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.4066G>A (p.Glu1356Lys)

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

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1208G>A (p.Arg403Gln)

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

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.1051A>G (p.Lys351Glu)

ClinVar: 181335, https://www.ncbi.nlm.nih.gov/clinvar/variation/181335/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.2770G>A (p.Glu924Lys)

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

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 5 individuals

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

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

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

CaseA: Female, 49 yrs report

DiseaseEntity: Hypertrophic Cardiomyopathy (AD)

FamilyInfo: Has a monozygotic twin sister w/ same genotype and similar phenotype who lived far apart and had different living environments / life habits, Other family members were diagnosed with HCM afterwards and were genotype positive, See Figure 3 for pedigree

CasePresentingHPOs: HP:0001962, HP:0002875, HP:0001639, HP:0005110, HP:0031185, HP:0011713, HP:0001670, HP:0031295, HP:0030718, HP:0006683, HP:0001712 (Palpitations, Exertional dyspnea, Hypertrophic cardiomyopathy, Atrial fibrillation, Increased NT-proBNP level, Left bundle branch block, Asymmetric septal hypertrophy, Left atrial enlargement, Right atrial enlargement, Abnormal ventricular filling, Left ventricular hypertrophy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0031480 (Abnormal mitral valve leaflet morphology)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Elevated cardiac troponin T (cTnT) (19 ng/L; reference 0-14), Elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (10,214 pg/mL; reference 0-88 pg/mL), Electrocardiogram (ECG) and multi-modality imaging

CaseGenotypingMethod: Whole exome sequencing was performed in the twins using Illumina Hiseq 2500. Low quality variations were filtered and analysed to find potentially pathogenic mutations. The findings were then confirmed using Sanger sequencing.

Variant: NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)

ClinVar: 164337 https://www.ncbi.nlm.nih.gov/clinvar/variation/164337/

gnomAD: Not in gnomAD

Case1: 18 year old male

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: parents and 2 siblings all phenotype negative for HCM, tested negative for the mutation

CasePresentingHPOs: HP:0001639, HP:0031992, HP:0031972, HP:0004755, HP:0004756

"Hypertrophic cardiomyopathy, Apical hypertrophic cardiomyopathy, presyncope, Supraventricular tachycardia, Ventricular tachycardia"

CasePreviousTesting: Authors simply state "on genetic testing"

Variant: NM_000257.4:c.1588A>G

ClinVar: 520309

CAID: CA028909

gnomAD: https://gnomad.broadinstitute.org/variant/14-23897094-T-C?dataset=gnomad_r2_1

Total Allele Frequency 0.000003980 South Asian 0.00003266

Case1: 16 yo Caucasian female

DiseaseAssertion: MYH7 mediated cardiomyopathy

FamilyInfo: 6 additional family members were found to be at risk for HCM and were advised of recommendations for both

CasePresentingHPOs: HP:0001640, HP:0031319, HP:0031318, HP:0001655, HP:0002181

"Cardiomegaly, Cardiomyocyte hypertrophy, Myofiber disarray, Patent foramen ovale, Cerebral edema"

CaseHPOFreeText: moderately enlarged heart (352 g; expected range, 119–290 g), myocardium exhibited marked myocyte hypertrophy, myocyte disarray, and mild interstitial fibrosis, most notably in the anterolateral left ventricle, fatty streaks present in the thoracic aorta

CaseNotHPOs: n/a

CaseNotHPOFreeText: overt septal hypertrophy

CasePreviousTesting: n/a

GenotypingMethod: Whole Exome Next-Generation DNA Sequencing, gene-specific surveillance of all known LQTS, CPVT, BrS, HCM, DCM, and ACM genes (90 total; Table 1 and Figure 1), pathogenic mutations were confirmed in the SUD case's genomic DNA by using standard polymerase chain reaction and Sanger DNA sequencing methods

Variant: NM_000257.4:c.746G>A

ClinVar: 14088

CAID: CA016781

gnomAD: not found

CaseIII-1: Male, China, Asian, 51 years report

CasePresentingHPOs: HP:0001962, HP:0100749, HP:0002094, HP:0500020, HP:0031185, HP:0004755, HP:0031295, HP:0011103 (Heart palpitations, Chest pain, Dyspnea, Abnormal cardiac biomarker test, Increased NT-proBNP level, Supraventricular tachycardia, Left atrial enlargement, Abnormality of the left ventricular outflow tract)

HPOsFreeText: Experienced palpitations for 9 years, Chest pain and mild dyspnea for 2 years, Slightly elevated cardiac troponin T level of 21.8 ng/L (normal 0 to 14 ng/L), Significantly elevated N-terminal pro-brain natriuretic peptide level of 537 pg./mL (normal 0 to 125 pg/mL), ECG showed non-specific ST_T change, Preserved biventricular systolic function, Severe LV outflow tract obstruction (peak aortic outflow velocity = 4.8 m/s, peak gradient = 92 mmHg), Proband had a sigmoid septum with LV outflow tract obstruction and LV mass index to body surface area (BSA) of 87.2 g/m2

CaseNotHPOs: HP:0001677 (Coronary artery disease)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: Genomic DNA was acquired from the proband and all surviving members of his extended family. These were all tested by a 117 gene screening panel that were connected to Cardiomyopathy. The results were confirmed by Sanger sequencing and the variants found were filtered for pathogenicity.

Variant: NM_000257.3:c.4130C>T (p.Thr1377Met)

ClinVar: 42992 https://www.ncbi.nlm.nih.gov/clinvar/variation/42992/

gnomAD: European (Non-Finnish) 8.791e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23887458-G-A

Segregation

Affected: 9

Unaffected: 17

Segregations: 23

PublishedLOD: N/A

eLOD: 6.92

AddSegInfo: 6 individuals died before this investigation so clinical data and phenotypes could not be collected, 10 individuals were genotype positive but phenotype negative

PMID: 23800289

Gene: MYH7

HGNC: 7577

"This is the first indication that a mutation in the MYH7B gene causes LVNC cardiomyopathy. We demonstrated that the arginine at position 890 of the MYH7B gene is highly conserved in all species; this region is also conserved in the MYH7 gene, which, when mutated, causes LVNC. These data further support the concept that sarcomere genes are associated with LVNC."

PMID: 32424548

Gene: MYH7

HGNC: 7577

Supplementary Data Table S3

Case: 245

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) DES Variant

Variant: NM_001927.4(DES):c.638C>T (p.Ala213Val)

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(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

(3) TTN Variant

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

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

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

Supplementary Data Table S3

Case: 25

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) GAL Variant

Variant: NM_015973.5(GAL):c.47C>T (p.Ala16Val)

ClinVar: 475915, https://www.ncbi.nlm.nih.gov/clinvar/variation/475915/

gnomAD: 0.006938, https://gnomad.broadinstitute.org/variant/11-68452438-C-T

Supplementary Data Table S3

Case: 47

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) DOLK Variant

Variant: NM_014908.3(DOLK):c.1dup (p.Met1fs)

ClinVar: 167006, https://www.ncbi.nlm.nih.gov/clinvar/variation/167006/

gnomAD: 0.006541, https://gnomad.broadinstitute.org/variant/9-131709581-A-AT

Supplementary Data Table S3

Case: 373

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.4903A>G (p.Met1635Val)

CAID: CA044177 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA044177

gnomAD: 0.0005972, https://gnomad.broadinstitute.org/variant/14-23885263-T-C

MultipleGeneVariants:

(1) LMNA Variant

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

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

gnomAD: 0.01294, https://gnomad.broadinstitute.org/variant/1-156100408-C-T

(2) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.3181C>T (p.Gln1061Ter)

ClinVar: 42690 https://www.ncbi.nlm.nih.gov/clinvar/variation/42690/

gnomAD: 0.0001913, https://gnomad.broadinstitute.org/variant/11-47355117-G-A

(3) SCN5A Variant

Variant: NM_000335.4(SCN5A):c.553G>A (p.Ala185Thr)

ClinVar: 67996 https://www.ncbi.nlm.nih.gov/clinvar/variation/67996/

gnomAD: 0.004251, https://gnomad.broadinstitute.org/variant/3-38662392-C-T

(4) VCL Variant

Variant: NM_014000.2(VCL):c.1535G>A (p.Arg512His)

ClinVar: 450167 https://www.ncbi.nlm.nih.gov/clinvar/variation/450167/

gnomAD: 0.0001973, https://gnomad.broadinstitute.org/variant/10-75854211-G-A

Supplementary Data Table S3

Case: 123

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) DES Variant

Variant: NM_001927.4(DES):c.638C>T (p.Ala213Val)

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.01512, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(2) RBM20 Variant

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

ClinVar: 44265 https://www.ncbi.nlm.nih.gov/clinvar/variation/44265/

gnomAD: 0.02090, https://gnomad.broadinstitute.org/variant/10-112581039-G-A

CaseIII-6: Female, 32 years report, 17 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Proband's son had the same variant; the father had echocardiograph results but was asymptomatic

CasePresentingHPOs: HP:0001639, HP:0002094, HP:0100749, HP:0001962, HP:0001279, HP:0030879 (Hypertrophic cardiomyopathy, Dyspnea, Chest pain, Palpitations, Syncope, Interlobular septal thickening on pulmonary HRCT)

HPOsFreeText: Septum thickness 25 mm, Left ventricle at 44 mm, Left atrium at 40 mm, Ejection fraction at 54%

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mutation is classified as de novo

CasePreviousTesting: See list of 26 genes under Target sequence capture sequencing

CaseGenotypingMethod: Genomic DNA was extracted from the proband and other family members. Afterwards, it was subject to PCR amplification and sequencing. Any variants found were confirmed with Sanger sequencing before being filtered for pathogenicity.

Variant: NM_000257.3:c.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: Not in gnomAD

Case309: Female, 0.01 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 39%, LVDD-Z score at 1.08

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: Father and brother also have 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.1085T>G (p.Met362Arg)

CAID: CA389051391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3:c.1085T%3EG

gnomAD: Not in gnomAD

Case280: 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 40%, LVDD-Z score at 2.16

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history, Died since publication

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 listed as K542N, could be either CA389050168 or CA389050167.

Variant: NP_000248.2:p.Lys542Asn

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

JUP Variant

Variant: NM_002230.2:c.436G>A (p.Glu146Lys)

CAID: CA8565496 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002230.2:c.436G%3EA

gnomAD: African 6.353e-5, Overall 2.030e-5 https://gnomad.broadinstitute.org/variant/17-39925702-C-T

PMID: 33098074

Gene: MYH7

HGNC: 7577

"This study aimed to identify the dominant function of Myh7 after birth and determine whether its removal would affect CM maturation or contribute to reversal of pathological hypertrophy phenotypes."

CaseMYH7-9: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 1 other proband shares this genotype

CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.

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

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

gnomAD: European (Non-Finnish) 1.548e-5, Overall 7.070e-6 https://gnomad.broadinstitute.org/variant/14-23896866-C-T

CaseMYH7-28: 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.2782G>A (p.Asp928Asn)

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

gnomAD: Not in gnomAD

CaseMYH7-20: 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.2945T>C (p.Met982Thr)

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

gnomAD: European (Non-Finnish) 1.416e-3, Overall 8.484e-4 https://gnomad.broadinstitute.org/variant/14-23892910-A-G

CaseMYH7-31: 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.788T>C (p.Ile263Thr)

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

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

Case1: Male

DiseaseAssertion: HCM and LVNC

FamilyInfo: daughter with same diagnoses and variant 1

Variant1: NM_000257.4:c.1859T>C

ClinVar: not found

CAID: CA389049669

gnomAD: not found

Variant2: NM_000257.4:c.4377G>T

ClinVar: 43012

CAID: CA014901

gnomAD: https://gnomad.broadinstitute.org/variant/14-23886504-C-A?dataset=gnomad_r2_1

0.0005349 European (non Finnish)

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.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: 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.1915A>G

CAID: CA389049545, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049545

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.1106G>A (p.Arg369Gln)

ClinVar: 42822, https://www.ncbi.nlm.nih.gov/clinvar/variation/42822/

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.3928C>G

CAID: CA389041570, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041570

gnomAD: n/a

CaseMYH7-3: 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.5222_5223del (p.Val1741Glyfs*11)

CAID: CA913184899 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184899

gnomAD: Not in gnomAD

CaseMYH7-15: 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.2738T>C (p.Ile913Thr)

CAID: CA389047215 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2738T%3EC

gnomAD: Not in gnomAD

CaseMYH7-1: 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.5452C>T (p.Arg1818Trp)

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

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

CaseCM1762: Female, 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, Father shows positive for this variant with no symptoms while Mother shows negative for this variant with no symptoms

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.1845G>C (p.Lys615Asn)

CAID: CA389049696 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.1845G%3EC

gnomAD: Not in gnomAD

CaseCM1824: Female, 13 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, Father afflicted with HCM and also positive for same 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.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

gnomAD: Not in gnomAD

CaseCM1811: Female, 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: No family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Mother shows positive for this variant with no symptoms while Father shows negative for this variant with no symptoms

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.1988G>A (p.Arg663His)

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

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

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_000257.3:c.2714G>A (p.Cys905Tyr)

CAID: CA389047298 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389047298

gnomAD: Not in gnomAD

DiseaseAssertion: None

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

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

Variant: NM_000257.4(MYH7):c.2945T>C (p.Met982Thr)

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

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

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.958G>A (p.Val320Met)

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

gnomAD: 0.00006154, http://gnomad.broadinstitute.org/variant/14-23899810-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 two PanCM probands

Variant: NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp)

ClinVar: 164284 https://www.ncbi.nlm.nih.gov/clinvar/variation/164284/

gnomAD: Not in gnomAD

Supplementary Data: S2 Table

Case 47: 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.4066G>A (p.Glu1356Lys)

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

gnomAD: n/a

Case: Patient 7, male, 8yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0002650, HP:0030682, HP:0003458 (axial muscle weakness, scoliosis, left ventricular noncompaction, EMG: myopathic abnormalities)

HPOsFreeText: minicores present on muscle biopsy

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.5655+1G>A

CAID: CA389034770, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389034770

gnomAD: absent

Supplementary Material 4

Case M-30: 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.2803G>A (p.Glu935Lys)

ClinVar: 14106, https://www.ncbi.nlm.nih.gov/clinvar/variation/14106/

gnomAD: n/a

Supplementary Material 4

Case M-9: 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.1987C>T (p.Arg663Cys)

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

gnomAD: n/a

Supplementary Material 4

Case M-26: 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.2609G>A (p.Arg870His)

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

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

Case II-3: Female, 40yo

DiseaseAssertion: Left ventricular hypertrophy

CasePresentingHPOs: HP:0001712 (left ventricular hypertrophy)

CaseHPOFreeText: double-chambered left ventricle, reduced exercise capacity for 13yrs, mild heart failure symptoms, normal thickness of septum and left ventricle, 2 chambers of left ventricle have 18.5mm diameter of communication and they contract almost normally, left ventricle ventricle end-diastolic diameter = 74.3mm, left ventricular ejection fraction = 45%

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

DiseaseAssertion: DCM

Variant1: NM_000257.3(MYH7):c.602T>C (p.Ile201Thr)

ClinVar: 43093, https://www.ncbi.nlm.nih.gov/clinvar/variation/43093/

gnomAD: n/a

Variant2: NM_000257.3(MYH7):c.667G>A (p.Ala223Thr)

ClinVar: 14112, https://www.ncbi.nlm.nih.gov/clinvar/variation/14112/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23900859-C-T

Variant3: NM_000257.3(MYH7):c.709C>T (p.Arg237Trp)

ClinVar: 43098, https://www.ncbi.nlm.nih.gov/clinvar/variation/43098/

gnomAD: 0.00001193, https://gnomad.broadinstitute.org/variant/14-23900817-G-A

Variant4: NM_000257.3(MYH7):c.1594T>C (p.Ser532Pro)

ClinVar: 14108, https://www.ncbi.nlm.nih.gov/clinvar/variation/14108/

gnomAD: n/a

Variant5: NM_000257.3(MYH7):c.2292C>G (p.Phe764Leu)

ClinVar: 14109, https://www.ncbi.nlm.nih.gov/clinvar/variation/14109/

gnomAD: n/a

Case IV-1: Female, 10mo, carrier with no clinical manifestation

CaseHPOFreeText: interventricular septum = 4mm, posterior wall of left ventricle = 4mm, normal electrocardiogram

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

CasePT-35: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo: PT-36 and PT-37 are the proband's siblings in Family 18 with the same genotype

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

Variant: NM_000257.3:c.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

gnomAD: Ashkenazi Jewish 1.984e-4, Overall 7.953e-6 https://gnomad.broadinstitute.org/variant/14-23897796-C-A

PMID: 23782526

Gene:MYH7

HGNC: 7577

Additional annotations found in:

https://www-jstage-jst-go-jp.libproxy.lib.unc.edu/article/circj/77/9/77_CJ-13-0294/_pdf/-char/en

CaseHCM085: 49 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001712, HP:0002875, HP:0011103, HP:0031295, HP:0001653, HP:0001279 (Left ventricular hypertrophy, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement, Mitral regurgitation, Syncope)

HPOsFreeText: Maximal LV thickness 19 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser)

ClinVar: 42862 https://www.ncbi.nlm.nih.gov/clinvar/variation/42862/

gnomAD: Not in gnomAD

Case#: HCM483, male, 37 years, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 23mm LVST, 40mm LVEDD, 72% LVEF, 26mm Maxi LVWT, 70mmHg Maxi LVOTG, 132375212 raw RNA-seq reads, 125845538 HQ reads (95.07%), 96.52% mapping rate, 838862 total variant, 35806 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

Case3: Male, 53 yrs diagnosis, Portugal

DiseaseAssertion: Dilated Cardiomyopathy

FamilyInfo: No family history

CasePresentingHPOs: HP:0001644, HP:0001635, HP:0011675, HP:0011713, HP:0012665, HP:0031192 (Dilated cardiomyopathy, Congestive heart failure, Arrhythmia, Left bundle branch block, Moderately reduced ejection fraction, Abnormal morphology of left ventricular trabeculae)

HPOsFreeText: Left ventricular end-diastolic diameter of 56 mm

CaseNotHPOs: HP:0002540, HP:0011706, HP:0001709, HP:0006682 (Inability to walk, Second degree atrioventricular block, Third degree atrioventricular block, Premature ventricular contractions)

NotHPOsFreeText: N/A

CasePreviousTesting: Proband has been studied before as part of FATIMA with general clinical assessment and cardiological investigations as well as exclusion criteria subject there. Tested genes include: LMNA, MYH7, MYBPC3, TNNT2, ACTA1, TPM1, CSRP3, TCAP, SGCD, PLN, MYL2, MYL3, TNNI3, TAZ, LDB3.

CaseGenotypingMethod: Blood samples were obtained and NGS was performed on a panel of 15 different genes covering the coding sequence and flanking exon/intron boundaries. Sanger sequencing was used to validate the variants and provide additional coverage. Variants were interpreted and filtered for pathogenicity.

CaseAddInfo: More info in 19044174 but paper is unavailable at this time

Variant: NM_000257.3:c.5623G>T (p.Val1875Phe)

CAID: CA389034842 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5623G%3ET

gnomAD: Not in gnomAD

Case#: A 29 years old male DCM patient

DiseaseAssertion:Familial dilated cardiomyopathy (FDCM), associated with the TNNT2 gene missense variant p.Arg144Trp (R144W)

FamilyInfo: Family members had revealed its presence in three other individuals with DCM. A history of sudden cardiac deaths (SCD) in the family. Two individuals in the family, who were diagnosed with DCM, had died due to severe congestive heart failure at the age of 45 and 25 years. However, a 66-year-old individual in the same family with DCM having mild symptoms.

ParentalTesting:NR

CasePresentingHPOs: HP:0001644, HP:4000141, HP:0012664, HP:0004308, HP:0012828, HP:0001653

CaseHPOFreeText: Dilated cardiomyopathy with left ventricular dilation, Age of onset, 25, left ventricular internal diastolic dimension of 72mm, reduced ejection fraction of 26%, has Ventricular arrhythmia, severe mitral regurgitation.

CaseNotHPOs:NR

CaseNotHPOFreeText: NR

CasePreviousTesting:NR

Genotyping Method: Used PCR with GenBank No. NM_000364, then followed by mutation subsequent screening analysis

FunctionalAnalysis:The R144W mutation was found to be within the tropomyosin-binding domain of cTnT and alters the charge of the residue, so it is expected to have a significant impact on the structure and function of the protein. The novel unique/private R144W mutation identified in our present study is associated with FDCM

Variant:NM_001276345.2:c.445C>T

ClinVar:43640

CAID:CA004505

gnomAD: gnomAD v2: 1:201333470 G / A https://gnomad.broadinstitute.org/variant/1-201333470-G-A?dataset=gnomad_r2_1 gnomAD v4: chr1-201364342-G-A https://gnomad.broadinstitute.org/variant/chr1-201364342-G-A?dataset=gnomad_r4

AdditionalInfo:25 bp deletion was found to be associated with both HCM and DCM in India and south Asia

PMID: 24992688

Gene: TNNT2

HGNC ID: 11949

Supplementary Data table 1

Variant noted to be present in 2 individuals

Variant: NM_000257.3(MYH7):c.1063G>A (p.Ala355Thr)

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

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp)

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

gnomAD: n/a

Case1: 43 year old Caucasian female

DiseaseAssertion: LVHT, mild distal myopathy

FamilyInfo: LVHT was absent in all other family members who had undergone echocardiography, same MYH7 mutation detected in mother, who manifested with a mild distal myopathy

CasePresentingHPOs: HP:0001962, HP:0001279, HP:0004756, HP:0004308, HP:0012391

"Palpitations, Syncope, Ventricular tachycardia, Ventricular arrhythmia, Hyporeflexia of upper limbs"

CaseHPOFreeText: ectopic atrial tachycardia, mild weakness for foot extension on the right side, reduced Achilles tendon reflexes

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: n/a

Variant: NM_000257.4:c.5566G>A

ClinVar: 190403

CAID: CA347253

gnomAD: https://gnomad.broadinstitute.org/variant/14-23883305-C-T

0.000008795 European (non-Finnish)

Case1: deceased 16 year old female

DiseaseAssertion: HCM

FamilyInfo: 6 additional family members were found to be at risk for HCM

CasePresentingHPOs: HP:0001640, HP:0031319, HP:0002181

"Cardiomegaly, Cardiomyocyte hypertrophy, Cerebral edema

CaseHPOFreeText: Moderately enlarged heart, myocyte disarray, mild interstitial fibrosis

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: Whole Exome Next-Generation DNA Sequencing

Variant: NM_000257.4:c.746G>A

ClinVar: 14088

CAID: CA016781

gnomAD: not found

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias PMID: 28491642

Gene: ACTC1

HGNC ID: 143

Case: Pedigree 3 proband, female, 3mo at diagnosis, North African and Jewish

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

HPOsFreeText: clinical severity: severe (fatal)

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: exact genes sequenced not specified

CaseGenotypingMethod: DCM CardioChip, included 19 genes known to cause DCM

Variant 1: 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

Variant 2: NM_000257.4(MYH7):c.4588C>T (p.Arg1530Ter)

ClinVar: 43029, https://www.ncbi.nlm.nih.gov/clinvar/variation/43029/

gnomAD: 0.00001591, https://gnomad.broadinstitute.org/variant/14-23886133-G-A

FamilyInfo: mother is of North African and Iraqi‐Jewish descent, while the father is of North African and Balkan Jewish descent, probands brother died at 3.5mo and also carried both variants, maternal cousin died of RCM in early childhood, maternal aunt carried p.R143W

Case8: Female, 12 yrs onset, Slovakia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Affected family members

CasePresentingHPOs: HP:0001639 (Hypertrophic Cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: Normal LV ejection fraction

CasePreviousTesting: ABCC9, ACTC1, ACTN2, ANKRD1, CASQ2, CAV3, CRYAB, CSRP3, CTF1, DES, DSC2, DSG2, DSP, DTNA, EMD, FHL2, GLA, JUP, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, NEXN, PKP2, PLN, PRKAG2, RBM20, RYR2, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL were all tested on NGS panel

CaseGenotypingMethod: Genomic DNA was extracted from whole blood and samples were purified and amplified. The coding exons for the above genes were enriched and sequenced. The resulting variants were analyzed and filtered for predicted pathogenicity.

CaseAddInfo: N/A

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

MultipleGeneVariants

(1) DSP Variant

Variant: NM_004415.4(DSP):c.484C>G (p.Arg162Gly)

ClinVar: 546994 https://www.ncbi.nlm.nih.gov/clinvar/variation/546994/

gnomAD: 0.00006152, http://gnomad.broadinstitute.org/variant/6-7559520-C-G

PMID: 36128439

Gene: MYL2

HGNC ID: 7583

PMID: 21823217

Gene: MYL2

HGNC ID: 7583

PatientID: IV-13

KindredID: 2

Case: F, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-12

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666 (Renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 25

KindredID: 6012

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of her family, (patient 26) presented with one radiologic pancreatic neuroendocrine tumor and had the same VHL gene mutation.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with two radiologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: p.A149S (c.658G>T)

CaseProblemVariantFreeText: N/A

ClinVar:127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: CA020355 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.445G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A

PMID: 33397040

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: HGB-19

KindredID: 4

Case: Sex Unknown, 44Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

CasePresentingHPOs: HP:0006880, HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 32. The patient had a spinal cord hemangioblastoma at age 40.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114V(c.341G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753604 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.341G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114V (c.341G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 7

Case: F, 13Y0M, Ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: No familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Benign bilateral pheochromocytoma at age 13 Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: F, 18Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0010797; HP:0030405 (Pheochromocytoma; paraganglioma; hemangioblastoma; pancreatic endocrine tumor)

CaseHPOFreeText: Benign bilateral pheochromocytoma and sympathetic PGL, CNS hemangioblastoma and PNET at age 18

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

Recently, Lenglet et al., 2018 identified a new VHL cryptic exon termed E1' deep in intron 1 that is naturally expressed in many tissues, and found E1' mutations in eight families with either erythrocytosis or VHL disease. The goal of this study was to determine the prevalence of E1' germline mutations from two cohorts, 221 patients with a single or multiple tumours, suggestive of VHL disease, and 946 patients with a Pheochromocytoma/paraganglioma (PPGL) but without an identified mutation in the three VHL exons or in the main PPGL susceptibility genes. They identified a rare germline genetic variant (maf <1%) in the E1’ VHL cryptic exon in 1% of patients (12/1167). Patient 11 was diagnosed at the age of 12 due to multiple head and neck paragangliomas, and was found to have a rare germline c.340+725A>T E1' variant.

PatientID: 10

KindredID: 10

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A - not stated

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: A pheochromocytoma (PCC) diagnosed first at 11Y was found, with follow up of a 15 year duration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.340+682T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 964770 https://www.ncbi.nlm.nih.gov/clinvar/variation/964770

CAID: N/A

gnomAD: N/A

VariantEvidence: Tumor analysis was performed since there was a paraffin embedded sample. Patient 10 did not have loss of heterozygosity, but was found to have a somatic variant in the exon 3 of VHL (c.482G>A; p.Arg161Gln). This was the only patient observed to have a cluster of tumor cells with a positive membranous CA9 immunostaining, this can be seen in VHL-related PPGL. CA9 is a protein reported to influence regulation cell proliferation and tumor progression and is known to be expressed at the membrane of tumour cells in the case of VHL inactivation can be seen in VHL-related PPGL. Subsequently as expected, the PPGL of patient 10 had a significantly low expression of VHL E1-E1' mRNA VHL and PNMT mRNA compared to VHL-tumours used as controls. This suggests that the two VHL variants change the VHL mRNA splicing.

MutationType: splice_site_variant

CivicName: Splice Site (c.340+682T>C); intron_variant

MultipleGeneVariants: Somatic, VHL, c.482G>A (p.Arg161Gln)

PatientID: 26

KindredID: 1

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. She had adrenal pheochromocytoma and diagnosed with VHL subtype 2A (see table 1).

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 5

Case: M, 19Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient had 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: HP:0005584; HP:0000107; HP:0006748; HP:0009713; HP:0001737; HP:0030939; HP:0100684 (renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor, salivary gland neoplasm)

CaseHPOFreeText: Patient presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. Patient was diagnosed with VHL type 1 (see table 2).

CaseNotHPOs: HP:0002668; HP:0030405 (paraganglioma; pancreatic endocrine tumor)

CaseNotHPOFreeText: Patient negative for paraganglioma and pancreatic endocrine tumor.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: X-I

KindredID: 10

Case: M, 28Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported.

CasePresentingHPOs: HP:0010797; HP:0006880; HP:0009711; HP:0009713; HP:0001737 (hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, spinal hemangioblastoma, pancreatic cyst)

CaseHPOFreeText: Patient presented with CNS, spinal, retinal and cerebellar hemangioblastoma, as well as a pancreatic cyst at age 28Y0M and was diagnosed with VHL type 2A (see table 2).

CaseNotHPOs: HP:0000107; HP:0005584; HP:0006748; HP:0002668; HP:0030405 (renal cyst; renal cell carcinoma; adrenal pheochromocytoma; paraganglioma; pancreatic endocrine tumor)

CaseNotHPOFreeText: Patient negative for renal cyst, renal cell carcinoma, adrenal pheochromocytoma, paraganglioma, and pancreatic endocrine tumor.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: partial deletion (<1kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: partial_deletion

CivicName: NULL (partial deletion)

MultipleGeneVariants: N/A

Two families where index patients had mosaic parents from the NIH-VHL Family Registry were reviewed. Family 2 had an index patient (IV-6), 23Y female, with brainstem and spinal hemangioblastoma (15Y old), solid renal lesion, retinal angioma, and pancreatic cysts (20Y old). Direct DNA sequencing found a NM_000551.3:c.226_228del germline mutation in the VHL gene. Note that the paper describes it as c.439_441del since it uses an older reference sequence (Latif et al.). She had 5 siblings, 3 of which tested negative for the VHL mutation and the other 2 were not evaluated. The patient's father was tested and confirmed to be mosaic for the mutation with the mutation present in approximately one of seven peripheral blood lymphocytes. The presently 48Y father (III-4) was 39Y old and found with renal cell carcinoma, brainstem and cerebellar hemangioblastoma, pancreatic cysts, and renal cysts. ACMG PP4

PatientID: III-4

KindredID: 1

Case: M, 81Y0M, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Eight affected individuals in the patient’s family were retrospectively identified by reviewing medical records and from the recall of relatives. Three had passed away before 40 years of age because of central nervous system hemangioblastoma. Among the 10 living family members that carried the same NM_000551.3:c.326_339dupTCCACAGCTACCGA the patient carried, 3 had renal cysts and 1 had developed renal cell carcinoma, 2 had central nervous system hemangioblastoma, 1 had retinal hemangioblastomas, 1 was diagnosed with glioblastoma, and 5 were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Gly114Serfs*50(c.326_339dupTCCACAGCTACCGA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573051018, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573051018

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: G114fs (c.326_339dupTCCACAGCTACCGA)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history of VHL.

CohortInfo: An international consortium registered patients with head and neck paragangliomas with VHL or RET gene mutations.

CasePresentingHPOs: HP:0000618; HP:0009711; HP:0010797; HP:0002668 (blindness, retinal capillary hemangioma, hemangioblastoma, paraganglioma)

CaseHPOFreeText: At 15Y she presented with loss of visual acuity, leading to the diagnosis of bilateral retinal hemangioblastomas (treated with laser and cryotherapy), with the outcome of unilateral blindness. The patient was then operated 3 times for CNS hemangioblastomas between ages 18 and 24. At age 26, she presented with a palpable lateral neck mass. CT of the head and neck revealed a 3-cm carotid body tumor (paraganglioma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T105P (c.313A>C)

LegacyVariant: p.T105P

CaseProblemVariantFreeText: As the publication only provides the p., the mutation was deduced to p.T105P (c.313A>C)

ClinVarID: 496055 https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: T105P (c.313A>C)

MultipleGeneVariants: N/A

An international consortium of registered patients with head and neck paragangliomas with VHL or RET gene mutations were analyzed. Eleven of the 12 patients were found to carry germline mutations in theVHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 26 year old female proband was found to harbour the p.Ser139fs mutation of the VHL gene. She had a family history of VHL and presented with lumbar pain. CT showed a right adrenal pheochromocytoma that was removed. Two years later, she had left nephrectomy for multiple renal cell carcinoma. At age 33, she presented with a lateral cervical mass associated with Horner’s syndrome and pain in the right ear. CT showed a 6cm carotid paraganglioma that was removed and histologically confirmed. At age 42, a cerebellar hemangioblastoma was removed. As the publication only provides the p., the mutation p.Ser139fs was not able to be matched to the exact mutation.

PatientID: None

KindredID: 13

Case: Sex Unknown, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0009713; HP:0005584; HP:0000107; HP:0002666 (Retinal capillary hemangioma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: F, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's sibling was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. Her niece also had the mutation but was asymptomatic. Another member of her family also had this mutation and was asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0009711, HP:0002666, HP:0005584, HP:0001732 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 153

KindredID: 56

Case: F, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband presented with a retinal angioma at 26, and multiple pancreatic cysts/tumors at 31.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0005584 (Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.I151N (c.452T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754356; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA351754356

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: I151N (c.452T>A)

MultipleGeneVariants: N/A

PatientID: 217

KindredID: 81

Case: F, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's brother had the same germline mutation, and presented with a CNS hemangioblastoma at 20, and a pheochromocytoma at 26. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33.

CaseNotHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #50. Only the proband (patient 132) was genetically confirmed with the mutation. The proband (female) was diagnosed with a CNS hemangioblastoma at 26Y, renal cell carcinoma at 45Y, and multiple pancreatic cysts/tumors at 45Y. Her father (patient 135) was diagnosed with CNS hemangioblastoma at 25Y, but passed away before VHL disease diagnosis/ mutation confirmation. Her first brother (patient 133) was diagnosed with CNS hemangioblastoma at 29Y, RCC at 48Y, and multiple pancreatic cysts/tumors at 48Y, but no DNA sample was available for testing. Her second brother (patient 134) was diagnosed with CNS hemangioblastoma at 27Y, but passed away before VHL disease diagnosis/ mutation confirmation. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 122

KindredID: 43

Case: F, Age 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 19, and multiple pancreatic cysts/tumors at 26.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #43 with 2 affected members that were both genetically confirmed for the mutation. A female proband was diagnosed with CNS hemangioblastoma at 19Y and multiple pancreatic lesions at 26Y. Her father was diagnosed with CNS hemangioblastoma at 27Y, renal cell carcinoma at 48Y, and multiple pancreatic lesions at 60Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336). It is likely that both papers published the same family.

PatientID: 155

KindredID: 58

Case: M, 26Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

CasePresentingHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The proband presented at age 21 with retinal angioma, and at age 26 with multiple pancreatic cysts/tumors and renal cell carcinoma.

CaseNotHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

MultipleGeneVariants: N/A