Supplementary Data: Table 2

Case K:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) VCL Variant:

Variant: NM_014000.2(VCL):c.688C>T (p.Arg230Cys)

ClinVar: 45620, https://www.ncbi.nlm.nih.gov/clinvar/variation/45620/

gnomAD: 0.00008137, https://gnomad.broadinstitute.org/variant/10-75834566-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

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 18, female, 18yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0009053, HP:0002650, HP:0011713, HP:0003458 (axial muscle weakness, distal lower limb muscle weakness, scoliosis, left bundle branch block, EMG: myopathic abnormalities)

HPOsFreeText: respiratory involvement, NIV required from 7yo, normal CK levels

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.5655G>A (p.Ala1885=)

ClinVar: 378215, https://www.ncbi.nlm.nih.gov/clinvar/variation/378215/

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

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

Case1: Male, 65, Chinese DiseaseAssertion: Non‐obstructive HCM, heart failure, and atrial fibrillation FamilyInfo:Family history of HCM and sudden cardiac death CasePresentingHPOs: HP:0031295, HP:0001685, HP:0001712, HP:0012664, HP:0025169, HP:0005110, HP:0001658, HP:0001635 CaseHPOFreeText: Presented with stenosis in the circumflex artery and has a history of non‐obstructive HCM, heart failure NYHA class III, AF, myocardial infarction, and coronary atherosclerosis CasePreviousTesting: Exercise stress echocardiography test, transthoracic echocardiography, electrocardiogram, cardiovascular magnetic resonance (CMR), computerized tomography coronary angiogram, and peripheral blood draw Genotyping Method: Genomic DNA for whole-exome sequencing (WES) by NovaSeq 6000 platform from the peripheral blood draw of proband. FunctionalAnalysis:C to T transition at nucleotide 1522 in coding exon 16 of MYBPC3 replaces the glutamine residue with a premature translational stop signal (p.Gln508Ter) Variant: NM_000256.3:c.1522C>T MANE Select <br /> ClinVar:180941

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

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.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

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 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#: 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: 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(MYH7):c.698C>T (p.Ala233Val)

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

gnomAD: n/a

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 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-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

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

CaseMYH7-15: 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 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: 208

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.2207T>C (p.Ile736Thr)

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) ABCC9 Variant

Variant: NM_005691.3(ABCC9):c.2200G>A (p.Val734Ile)

ClinVar: 35627 https://www.ncbi.nlm.nih.gov/clinvar/variation/35627/

gnomAD: 0.01123, https://gnomad.broadinstitute.org/variant/12-22017410-C-T

(2) PLB1 Variant

Variant: NM_153021.4:c.275A>G (p.Lys92Arg)

ClinVar: CA1586810 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_153021.5%3Ac.275A%3EG

gnomAD: 0.03209, https://gnomad.broadinstitute.org/variant/2-28748165-A-G

(3) TTN Variant

Variant: NM_001267550.2(TTN):c.33501_33503AGA[6] (p.Glu11172dup)

ClinVar: 46889 https://www.ncbi.nlm.nih.gov/clinvar/variation/46889/

gnomAD: 0.01788, https://gnomad.broadinstitute.org/variant/2-179544685-C-CTCT

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

CaseHCM16.1: Mixed ancestry

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000819 (Diabetes mellitus)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.

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

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

gnomAD: Not in gnomAD

CaseMYH7-16: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 3 other probands have the same genotype

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.2681A>G (p.Glu894Gly)

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

gnomAD: Not in gnomAD

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

CaseBII-3: Female, 64 years diagnosis, Italy, Caucasian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: See Figure 1

CasePresentingHPOs: HP:0001639, HP:0002094 (Hypertrophic cardiomyopathy, Dyspnea)

HPOsFreeText: Max Left ventricular wall thickness of 19 mm, Left atrium diameter of 42 mm, Left ventricular ejection fraction of 64%

CaseNotHPOs: HP:0003115, HP:0011675 (Abnormal ECG, Arrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

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

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

gnomAD: Not in gnomAD

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

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

PMID: 24298987

Gene: MYH7

HGNC: 7577

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

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

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