric septal hypertrophy (ASH) with mid LV obstruction

CasePreviousTesting: systematic mutation screening of eight sarcomeric genes: (MYH7), (MYBPC3), (TNNT2), (TNNI3), (MYL2), (MYL3), (TPM1), and (ACTC), using direct DNA sequencing

GenotypingMethod: Genomic DNA was isolated from the leukocytes of the peripheral blood. Polymerase chain reaction was used to amplify the exons and flanking intronic bases of the eight genes, including MYH7, MYBPC3, TNNT2, TNNI3, MYL2, and MYL3. When no mutation was found, analysis of the TPM1 and ACTC genes was performed.

Variant: NM_000257.4:c.441G>C

ClinVar: 643664

CAID: CA389052814

gnomAD: not found

CaseIII:2: 44 year old male, South Asian

DiseaseAssertion: HCM, septal hypertrophic obstructive cardiomyopathy

FamilyInfo: family history of two sudden cardiac deaths at ages 35 and 19, and three family members with septal hypertrophic obstructive cardiomyopathy

CasePresentingHPOs: HP:0001279, HP:0002094, HP:0001962

"Syncope, Dyspnea, Palpitations"

CasePreviousTesting: screened sarcomeric thin filament protein gene, α-tropomyosin (TPM1), screening of seven other sarcomeric genes: MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC

GenotypingMethod: sequences covering all the exons and exon–intron boundaries of TPM1 and seven other sarcomeric genes (MYH7, MYBPC3, TNNT2, TTN, TNNI3, MYL2, MYL3, and ACTC) were synthesized

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.2686G>A

ClinVar: 132908

CAID: CA012857

gnomAD: not found

VariantMYH7: NP_000248.2:p.Ile524Lys

ClinVar: not found

CAID: valid allele but not present in the registry

gnomAD: not found

VariantTPM1: NM_000366.6:c.644C>T

ClinVar: 31883

CAID: CA018243

gnomAD: https://gnomad.broadinstitute.org/variant/15-63354418-C-T

0.000008806 European (non-Finnish)

CaseHCM006: 15 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0031295, HP:0011103, HP:0001653 (Exertional dyspnea, Left ventricular hypertrophy, Left atrial enlargement, Abnormality of the left ventricular outflow tract, Mitral regurgitation)

HPOsFreeText: Maximal LV thickness 33 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.2207T>C (p.Ile736Thr)

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

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) NEXN Variant

Variant: NM_144573.3(NEXN):c.835C>T (p.Arg279Cys)

ClinVar: 30994 https://www.ncbi.nlm.nih.gov/clinvar/variation/30994/

gnomAD: 0.006303, http://gnomad.broadinstitute.org/variant/1-78392548-C-T

CaseHCM147: 31 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of Sudden Cardiac Death and Hypertrophic Cardiomyopathy, Has a 9 year old daughter with the same variant but no symptoms

CasePresentingHPOs: HP:0100749, HP:0006698, HP:0031295 (Chest pain, Dilatation of the ventricular cavity, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 32 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.2156G>A (p.Arg719Gln)

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

gnomAD: Not in gnomAD

PMID: 24502034

Gene: MYH7

HGNC: 7577

General overview of Ebstein's Anomaly

PMID: 32369506

Gene: MYH7

HGNC: 7577

PMID: 24134628

Gene: MYH7

HGNC: 7577

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.715G>A (p.Asp239Asn)

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

gnomAD: 0.00002891, http://gnomad.broadinstitute.org/variant/14-23900811-C-T

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 three HCM probands

Variant: NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly)

ClinVarID: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

gnomAD: Not in gnomAD

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.4399C>G (p.Leu1467Val)

ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

gnomAD: 0.001111, http://gnomad.broadinstitute.org/variant/14-23886482-G-C

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 two HCM probands

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

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

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

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 proband

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

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

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 two HCM probands

Variant: NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)

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

gnomAD: 0.00006482, http://gnomad.broadinstitute.org/variant/14-23893316-G-C

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.3803G>A (p.Arg1268His)

ClinVar: 42975 https://www.ncbi.nlm.nih.gov/clinvar/variation/42975/

gnomAD: 0.0009786, http://gnomad.broadinstitute.org/variant/14-23888742-C-T

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.2609G>A (p.Arg870His)

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

gnomAD: 0.00001549, http://gnomad.broadinstitute.org/variant/14-23894048-C-T

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.1816G>A (p.Val606Met)

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

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

Case#: index case, III.4, female, 52 yrs,

DiseaseAssertion: HCM

FamilyInfo: Yes, III.3, IV.3 and IV.4 also diagnosed

CasePresentingHPOs: Cafe-au-lait spot, freckling, neurofibromas, heart murmur, left ventricular hypertrophy (HP:0000957, HP:0001480, HP:0001067, HP:0030148, HP:0001712)

CaseHPOFreeText: 20 mm IVS, 56% EF, 50 mmHg LVOTO, NSVT (VA)

CaseNotHPOs: N/A

CaseNotHPOFreeText: No AV, no ICD

CasePreviousTesting: N/A

CaseGenotypingMethod: ECG, cardiac magnetic resonance, physical examination, NGS tech

Variant: NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

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

CAID: N/A

gnomAD: absent

MultipleGeneVariants:

(1) NF1 Variant:

Variant: NM_000267.3(NF1):c.6709C>T (p.Arg2237Ter)

ClinVar: 230389 https://www.ncbi.nlm.nih.gov/clinvar/variation/230389/

CAID: N/A

gnomAD: absent

PMID: 25189259

Gene MYH7

HGNC: 7577

https://www.ias.ac.in/article/fulltext/jgen/093/02/0557-0560

CaseIX: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM

CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.788T>C (p.Ile263Thr)

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

gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23900635-A-G

Case#: WPW381

DiseaseAssertion: WPW, LY non compaction cardiomyopathy

FamilyInfo: inherited

CasePresentingHPOs: Wolff-Parkinson-White syndrome, Left ventricular noncompaction cardiomyopathy (HP:0001716, HP:0011664)

CaseHPOFreeText: 0 ARIC, 0 THou, 8.12e-6 gnomAD, 8.24e-6 Exac, 0 esp6500, 34 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.728G>A (p.Arg243His)

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

CAID: N/A

gnomAD: 0.00002891 Latino/Admixed American https://gnomad.broadinstitute.org/variant/14-23894525-C-T

Case16:

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: 4 family members tested, 1 family member tested positive for cardiomyopathy

CasePresentingHPOs: HP:0001639

"hypertrophic 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 hypertrophic cardiomyopathy (HCM) was suspected, the sarcomere genes MYPBC3, MYH7, TPM1, MYL2, TNNI3, and TNNT2 were sequenced.

GenotypingMethod: Sanger sequencing

Variant: NM_000257.4:c.3134G>T

ClinVar: 42948

CAID: CA013375

gnomAD: https://gnomad.broadinstitute.org/variant/14-23891500-C-A

Total Allele Frequency: 0.00001591

European (non-Finnish): 0.00003517

Case12:

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: 2 family members tested, 1 family member 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.2945T>C

ClinVar: 42941

CAID: CA013227

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

Total Allele Frequency: 0.0008484

European (non-Finnish): 0.001416

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

Case404: Female, 0.083 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 48.9%, LVDD-Z score at 0.0408

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.67C>T (p.Arg23Trp)

ClinVar: 181295 https://www.ncbi.nlm.nih.gov/clinvar/variation/181295/

gnomAD: European (Finnish) 7.961e-5, Overall 2.475e-5 https://gnomad.broadinstitute.org/variant/14-23902875-G-A

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

Case: Patient 12, male, 7yo

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

HPOsFreeText: CK = 1400U/l

CaseNotHPOs:

NotHPOsFreeText: no muscle symptoms, 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.5401G>A (p.Glu1801Lys)

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

gnomAD: absent

Case: Patient 21, female, 40yo, symptom onset in adulthood

CasePresentingHPOs: HP:0009027, HP:0002460, HP:0003458, HP:0025115 (foot drop, distal muscle weakness, EMG: myopathic abnormalities, hyalin bodies)

HPOsFreeText: CK = 500 U/l

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.1322C>T (p.Thr441Met)

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

gnomAD: 0.0002227, https://gnomad.broadinstitute.org/variant/14-23898249-G-A?dataset=gnomad_r2_1

Case1: Male, 50 years report, Netherlands

CasePresentingHPOs: HP:0011663, HP:0011675, HP:0001279, HP:0005135, HP:0001707, HP:0001711, HP:0004308, HP:0001635 (Right ventricular cardiomyopathy, Arrhythmia, Syncope, Abnormal T-wave, Abnormality of the right ventricle, Abnormality of the left ventricle, Ventricular arrhythmia, Congestive heart failure)

HPOsFreeText: Positive EPS inducibility, Cardiac transplant required

CaseNotHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

NotHPOsFreeText: N/A

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.2541_2549del (p.Lys847_Ala850delinsAsn)

CAID: CA913184863 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184863

gnomAD: Not in gnomAD

Supplementary Data: S2 Table

Case 198: Spanish, 56, 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>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 233: Spanish, 57yo, 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

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_133378.4:c.89954C>T

CAID: CA1986510, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.89954C%3ET

gnomAD: 0.00001430, https://gnomad.broadinstitute.org/variant/2-179406146-G-A

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#: SF No. 29, GC Case No. 22, female, 79

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: No

CasePresentingHPOs: N/A

CaseHPOFreeText: Colorectal cancer,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: WES, Sanger sequencing,

Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)

ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/

CAID: N/A

gnomAD: absent

Supplementary Data table 1

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.1816G>A (p.Val606Met)

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

gnomAD: 0.000007070, https://gnomad.broadinstitute.org/variant/14-23896866-C-T

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

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.2081G>A (p.Arg694His)

ClinVar: 264068, https://www.ncbi.nlm.nih.gov/clinvar/variation/264068/

gnomAD: 0.00001061, https://gnomad.broadinstitute.org/variant/14-23895254-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.2104A>G (p.Ile702Val) listed in paper as p.Arg719Gln

ClinVar: 217470, https://www.ncbi.nlm.nih.gov/clinvar/variation/217470/

gnomAD: n/a

CaseMYH7-29: 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.1988G>A (p.Arg663His)

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

gnomAD: European (Non-Finnish) 3.097e-5, Overall 1.414e-5 https://gnomad.broadinstitute.org/variant/14-23896042-C-T

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

CaseMYH7-10: 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

CaseMYH7-4: 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

Case#: Consequence 29 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

Variant: NM_000257.4(MYH7):c.2782G>A (p.Asp928Asn)

ClinVar: 164313 https://www.ncbi.nlm.nih.gov/clinvar/variation/164313/

CAID: n/a

gnomAD: absent

Case#: Consequence 14 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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