Case III-4: proband, Chinese, male, 46yo, diagnosed with HCM at 18yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0012250, HP:0010872, HP:0011713 (exertional dyspnea, chest pain, ST segment depression, T wave inversion, left bundle branch block)

CaseHPOFreeText: electrocardiography showed abnormal Q wave, atrium expansion, ventricular septum thickness = 13mm, left ventricular posterior wall = 10mm, left ventricular end-diastolic diameter = 52mm, left ventricular ejection fraction = 55%, small amount of tricuspid regurgitation

FamilyInfo: study assessed 3 generations of this family (22 individuals), all participants were genotyped, 8 family members were carriers of variant (p.Asn391Thr) 6 of which were diagnosed with HCM, four individual in the family died (3 of which had been diagnosed with HCM)

CasePreviousTesting: Full testing of 7 sarcomere genes (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional gene testing (MYH6, TTN, TNNC1, PRKAG2, LAMP2, GLA, CSPR3, MYOZ2, JH2, ACTN2, CAV3, LDB3, VCL, PLN, MYPN, NEXN, CALR3, ANKRD1), electrocardiogram, echocardiogram

CaseGenotypingMethod: genomic DNA collected from peripheral venous blood leukocytes, high-throughput sequencing used to sequence 26 genes (exons and 5bps of upstream and downstream intron sequences), amplified via PCR

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 III-11: Male, 32yo, Chinese, unknown age of diagnosis

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0005135 (abnormal T wave)

CaseHPOsFreeText: ventricular septum thickness = 16mm, posterior wall of left ventricle = 10mm

CaseNotHPOs: HP:0012250 (ST segment depression)

CaseNotHPOsFreeText: no clinical manifestation, abnormal Q wave

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 III-16: Male, 17yo, Chinese, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0002875, HP:0100749, HP:0100576, HP:0012250 (exertional dyspnea, chest pain, amaurosis fugax, ST segment depression)

CaseHPOFreeText: abnormal Q wave, interventricular septum = 21mm, posterior wall of left ventricle = 10mm, outflow obstruction

CaseNotHPOs: HP:0005135 (abnormal T wave)

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

Case1:

DiseaseAssertion: Hypertrophic cardiomyopathy

CaseHPOFreeText: severe congestive heart failure

GenotypingMethod: bi-directional Sanger sequencing

Variant: NM_000257.4:c.2191C>T

ClinVar: 181176

CAID: CA011922

gnomAD: not found

CaseMYH7-8: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

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

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

gnomAD: Not in gnomAD

CaseMYH7-7: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.1358G>A (p.Arg453His)

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

gnomAD: Not in gnomAD

CaseMYH7-9: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.1012G>A (p.Val338Met)

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

gnomAD: Not in gnomAD

Case120682: 62 year old Caucasian female

DiseaseAssertion: LVNC

FamilyInfo: family history was negative for cardiomyopathy or CHF, one daughter was noted to have a persistent high resting pulse

CasePresentingHPOs:

CaseHPOFreeText: first degree AV-block on ECG and prominent trabeculations at the left ventricular (LV) apex, mild aortic regurgitation

CaseNotHPOs:

CaseNotHPOFreeText:pulmonary hypertension

CasePreviousTesting: 41 cardiomyopathy-associated genes

GenotypingMethod: next generation sequencing and variant analysis, WES or WGS

Variant: NM_000257.4:c.732+1G>A

ClinVar: 14127

CAID: CA016715

gnomAD: 0.00005437 East Asian

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

Supplementary Material 4

Case M-18: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

gnomAD: n/a

Supplementary Material 4

Case M-2: 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.611G>A (p.Arg204His)

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

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23900998-C-T

Supplementary Material 4

Case M-8: 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.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 Material 4

Case M-25: 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.2596T>C

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

gnomAD: n/a

Supplementary Material 4

Case M-14: 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.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

Supplementary Material 4

Case M-22: 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.2333A>G (p.Asp778Gly)

ClinVar: 14100, https://www.ncbi.nlm.nih.gov/clinvar/variation/14100/

gnomAD: n/a

Supplementary Material 4

Case M-15: 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.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

PMID: 23896226

Gene: MYH7

HGNC: 7577

"Myosin-binding protein C (Mybpc3)-targeted knock-in mice (KI) recapitulate typical aspects of human hypertrophic cardiomyopathy. We evaluated whether these functional alterations can be reproduced in engineered heart tissue (EHT) and yield novel mechanistic information on the function of cMyBP-C."

Supplementary Data: Table S3

Case 140:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.3286G>T (p.Asp1096Tyr)

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

gnomAD: 0.0001414, https://gnomad.broadinstitute.org/variant/14-23890217-C-A

MultipleGeneVariants:

(1) SDHA Variant:

Variant: NM_004168.3(SDHA):c.830C>T (p.Thr277Met)

ClinVar: 222817, https://www.ncbi.nlm.nih.gov/clinvar/variation/222817/

gnomAD: 0.00008359, https://gnomad.broadinstitute.org/variant/5-231050-C-T

(2) TTN Variant:

Variant: p.32991_32992del no ClinVar or CAID

Supplementary Data: Table S3

Case: 63

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: suspected LVNC, >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio < 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.3337-3dupC written in paper as g.23889445insG

ClinVar: 42956, https://www.ncbi.nlm.nih.gov/clinvar/variation/42956/

gnomAD: 0.02126, https://gnomad.broadinstitute.org/variant/14-23889445-T-TG

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_133378.4(TTN):c.29331A>G (p.Glu9777=) written in paper as p.Arg9778Ter, g.179547454

ClinVar: 46884, https://www.ncbi.nlm.nih.gov/clinvar/variation/46884/

gnomAD: 0.005805, https://gnomad.broadinstitute.org/variant/2-179547455-T-C

Supplementary Data: Table S3

Case 35:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.115G>A (p.Val39Met)

ClinVar: 42827, https://www.ncbi.nlm.nih.gov/clinvar/variation/42827/

gnomAD: 0.00004596, https://gnomad.broadinstitute.org/variant/14-23902827-C-T

Case153: 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 46%, LVDD-Z score at 0.795

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: Sister also has LVNC

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.1342G>A (p.Glu448Lys)

CAID: CA389050830 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1342G%3EA

gnomAD: Not in gnomAD

Case361: Female, Birth 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 0.977

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.896-1G>A

CAID: CA389051805 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.896-1G%3EA

gnomAD: Not in gnomAD

Case333: Male, Birth 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 10%, LVDD-Z score at -0.4

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.668C>T (p.Ala223Val)

CAID: CA389052292 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.668C%3ET

gnomAD: Not in gnomAD

Case250: Male, 0.04 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 60%, LVDD-Z score at 1.6326

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.2030A>T (p.Glu677Val)

CAID: CA389049283 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2030A%3ET

gnomAD: Not in gnomAD

Case427: Female, 1.5 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

FamilyInfo: Father has DCM

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

HPOsFreeText: Left Ventricular Ejection Fraction at 44.1%, LVDD-Z score at 1.3709

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

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo:

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.2821C>T (p.Arg941Cys)

CAID: CA389046936 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.2821C%3ET

gnomAD: Not in gnomAD

Case392: Male, 0.083 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 29%, LVDD-Z score at 2.1428

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.944A>G (p.Gln315Arg)

CAID: CA389051698 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.944A%3EG

gnomAD: Not in gnomAD

Case378: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

FamilyInfo: Sister has LVNC

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635, HP:0005110 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure, Atrial fibrillation)

HPOsFreeText: Left Ventricular Ejection Fraction at 20%, LVDD-Z score at 0.1

CaseNotHPOs: N/A

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo:

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.1859T>C (p.Leu620Pro)

CAID: CA389049669 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1859T%3EC

gnomAD: Not in gnomAD

Case298: Female, 6 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (Left ventricular noncompaction)

HPOsFreeText: Left Ventricular Ejection Fraction at 65%, LVDD-Z score at 2.1

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.2710C>T (p.Arg904Cys)

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

gnomAD: Ashkenazi Jewish 9.921e-5, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23893328-G-A

Case1: n/a

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened.

Variant: NM_000257.4:c.3158G>A

ClinVar: 155814

CAID: CA013417

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

0.0006368 European - Finnish

Case#: SF No. 28, GC Case No. 21, male, 83

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: No

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric 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

Case#: SF No. 30, GC Case No. 23, female, 31

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: Yes, one affected

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric 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

Case KMP 4: Eastern Slovakia, Female, 69yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular ejection fraction = 60%, New York Heart Association Classification II-III

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 16: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 39-40%, New York Heart Association Classification = I, 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.2845G>A (p.Glu949Lys)

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

gnomAD: n/a

Case KMP 8: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction , left ventricular ejection fraction = 55-60%,

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

MultipleGeneVariants:

(1) SCN5A Variant:

Variant: NM_198056.2(SCN5A):c.3784G>A (p.Gly1262Ser)

ClinVar: 9399, https://www.ncbi.nlm.nih.gov/clinvar/variation/9399/

gnomAD: 0.00002828, https://gnomad.broadinstitute.org/variant/3-38607956-C-T

Case KMP 11: Eastern Slovakia, Female, 57yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: positive family history

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

CaseNotHPOFreeText: left ventricular outflow tract obstruction

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

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

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

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

gnomAD: n/a

Case#: KMP 1, female, 39 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.; ECG; echocardiography

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

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

CAID: n/a

gnomAD: absent

Case#: KMP 16, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVOTO yes; LVEF 39-40%; NYHA I.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

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

CAID: n/a

gnomAD: absent

Case#: KMP 1, female, 39 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.; ECG; echocardiography

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

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

CAID: n/a

gnomAD: absent

Case#: KMP 16, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVOTO yes; LVEF 39-40%; NYHA I.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

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

CAID: n/a

gnomAD: absent

PMID: 32481709

Gene: MYH7

HGNC: 7577

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.2722C>G (p.Leu908Val)

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

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23893316-G-C

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.428G>A (p.Arg143Gln)

ClinVar: 43006, https://www.ncbi.nlm.nih.gov/clinvar/variation/43006/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23901922-C-T

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.611G>A (p.Arg204His)

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

gnomAD: 0.00001767, https://gnomad.broadinstitute.org/variant/14-23900998-C-T

Supplementary Data, Table 2

Variant noted to be present in 3 individuals

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

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

gnomAD: n/a

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.1727A>G (p.His576Arg)

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

gnomAD: 0.00001768, https://gnomad.broadinstitute.org/variant/14-23896955-T-C

Supplementary Data, Table 2

Variant noted to be present in 3 individuals

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

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.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

Supplementary Data, Table 2

Variant noted to be present in 7 individuals

Variant: NM_000257.3(MYH7):c.2093T>C (p.Val698Ala)

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

gnomAD: n/a

Table 1 and 4

Case A36: Female, 49yo

DiseaseAssertion: HCM

FamilyInfo: positive family history

CaseHPOFreeText: interventricular septum thickness = 22mm, left ventricular end diastolic diameter = 42.2mm, left ventricular end systolic diameter = 31.7mm, left ventricular posterior wall thickness = 10.9mm, left atrium = 32mm, left ventricular ejection fraction = 54%

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:c.2654A>C

CAID: CA389047874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047874

gnomAD: n/a

Table 1 and 4

Case A12: Female, 21yo

DiseaseAssertion: HCM

FamilyInfo: positive family history

CaseHPOFreeText: interventricular septum thickness = 25.9mm, left ventricular end diastolic diameter = 32.0mm, left ventricular end systolic diameter = 18.4mm, left ventricular posterior wall thickness = 9.4mm, left atrium = 26.9mm, left ventricular ejection fraction = 75%

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

Supplementary Data Table S3

Case: 210

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.1021T>C (p.Phe341Leu)

CAID: CA389051533 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051533

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYH6 Variant

Variant: NM_002471.3:c.5209A>T (p.Thr1737Ser)

CAID: CA257777730 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257777730

gnomAD: Not in gnomAD

(2) VCL Variant

Variant: NM_014000.2(VCL):c.1907A>G (p.His636Arg)

ClinVar: 45594 https://www.ncbi.nlm.nih.gov/clinvar/variation/45594/

gnomAD: 0.006330, https://gnomad.broadinstitute.org/variant/10-75860740-A-G

Supplementary Data Table S3

Case: 329

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

Supplementary Data Table S3

Case: 154

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

MultipleGeneVariants:

(1) FBN1 Variant

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

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

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

(2) JUP Variant

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

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

gnomAD: 0.01341, https://gnomad.broadinstitute.org/variant/17-39913771-C-T

Supplementary Data Table S3

Case: 204

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

Supplementary Data Table S3

Case: 145

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

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

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

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

MultipleGeneVariants:

(1) 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

(2) 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

Supplementary Data Table S3

Case: 355

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.2945T>C (p.Met982Thr)

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

gnomAD: 0.001416, https://gnomad.broadinstitute.org/variant/14-23892910-A-G

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3413G>A (p.Arg1138His)

ClinVar: 177689 https://www.ncbi.nlm.nih.gov/clinvar/variation/177689/

gnomAD: 0.01063, https://gnomad.broadinstitute.org/variant/11-47354442-C-T

Supplementary Data Table S3

Case: 19

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: 46

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) EYA4 Variant

Variant: NM_004100.5(EYA4):c.1495G>A (p.Val499Ile)

ClinVar: 534385, https://www.ncbi.nlm.nih.gov/clinvar/variation/534385/

gnomAD: 0.0002548, https://gnomad.broadinstitute.org/variant/6-133834170-G-A

(2) FKTN Variant

Variant: NM_006731.2(FKTN):c.1297A>G (p.Thr433Ala)

ClinVar: 36137, https://www.ncbi.nlm.nih.gov/clinvar/variation/36137/

gnomAD: 0.002206, https://gnomad.broadinstitute.org/variant/9-108397456-A-G

Case: 8

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

(1) LAMA4 Variant: c.2593C>G (unknown HGVS descriptor)

ClinVarID: unknown

gnomAD: unknown

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

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.0000601 European (Finnish): 0.0006368

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case: 2

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

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

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.00006010 European Finnish: 0.0006368

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

ClinVarID: 181035

gnomAD: http://gnomad.broadinstitute.org/variant/11-47371630-G-A

Total Allele Frequency: 0.0005896 European (Finnish): 0.005563

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

ClinVarID: 30509

gnomAD: http://gnomad.broadinstitute.org/variant/4-120107298-A-G

Total Allele Frequency: 0.0023 European (Finnish): 0.02188

(4) PSEN2 Variant: NM_012486.2:c.211C>T

ClinVarID: 192130

gnomAD: http://gnomad.broadinstitute.org/variant/1-227071475-C-T

Total Allele Frequency: 0.003711 European (Finnish): 0.01791

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

ClinVarID: 67683

gnomAD: http://gnomad.broadinstitute.org/variant/3-38645378-G-T

Total Allele Frequency: 0.005175 European (Finnish): 0.03855

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case: 8

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

(1) LAMA4 Variant: c.2593C>G (unknown HGVS descriptor)

ClinVarID: unknown

gnomAD: unknown

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

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.0000601 European (Finnish): 0.0006368

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case: 2

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

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

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.00006010 European Finnish: 0.0006368

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

ClinVarID: 181035

gnomAD: http://gnomad.broadinstitute.org/variant/11-47371630-G-A

Total Allele Frequency: 0.0005896 European (Finnish): 0.005563

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

ClinVarID: 30509

gnomAD: http://gnomad.broadinstitute.org/variant/4-120107298-A-G

Total Allele Frequency: 0.0023 European (Finnish): 0.02188

(4) PSEN2 Variant: NM_012486.2:c.211C>T

ClinVarID: 192130

gnomAD: http://gnomad.broadinstitute.org/variant/1-227071475-C-T

Total Allele Frequency: 0.003711 European (Finnish): 0.01791

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

ClinVarID: 67683

gnomAD: http://gnomad.broadinstitute.org/variant/3-38645378-G-T

Total Allele Frequency: 0.005175 European (Finnish): 0.03855

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case: Patient 20, female, 39yo, symptom onset in adulthood

CasePresentingHPOs: HP:0002460, HP:0003327, HP:0003701, HP:0003458 (distal muscle weakness, axial muscle weakness, proximal muscle weakness, EMG: myopathic abnormalities)

HPOsFreeText: normal CK levels, cores present on muscle biopsy

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_000257.3:c.5808G>C

CAID: CA389033338, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389033338

gnomAD: absent

Case1: Male, 27 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy)

HPOsFreeText: 0 SCD risk factors, NYHA class is I, Right ventricular wall thickness 13 mm

CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680, HP:0011675 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease, Arrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.

Variant listed as MYH7-478N. Typo is suspected, below is the entry for MYH7-I478N, the actual variant at this location

Variant: NM_000257.3:c.1433T>A (p.Ile478Asn)

CAID: CA389050614 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1433T%3EA

gnomAD: Not in gnomAD

MultipleGeneVariants:

TTN Variants:

Unknown Variant

Variant1: TTN-S3872fs

CAID: N/A

gnomAD: N/A

Unknown Variant

Variant2: TTN-S6350A

CAID: N/A

gnomAD: N/A

Unknown Variant

Variant3: TTN-P10663R

CAID: N/A

gnomAD: N/A

ACTN2 Variant

Unknown Variant

Variant: ACTN2-P32fs

CAID: N/A

gnomAD: N/A

CaseMYH7-21: Australia

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

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.2389G>A (p.Ala797Thr)

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

gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894525-C-T

CaseMYH7-34: 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.1370T>C (p.Ile457Thr)

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

gnomAD: European (Non-Finnish) 8.790e-6, Overall 3.976e-6 https://gnomad.broadinstitute.org/variant/14-23898201-A-G

CaseMYH7-25: Australia

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

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.2207T>C (p.Ile736Thr)

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

gnomAD: Not in gnomAD

CaseMYH7-28: 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.2155C>T (p.Arg719Trp)

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

gnomAD: European (Non-Finnish) 6.481e-5, Overall 3.185e-5 https://gnomad.broadinstitute.org/variant/14-23895180-G-A

CaseMYH7-36: 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.1208G>A (p.Arg403Gln)

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

gnomAD: Not in gnomAD

CaseMYH7-24: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

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

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

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

gnomAD: Not in gnomAD

CaseMYH7-6: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 2 other probands have this genotype

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.4135G>A (p.Ala1379Thr)

ClinVar: 42993 https://www.ncbi.nlm.nih.gov/clinvar/variation/42993/

gnomAD: Latino 2.822e-5, Overall 3.535e-6 https://gnomad.broadinstitute.org/variant/14-23887453-C-T

CaseMYH7-37: 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.1207C>T (p.Arg403Trp)

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

gnomAD: Not in gnomAD

CaseMYH7-13: 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.3064A>G (p.Lys1022Glu)

CAID: CA389045738 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.3064A%3EG

gnomAD: Not in gnomAD

PMCID: 32040801

Gene: MYH7

HGNC: 7577

"The purpose of this article is to summarize current data regarding all HCM phenotypes, from genetics to pathogenesis, clinical manifestations, diagnosis, and treatment."

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.2332G>A (p.Asp778Asn)

ClinVarID: 181369 https://www.ncbi.nlm.nih.gov/clinvar/variation/181369/

gnomAD: Not in gnomAD

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

VariantAddInfo: Seen in one proband

Variant: NM_000257.4(MYH7):c.1231G>A (p.Val411Ile)

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

gnomAD: 0.00005643, http://gnomad.broadinstitute.org/variant/14-23898464-C-T

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.2360G>A (p.Arg787His)

ClinVar: 42900 https://www.ncbi.nlm.nih.gov/clinvar/variation/42900/

gnomAD: 0.001339, http://gnomad.broadinstitute.org/variant/14-23894554-C-T

DiseaseAssertion: Cardiomyopathy

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

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 305 PanCM 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 PanCM proband

Variant: NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys)

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

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.2156G>A (p.Arg719Gln)

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

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 probands

Variant: NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)

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

gnomAD: Not in gnomAD

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

VariantAddInfo: Seen in one HCM probands

Variant: NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)

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

gnomAD: Not in gnomAD

Case1: male, 38, caucasian

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

GenotypingMethod: the presence of p.M659I (c.1977G > A) mutation in the iPSC lines was confirmed by Sanger sequencing of exon 18 of MYH7 (Fig. 1F).

Variant: NM_000257.4:c.1977G>A

ClinVar: not found

CAID: CA389049400

gnomAD: not found

Case: HCM mutation carrier

DiseaseAssertion: Hypertrophic cardiomyopathy

CasePresentingHPOs: n/a

CasePreviousTesting: n/a

CaseGenotypingMethod: n/a

Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His), variant noted to be in 2 individuals utilized in this study

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

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

Case1: 3 year old female

DiseaseAssertion: LVNC

FamilyInfo: sister and brother diagnosed with Ebstein's anomaly, LVNC, and VSD, and same novel mutation was identified in sister, brother, and father

CasePresentingHPOs: HP:0031664, HP:0010316, HP:0001631, HP:0002789, HP:0001649, HP:0001680

"Systolic heart murmur, Ebstein anomaly of the tricuspid valve, Atrial septal defect, Tachypnea, Tachycardia, Coarctation of aorta

CaseHPOFreeText: precordial systolic murmur at 4 days old, moderate tricuspid valve insufficiency, right heart enlargment, membranous VSD, feeding poorly at 11 days

CasePreviousTesting: No mutations were identified in the TAZ, LMNA/C, MYBPC3, TNNT2, TNNI3, ACTC, and TPM1 genes

GenotypingMethod: Sequence analysis of MYH7

Variant: NM_000257.4:c.1085T>G

ClinVar: not found

CAID: CA389051391

gnomAD: not found

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

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

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

Variant: NM_000257.3(MYH7):c.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 Data table 1

Variant noted to be present in 3 individuals

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

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

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

Supplementary Data 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.3100-2A>C

CAID: CA035633, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA035633

gnomAD: 0.00002475, https://gnomad.broadinstitute.org/variant/14-23891536-T-G

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.2945T>C (p.Met982Thr)

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

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

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1727A>G (p.His576Arg)

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

gnomAD: 0.00001768, https://gnomad.broadinstitute.org/variant/14-23896955-T-C

Case: Pedigree 2 proband, male, 37yo at diagnosis, Iraqi‐Jewish

CasePresentingHPOs: HP:0001639, HP:0005110, HP:0001708, HP:0005180 (hypertrophic cardiomyopathy, atrial fibrillation, right heart failure, tricuspid regurgitation)

HPOsFreeText: clinical severity: moderate to asymptomatic

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: Fifty‐six genes known to cause HCM were sequenced in parallel

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

FamilyInfo: older brother had sudden death at 33yo with postmortem diagnosis of HCM, patient's siblings, aged 67 and 70, were also found to be heterozygous for this variant, though they are both clinically asymptomatic with no echocardiographic evidence of HCM

Case#: 7

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: HP:0032092, HP:0031656, HP:0004756 (LV outflow tract obstruction, systolic anterior motion of the mitral valve, ventricular tachycardia)

CaseHPOFReeText: preserved ejection fraction (EF >60%)

Variant: NM_000257.4:c.1432A>G

ClinVar: 181347 https://www.ncbi.nlm.nih.gov/clinvar/variation/181347/

CAID: PA296828

gnomAD: not found

Case#: 6

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: HP:0032092, HP:0031656, HP:0025168 (LV outflow tract obstruction, systolic anterior motion of the mitral valve, diastolic dysfunction)

CaseHPOFReeText: preserved ejection fraction (EF >60%)

Variant: NM_000257.3:c.1988G>A

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

CAID: PA097667

gnomAD: 0.00003097 European (Non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T

PMID: 23727574

Gene: MYH7

HGNC: 7577

PMID: 24119082

Gene: MYH7

HGNC: 7577

24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2, and 13 in TTN) affecting 52 subjects in 25 families:

MYH7 (c.2945 T>C, p.M982T; c.4300 C>T, p.R1434C; c.4498 C>T, p.R1500W)

Case: male, 44yo at diagnosis

DiseaseAssertion: Dilated cardiomyopathy (DCM)

CasePresentingHPOs: HP:0012664, HP:0001635, HP:0100598, HP:0001324, HP:0003388 (reduced ejection fraction, heart failure, pulmonary oedema, muscle weakness, fatigability)

HPOsFreeText: reduced LVEF (=29%), diagnosed with congenital myopathy at 36yo, LVIDD = 74mm, creatine kinase < 600 U/l, ICD implantation, waiting heart transplantation at 48yo

CaseNotHPOs:

NotHPOsFreeText: anti-tachycardia pacing or shock therapy from the ICD

CasePreviousTesting: ACTA1, BIN1, DNM2, MYH7, MTM1, NEB, RYR1, SCN4A, SEPN1, TPM2, TPM3

CaseGenotypingMethod: PCR amplification of exons of genes investigated and Sanger sequencing or NGS

Variant: NM_000257.4(MYH7):c.5401G>A (p.Glu1801Lys)

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

gnomAD: absent

Case#: HCM506, male, 19 yr, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 48mm LAD, 20mm LVST, 43mm LVEDD, 75% LVEF, 21mm Maxi LVWT, 59mmHg Maxi LVOTG, 104464396 raw RNA-seq reads, 98442104 HQ reads (94.24%), 96.88% mapping rate, 721500 total variant, 33453 exonic variant

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

CAID: N/A

gnomAD: 0.00001548 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case#: HCM957, male, 30 years,

DiseaseAssertion: HCM

FamilyInfo: Yes, no other HCM in family

CasePresentingHPOs: syncope (HP:0001279)

CaseHPOFreeText: inverted T-waves, ST-segment depression, left anterior branch block, 28mm MLVWT, 58% LVE F, 1.25 E/A ratio, LVOT-PG 7mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

MultipleGeneVariants:

(1) Variant: NM_000257.4(MYH7):c.2360G>A (p.Arg787His)

ClinVar: 42900 https://www.ncbi.nlm.nih.gov/clinvar/variation/42900/

CAID: N/A

gnomAD: 0.001339 South Asian https://gnomad.broadinstitute.org/variant/14-23894554-C-T

(2) Variant: NM_000257.4(MYH7):c.5561C>T (p.Thr1854Met)

ClinVar: 161320 https://www.ncbi.nlm.nih.gov/clinvar/variation/161320/

CAID: N/A

gnomAD: 0.00005423 European (Non-Finnish) https://gnomad.broadinstitute.org/variant/14-23883310-G-A

Case#: HCM275, male, 59 years, I-1

DiseaseAssertion: HCM

FamilyInfo: Yes, daughter has HCM

CasePresentingHPOs: syncope (HP:0001279)

CaseHPOFreeText: inverted T-waves, ST-segment depression, 28mm MLVWT, 65% LVE F, 1.3 E/A ratio, LVOT-PG 68mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

MultipleGeneVariants:

(1) Variant: NM_000257.4(MYH7):c.2081G>A (p.Arg694His)

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

CAID: N/A

gnomAD: 0.00004008 African/African-American https://gnomad.broadinstitute.org/variant/14-23895254-C-T

(2) Variant: NM_000257.4(MYH7):c.4985G>A (p.Arg1662His)

ClinVar: 43049 https://www.ncbi.nlm.nih.gov/clinvar/variation/43049/

CAID: N/A

gnomAD: 0.0002894 Ashkenazi Jewish https://gnomad.broadinstitute.org/variant/14-23885010-C-T

Case#: II-9, female, 46 yrs

DiseaseAssertion: HCM

FamilyInfo: Yes, 2 siblings and niece have HCM

CasePresentingHPOs: chest tightness, palpitations (HP:0031352, HP:0001962)

CaseHPOFreeText: T flattened and inverted and left axis deviation (-48 degrees), 22mm MLVWT, 63% LVE F, 1.29 E/A ratio, LVOT-PG 4mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

MultipleGeneVariants:

(1) Variant: absent (MYH7- A934V)

ClinVar: N/A

CAID: CA389047003

gnomAD: absent

(2) Variant: NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

CAID: N/A

gnomAD: 0.00003266 South Asian https://gnomad.broadinstitute.org/variant/14-23887429-C-T

Supplementary Data: Online Table 2a

Case:

CasePresentingHPOs: HP:0001642 (pulmonary stenosis)

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.1325G>A (p.Arg442His)

ClinVar: 181342, https://www.ncbi.nlm.nih.gov/clinvar/variation/181342/

gnomAD: 0.00001414, https://gnomad.broadinstitute.org/variant/14-23898246-C-T

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.1245_1247dup

CAID: CA913184873, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184873

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.5773C>G

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

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.4048_4050del

CAID: CA913184874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184874

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.2085_2097dup

CAID: CA704294509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2085_2097dup

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.902T>A

CAID: CA389051788, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051788

gnomAD: n/a

Supplementary Data: Online Table 1a

Case:

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

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

Variant: NM_000257.3(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

Supplementary Data: S2 Table

Case 13: Spanish, 21yo, 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.920C>G

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

gnomAD: n/a

Supplementary Data: S2 Table

Case 135: 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(MYH7):c.958G>A (p.Val320Met)

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

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23899810-C-T

Supplementary Data: S2 Table

Case 39: Spanish, 33yo, 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.1168C>G

CAID: CA389051200, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051200

gnomAD: n/a

Supplementary Data: S2 Table

Case 193: Spanish, 47yo, 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

Supplementary Data: S2 Table

Case 121: 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, Next-gen sequencing panels of 55 or 78 genes

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

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

gnomAD: n/a

MultipleGeneVariants:

(1) TTN Variants:

Variant1: NM_133378.4(TTN):c.52301A>G

ClinVar: 47157, https://www.ncbi.nlm.nih.gov/clinvar/variation/47157/

gnomAD: 0.0005511, https://gnomad.broadinstitute.org/variant/2-179456541-T-C

Variant2: NM_133378.4:c.50516C>G

CAID: CA349508241, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.50516C%3EG

gnomAD: n/a

Supplementary Data: S2 Table

Case 160: Spanish, 67yo, 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.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:c.78641C>T

CAID: CA1988519, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_133378.4%3Ac.78641C%3ET

gnomAD: 0.00001646, https://gnomad.broadinstitute.org/variant/2-179424514-G-A

Supplementary Data: S2 Table

Case 2: 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, PCR, Sanger 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