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

CaseST4-90: Sweden

DiseaseAssertion: Idiopathic Dilated Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy)

HPOsFreeText: N/A

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

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

CaseAddInfo: N/A

CasePreviousTesting: See Supplemental Table 1

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

Variant: NM_000257.3:c.2776C>G (p.Leu926Val)

CAID: CA034272 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2776C%3EG

gnomAD: South Asian 1.307e-4, Overall 1.591e-5 https://gnomad.broadinstitute.org/variant/14-23893262-G-C

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

CaseDW: 16 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One affected relative, Father, died suddenly

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 21 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.937A>T (p.Ile313Phe)

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

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

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

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

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

Supplementary Material 4

Case M-3: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Supplementary Material 4

Case M-5: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.1012G>A (p.Val338Met)

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

gnomAD: n/a

Supplementary Material 4

Case M-17: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

gnomAD: n/a

Supplementary Material 4

Case M-13: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.2011C>T (p.Arg671Cys)

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

gnomAD: n/a

Supplementary Material 4

Case M-7: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

gnomAD: n/a

Supplementary Material 4

Case M-24: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.2546T>C (p.Met849Thr)

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

gnomAD: n/a

Supplementary Material 4

Case M-4: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.746G>A (p.Arg249Gln)

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

gnomAD: n/a

Case: Pedigree 5 proband, 28yo at diagnosis, Turkish-Jewish

CasePresentingHPOs: HP:0001639, HP:0001645, HP:0001712, HP:0001279, HP:0001653 (hypertrophic cardiomyopathy, sudden cardiac death, left ventricular hypertrophy, syncope, mild mitral regurgitation)

HPOsFreeText: clinical severity: asymptomatic, LVOT obstruction, anterior septal thickness of 16 mm with dynamic obstruction, normal EF of 60%, asymmetrical hypertrophy on MRI, septal wall thickness of 25 mm, normal sinus rhythm, ventricular premature beats

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: NGS (Health in Code, commercial 7-gene panel), contains genes known to cause HCM

Variant: NM_000257.4:c.2605C>T (p.Arg869Cys)

CAID: CA012714, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA012714

gnomAD: n/a

MultipleGeneVariants:

(1) MYL2 Variant:

Variant: NM_000432.3(MYL2):c.304G>A (p.Ala102Thr)

ClinVar: 626792, https://www.ncbi.nlm.nih.gov/clinvar/variation/626792/

gnomAD: 0.00001193, https://gnomad.broadinstitute.org/variant/12-111351099-C-T

FamilyInfo: no family history of cardiomyopathy, maternal grandfather died suddenly at 52yo

Case: Pedigree 1 proband, male, 11yo at diagnosis, Iraqi‐Jewish

CasePresentingHPOs: HP:0001639, HP:0004756, HP:0005110, HP:0002094, HP:0001712 (hypertrophic cardiomyopathy, ventricular tachycardia, atrial fibrillation, dyspnea, left ventricular hypertrophy)

HPOsFreeText: clinical severity: moderate to asymptomatic, systolic murmur, NYHA Class II, maximal wall thickness at the anterior septum = 30 mm, resting LVOT gradient of 35 mmHg, increasing to 48 mmHg, normal LV systolic function, estimated ejection fraction (EF) of 65%, Grade II (moderate) LV diastolic dysfunction, ECH showed sinus rhythm, LV strain, inverted T waves, eptal wall thickness of 31 mm, extensive late gadolinium enhancement involving 45% of the left ventricle

CaseNotHPOs: HP:0001279 (syncope)

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: mother was heterozygous for variant, she was asymptomatic, had mild nonobstructive hypertrophy, hypertension, and anterior septal thickness of 13 mm

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

PMID: 23991079

Gene: MYH7

HGNC: 7577

"we here applied un-biased transcriptome-wide interrogation to identify molecular changes associated with novel SLP."

Case: Male, born at 38 weeks gestation

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0030718, HP:0001667, HP:0002092, HP:0001670, HP:0200128 (enlarged right atrium, right ventricular hypertrophy, pulmonary hypertension, asymmetric septal hypertrophy, biventricular hypertrophy)

CaseHPOFreeText: birth weight = 3.283kg, apgar scores = 8,9, asymmetric septal hypertrophy of atrioventricular septum without outflow tract obstruction or myocardial scarring, confirmed diagnosis of HCM at 6mo

CaseNotHPOs: HP:0011611, HP:0001653, HP:0004308, HP:0005115 (aortic obstruction, mitral valve insufficiency, ventricular arrhythmia, supraventricular arrhythmia)

FamilyInfo: Both parents and only sibling underwent genetic testing, the father and brother harbored the same variant as the patient (p.Ala1328Thr), this variant was absent in the mother. Father (36yo) and brother (5yo) had normal echocardiograms.

CasePreviousTesting: fetal echocardiography at 32wks, postnatal echocardiography, routine cardiac follow-up at 6mo, cardiac MRI, 24hr Holter monitor, Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (CAV3, MTTG, MTTI, MTTK, MTTQ, TNNC1, TTR, PKRAG2, LAMP2, GLA)

CaseGenotypingMethod: blood and buccal cell samples collected from patient, coding regions and splice junctions of 18 genes were enriched with a proprietary targeted capture system by GeneDx, these then underwent NextGen sequencing, capillary sequencing used to confirm potentially pathogenic variants

Variant: NM_000257.3(MYH7):c.3982G>A (p.Ala1328Thr)

ClinVar: 42985, https://www.ncbi.nlm.nih.gov/clinvar/variation/42985/

gnomAD: 0.00002154, https://gnomad.broadinstitute.org/variant/14-23887606-C-T

InheritancePattern: autosomal dominant

PMID: 28790153

Gene: MYH7

HGNC:7577

Supplementary Data: S2 Table

Case 234: Spanish, 50yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3:c.2312G>C

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

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

Supplementary Data: S2 Table

Case 251: Spanish, 55yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.3610G>C (p.Gly1204Arg)

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

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

Supplementary Data: S2 Table

Case 10: Spanish, 69yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

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

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

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

Supplementary Data: S2 Table

Case 130: Spanish, 14yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.2167C>G (p.Arg723Gly)

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

gnomAD: n/a

MultipleGeneVariants:

(1) TCAP Variant:

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

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

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

Supplementary Data: S2 Table

Case 67: Spanish, 40yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.2389G>A (p.Ala797Thr)

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

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

MultipleGeneVariants:

(1) TTN Variant:

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

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

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

Case III.4: Female, age 30

DiseaseAssertion: Distal myopathy

FamilyInfo: Figure 1, similar distal muscle weakness in four relatives. Patients I.2 and II.2 experienced foot drop while walking. Patient III.2 muscle biopsy findings suggestive of core myopathy suggested a disorder similar to his youngest sister. Patient IV.1 displayed a less progressive muscular phenotype than her older relatives and tested negative for the mutation in RYR1

CasePresentingHPOs: HP:0001761, HP:0008994, HP:0002650

"Pes cavus, Proximal muscle weakness in lower limbs, Scoliosis"

CaseHPOFreeText: stepping gait

CasePreviousTesting: muscle biopsy showed fiber size variability, increased internal nuclei and histochemical evidence of eccentric core-like lesions, Analysis of RYR1 revealed a heterozygous c.880G > A:p.(Glu294Lys) mutation

GenotypingMethod: Amplicon-based Sanger sequencing, MotorPlex used to analyze a large set of genes that cause known forms of non-syndromic muscle disorders

MultipleGeneVariants:

(1) MHY7Variant: Novel

Variant: NM_000257.4:c.4303T>C

ClinVar: not found

CAID: CA389040164

gnomAD: not found

(2) RYR1Variant:

Variant: NM_000540.2:c.880G>A

ClinVar: 590621

CAID: CA072725

gnomAD: https://gnomad.broadinstitute.org/variant/19-38939074-G-A?dataset=gnomad_r2_1

Total allele frequency: 0.00006159 European (non-Finnish)

Table 5

Case EO9: Italian

DiseaseAssertion: HCM (early-onset)

FamilyInfo: positive family history

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography

CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing

Variant: NM_000257.3:c.2146G>C

CAID: CA389049033, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049033

gnomAD: n/a

MultipleGeneVariants:

(1) MYBPC3 Variant:

Variant: NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp)

ClinVar: 164114, https://www.ncbi.nlm.nih.gov/clinvar/variation/164114/

gnomAD: n/a

Table 5

Case EO32: Italian

DiseaseAssertion: HCM (early-onset)

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2, TNNC1, MYH6, CSPR3, PLN, TCAP, CAV3), electrocardiography

CaseGenotypingMethod: Genomic DNA extracted from periphera whole blood, emulsion PCR, 17 HCM genes sequenced using Personal Genome Machine (PGM) IonTorrent sequencer, variants confirmed via Sanger sequencing

Variant1: 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

MultipleGeneVariants:

(1) MYPBC3 Variant:

Variant: NM_000256.3(MYBPC3):c.3192dupC (p.Lys1065Glnfs)

ClinVar: 42693, https://www.ncbi.nlm.nih.gov/clinvar/variation/42693/

gnomAD: n/a

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#: 30

DiseaseAssertion: LVNC

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: 3.31 fathom, 0.002 sift, 0.997 polyphen, 0 GVGD, mutation taster 1, -2.08 provean, -4.22 CADD

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, variant screening and classification, genic collapsing test, group statistical analysis

Variant: NM_000257.4(MYH7):c.67C>T (p.Arg23Trp)

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

CAID: N/A

gnomAD: 0.00007961 European/Finnish https://gnomad.broadinstitute.org/variant/14-23902875-G-A

Case#: 28

DiseaseAssertion: LVNC

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: 7 sift, 0.969 polyphen, C65 GVGD, mutation taster 1, -4.06 provean, -6.25 CADD

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, variant screening and classification, genic collapsing test, group statistical analysis

Variant: NM_000257.3:c.1859T>C

ClinVar: absent

CAID: CA389049669

gnomAD: absent

Case339: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

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

Variant: NP_000248.2:p.Lys542Asn

CAID: N/A

gnomAD: N/A

Case377: Female, 0.0833 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

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

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.2078T>G (p.Leu693Arg)

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

gnomAD: Not in gnomAD

Case391: Female, 0.83 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

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

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.5401G>A (p.Glu1801Lys)

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

gnomAD: Not in gnomAD

Case362: Female, 0.0833 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 40%, LVDD-Z score at -0.823

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

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

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

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

gnomAD: Not in gnomAD

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 II-1: Italian, Male,

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs:

CaseHPOFreeText: interventricular septal and/or posterior wall thickness in end-diastole ≥15 mm

CasePreviousTesting: M-mode-2D and color-Doppler study to analyze cardiac chamber dimensions, global systolic and diastolic function, valve and great arteries anomalies, echocardiography,

CaseGenotypingMethod: exon 23 and flanking regionals analyzed via Sanger Sequencing, Variants found via exome sequencing tested for segregation in family by Sanger sequencing on an ABI PRISM 3130 DNA sequencer

Variant: NM_000257.3:c.2795T>A

CAID: CA389047028, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047028

gnomAD: n/a

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 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

CaseR147S: 52 year old male

DiseaseAssertion: HCM

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

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

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

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

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

ClinVar: 643664

CAID: CA389052814

gnomAD: not found

Case: proband, 2mo

DiseaseEntity: Left ventricular noncompaction (LVNC)

CasePresentingHPOs: HP:0001635 (congestive heart failure)

HPOsFreeText: required mechanical ventilation and inotropic support, depressed left ventricular function, deep left ventricle trabeculations

FamilyInfo: sibling with fetal demise at 24wks gestation due to pulmonary hypoplasia and biventricular noncompaction with deep recesses in myocardial walls of both ventricles, right ventricular dilation, and widespread fibrosis; signs of LVNC also present in 4yo sibling and father, paternal grandfather had history of arrhythmia

CaseGenotypingMethod: WES

Variant: NM_000257.4(MYH7):c.1159C>T (p.Leu387Phe)

ClinVar: 524975, https://www.ncbi.nlm.nih.gov/clinvar/variation/524975/

gnomAD: absent from gnomAD

MultipleGeneVariants:

(1) MLK2 Variant

Variant: NM_001308142.1:c.2010G>C

CAID: CA394829003, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA394829003

gnomAD: absent

(2) NKX2-5 Variant

Variant: NM_004387.4(NKX2-5):c.355G>T (p.Ala119Ser)

ClinVar: 9018, https://www.ncbi.nlm.nih.gov/clinvar/variation/9018/

gnomAD: 0.0009792, https://gnomad.broadinstitute.org/variant/5-172660192-C-A?dataset=gnomad_r2_1

Case#: DCM-12, female, Yunnan, China

DiseaseAssertion: DCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: physical exam, invasive examination, ECG,

CaseGenotypingMethod: NGS and Sanger Sequencing

Variant: NM_000257.4(MYH7):c.77C>T (p.Ala26Val)

ClinVar: 37375 https://www.ncbi.nlm.nih.gov/clinvar/variation/37375/

CAID: n/a

gnomAD: absent

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

4 mutations in MYH7 reported but no case information

(R204H, M493V, R719W, and R870H)

Case III-4: Female, 4yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: myocardium lesion, suspected double-chambered left ventricle, asymptomatic, normal thickness of septum and left ventricle, fibromuscular tissues left ventricular apex, left ventricle ventricle end-diastolic diameter = 38.4mm, left ventricular ejection fraction = 64%

CasePreviousTesting: same as proband

CaseGenotypingMethod: segregation analysis using the results from Sanger sequencing

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

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

gnomAD: n/a

PMID: 23713052

Gene: MYH7

HGNC: 7577

PMID: 24047955

Gene: MYH7

HGNC: 7577

"It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo."

Results suggest that small effects of mutations on helicity translate into a reduced ability to incorporate into sarcomeres, which may elicit compensatory hypertrophy.

Case1: female, 15 years old at last clinical evaluation

DiseaseAssertion: LVH, HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: cleft mitral valve during intrauterine life

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: evaluated previously by using a DHPLC/Sanger test to search for causative mutations within the exons of 8 sarcomeric genes: MYH7, MYBPBC3, TNNI3, TNNT2, TPM1, ACTC, MYL2, and MYL3

GenotypingMethod: Next generation sequencing, High-Throughput Sequencing

Variant: NM_000257.4:c.976G>C

ClinVar: 43117

CAID: CA017063

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

0.0001627 European (non-Finnish)

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: 25448463

Gene: MYH7

HGNC: 7577

CaseCM1856: Male, 15 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother with an ECG abnormality and 2 brothers with HCM tested positive for this variant, Father with no phenotypes tested negative for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.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

CaseCM1829: Male, 12 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Variant is asserted as novel, Mother and father are both negative for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.2459C>A (p.Ala820Asp)

CAID: CA389048368 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2459C%3EA

gnomAD: Not in gnomAD

PMID: 32160020

Gene: MYH7

HGNC: 7577

The goal of this study was to adjust the framework for interpreting MHY7 variants. In 97 probands and 2059 variants, they found that "15/97 (15.5%) probands have likely pathogenic/P variants."

Variant information found in Table 3.

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: 32607476

Gene: MYH7

HGNC: 7577

Case1: 12 year old boy

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: parents were clinically normal, and there was no family history of HCM

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Chest radiography showed protrusion of left third and fourth arches and the cardio-thoracic ratio was 0.50. Two-dimensional echocardiogram showed asymmetrical hypertrophy of the LV. Laboratory examinations showed elevated serum levels of brain natriuretic peptide. Cardiovascular magnetic resonance imaging revealed a markedly thickened IVS and decreased wall motion.

GenotypingMethod: DNA samples were extracted from the peripheral blood ofthe patient and his parents for use as templates to identify mutations in the genes for sarcomeric proteins. All PCR products were analysed for sequence variations by direct DNA sequencing of both strands. Direct sequencing of coding exons of MYH7.

Variant: NM_000257.4:c.2459C>A

ClinVar: 657112

CAID: CA389048368

gnomAD: not found

Case1: patient 1, 68 years old, male

DiseaseAssertion: HCM

FamilyInfo: positive family history of SCD and end stage heart failure

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: multiplex targeted high‐throughput sequencing, DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing

VariantMYH7: NM_000257.4:c.4130C>A

ClinVar: not found

CAID: CA389040836

gnomAD: not found

VariantMYBPC3:

ClinVar: 42813

CAID: CA016212

gnomAD: https://gnomad.broadinstitute.org/variant/11-47367871-C-T

0.01364 European (Finnish)

Supplementary Data: Table S3

Case 64:

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.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: g.179407388delC no ClinVar or CAID

CasePT-111: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.563C>A (p.Thr188Asn)

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

gnomAD: Not in gnomAD

Case#: D15, male, 43 years

DiseaseAssertion: FDCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)

ClinVar: 43005 https://www.ncbi.nlm.nih.gov/clinvar/variation/43005/

CAID: N/A

gnomAD: absent

Case#: a 9-year-old boy

DiseaseAssertion: Hypertrophic obstructive cardiomyopathy (HOCM) during clinical screening, presence of the familial mutation in the MYL2 gene MYL2, c.487G > A [p.(Glu163Lys) as pathogenic.

FamilyInfo: a family history of sarcomeric HCM who was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) during clinical screening. His father suffered from HCM and died 6 years ago in his 3rd decade due to a stroke. The paternal grandfather of the proband and his sister were also diagnosed with HCM. Other affected family members included a paternal uncle and his son as well as a paternal aunt and her son. Genetic testing of the latter family members revealed a mutation in the MYL2 gene.

ParentalTesting: Yes the family members

CasePresentingHPOs: HP:0034313, HP:0031666, HP:0001670

CaseHPOFreeText: He was well and asymptomatic. His weight was 44.6 kg (93rd centile) and height was 150.5 cm (94th centile); heart rate was 60 b.p.m. and right arm blood pressure was 111/67 mmHg with a mean arterial pressure of 83 mmHg. On auscultation, a 2/6 systolic murmur in the 3rd intercostal space at the left sternal edge was audible. N-terminal prohormone of brain natriuretic peptide level was 434 ng/L (normal range <112 ng/L). The echocardiogram showed asymmetric septal hypertrophy (maximal wall thickness 18 mm) of the left ventricle (LV) with mild flow acceleration in the mid-LV cavity (peak systolic velocity 2.6 m/s) consistent with HOCM. Left ventricle systolic function was hyperdynamic with LVEF of 80%. Late gadolinium enhancement (LGE) imaging showed an area of patchy LGE at the level of the maximal LV wall thickness (Figure 4).

CaseNotHPOs: HP:0001635 , HP:0001279, HP:0031656, HP:0001653

CaseNotHPOFreeText: No signs of congestive heart failure and no history of syncope. No systolic anterior movement (SAM) and no mitral regurgitation.

CasePreviousTesting: Clinical screening

Genotyping Method: Genetic testing confirmed

FunctionalAnalysis: NR

Variant: NM_000432.4:c.487G>A

ClinVar: 1051330

CAID: CA386696712

gnomAD: NR

AdditionalInfo: NR

PMID: 41488457

Gene: MYBPC3

HGNC ID: 7551

PMID: 35288424

Gene: MLY3

HGNC ID: 7584

PMID: 42074559

Gene: MYL2

HGNC ID: 7583

PMID: 35717150 Gene: MYBPC3 HGNC ID: 7551

PMID: 41033995 Gene: ACTC1 HGNC: 143

PMID: 36945405

Gene: ACTC1

HGNC ID: 143

CaseP4-GAA: female, ethnicity = European, country origin = Italy

CasePresentingHPOs:

HPOsFreeText: enzyme activity = 2.22

CaseNotHPOs: HP:0010899, HP:0010916, HP:0003236

CaseAddInfo: homozygous

CasePreviousTesting: initial and confirmatory DBS, biochemical tests

CaseGenotypingMethod: mutation analyses

Variant: NM_000152.4(GAA):c.533G>A (p.Arg178His)

ClinVar: 554969; https://www.ncbi.nlm.nih.gov/clinvar/variation/554969/

gnomAD: 2.646e-05, http://exac.broadinstitute.org/variant/17-78078918-G-A

Patient25: Male, 15 years report, 2 years onset

CasePresentingHPOs: HP:0002527 (Falls)

HPOsFreeText: GAA activity 5.6% from leukocyte

CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient6: Male, 5 years report, 1 month onset

CasePresentingHPOs: HP:0001640, HP:0001324, HP:0002098 (Cardiomegaly, Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.8% from leukocyte, Wheelchair needed, Respiratory Assistance needed

CaseNotHPOs: HP:0002240 (Hepatomegaly)

NotHPOsFreeText: N/A

CaseAddInfo: IOPD

Patient24: Female, 17 years report, 15 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 4.6% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

PMID: 31510962

Gene:GAA

Case#: Patient 4, Gender N/A, onset at 3-4 months. Died at 9 months, Southeast Asian

DiseaseAssertion:Pompe disease

FamilyInfo: N/A

CasePresentingHPOs: HP:0002094 HP:0001639. HP:0005165, HP:0001270 (Hypertrophic Cardiomyopathy, Dyspnea, Shortened PR interval, Motor delay )

CaseHPOFreeText: BVH, Died from dehydration (diarrhea)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: GAA activity in leukocytes was 0% of normal control value.

PCR of all exons was performed and subsequently subjected to capillary Sanger sequencing in both directions

Variant 1: c.1225dup (p.Asp409GlyfsX95)

ClinVar: N/A

CAID: CA923726362

gnomAD: N/A

Variant 2: c.2024_2026delACA (p.Asn675del)

ClinVar: 189006

CAID: CA274244

gnomAD: Highest population MAF = 0.0001106 (East asians)

ParentalGenotype: Father was carrier for Variant1 c.1226insG (p.Asp409GlyfsX95)

Mother was carrier of Variant 2 c.2024_2026delACA (p.Asn675del)

PreviouslyPublished: N/A

Case#: Subject number 11, male, 51 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.21 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.2104C>T (p.Arg702Cys)

Variant 2 ClinVarID: 189040

Variant 2 CAid: CA274304

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 15, male, 58 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0003546 (Exercise intolerance), HP:0002153 (hyperkalemia)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.31 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.655G>A (p.Gly219Arg)

Variant 2 ClinVarID: 189065

Variant 2 CAid: CA274334

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 14, female, 58 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0001324 (muscle weakness), HP:0001252 (Hypotonia)

CaseHPOFreeText:

CaseNotHPOs: HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea), HP:0001638 (cardiomyopathy), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002153 (hyperkalemia), HP:0002098 (respiratory distress)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.33 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.-32-13T>C

Variant 2 ClinVarID: 4027

Variant 2 CAid: CA116606

Zygosity: homozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 19, male, 63 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness)

CaseHPOFreeText:

CaseNotHPOs: HP:0001638 (cardiomyopathy), HP:0003546 (Exercise intolerance), HP:0001252 (Hypotonia), HP:0003326 (Myalgia), HP:0002015 (dysphagia), HP:0002098 (respiratory distress), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.47 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.2065G>A (p.Glu689Lys)

Variant 1 ClinVarID: 4030

Variant 1 CAid: CA116612

Variant 2: N/A

Variant 2 ClinVarID: N/A

Variant 2 CAid: N/A

Zygosity: Heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Subject number 17, male, 64 years (report)

DiseaseAssertion: Pompe disease

FamilyInfo: No known family member with PD

CasePresentingHPOs: HP:0002153 (hyperkalemia), HP:0001324 (muscle weakness), HP:0003326 (Myalgia), HP:0002015 (dysphagia)

CaseHPOFreeText:

CaseNotHPOs: HP:0001252 (Hypotonia), HP:0001638 (cardiomyopathy), HP:0002098 (respiratory distress), HP:0003546 (Exercise intolerance), HP:0002094 (dyspnoea)

CaseNotHPOFreeText: no biopsy, not asymptomatic

CasePreviousTesting: "Enzymatic activity was detected by fluorometric techniques" "The GAA sequence was performed in all patients whose enzyme activity measured in DBS and lymphocytes was decreased."

glucosidase activity: GAA activity was 0.54 mol/Lh in dried blood spots (normal range >0.75).

Variant 1: NM_000152.5(GAA):c.-32-13T>C

Variant 1 ClinVarID: 4027

Variant 1 CAid: CA116606

Variant 2: NM_000152.5(GAA):c.875A>G (p.Tyr292Cys)

Variant 2 ClinVarID: 370577

Variant 2 CAid: CA16041886

Zygosity: Compound heterozygous

ParentalGenotype: N/A

PreviouslyPublished: N/A

Patient23: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: 1.688e-05, http://exac.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.4(GAA):c.2024_2026delACA (p.Asn675del)

ClinVar: 189006, https://www.ncbi.nlm.nih.gov/clinvar/variation/189006/

gnomAD: 2.105e-05, http://exac.broadinstitute.org/variant/17-78086806-CACA-C

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)

ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/

gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A

Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C

Patient11: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD, survived beyond 2yo, left ventricular mass index and left ventricular posterior wall thickness decreased during ERT. Able to raise head, sit without support, stand, walk alone

CaseNotHPOs: no significant respiratory problems during ERT

NotHPOsFreeText:

CaseAddInfo: homozygous, only patient to receive ERT treatment (rhGAA) every 2wks beginning at 5mo of age. ERT lasted for 90wks.

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Patient17: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)

ClinVar: 371481, https://www.ncbi.nlm.nih.gov/clinvar/variation/371481/

gnomAD: 1.653e-05, http://exac.broadinstitute.org/variant/17-78093082-CTG-C

Patient14: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874, https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/