Supplementary Data, Table 2

Variant noted to be present in 16 individuals

Variant: NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly)

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

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 9 individuals

Variant: NM_000257.3(MYH7):c.4135G>A (p.Ala1379Thr)

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

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.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

Supplementary Data, Table 2

Variant noted to be present in 4 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 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.2087A>G (p.Asn696Ser)

ClinVar: 181173, https://www.ncbi.nlm.nih.gov/clinvar/variation/181173/

gnomAD: n/a

Supplementary Data, Table 2

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.438G>T (p.Lys146Asn)

ClinVar: 43013, https://www.ncbi.nlm.nih.gov/clinvar/variation/43013/

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.1370T>C (p.Ile457Thr)

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

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23898201-A-G

Supplementary Data table 1

Variant noted to be present in 4 individuals

Variant: NM_000257.3(MYH7):c.4130C>T (p.Thr1377Met)

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

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23887458-G-A

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

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.1357C>T (p.Arg453Cys)

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

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.3169G>A (p.Gly1057Ser)

ClinVar: 42950, https://www.ncbi.nlm.nih.gov/clinvar/variation/42950/

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23891465-C-T

Supplementary Data table 1

Case:

DiseaseAssertion: hypertrophic cardiomyopathy

CaseHPOFreeText: maximal wall thickness (MWT) ≥15 mm

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

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

Variant: NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg)

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

gnomAD: n/a

PMID: 20301725

Gene: MYH7

HGNC: 7577

"The purpose of this overview is to increase clinician awareness of the genetic basis of hypertrophic cardiomyopathy (HCM) and the benefits of early diagnosis and management to individuals with genetic HCM."

Supplementary Data Table S3

Case: 23

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

gnomAD: 0.00006010, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

Supplementary Data Table S3

Case: 67

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

Supplementary Data Table S3

Case: 20

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.2155C>T (p.Arg719Trp)

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

gnomAD: 0.00003185, https://gnomad.broadinstitute.org/variant/14-23895180-G-A

MultipleGeneVariants:

(1) LDB3 Variant

Variant: NM_007078.3(LDB3):c.295C>T (p.Pro99Ser)

ClinVar: 178059, https://www.ncbi.nlm.nih.gov/clinvar/variation/178059/

gnomAD: 0.0009830, https://gnomad.broadinstitute.org/variant/10-88439888-C-T

(2) RBM20 Variant

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

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

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

Supplementary Data Table S3

Case: 333

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) RBM20 Variant

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

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

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

Supplementary Data Table S3

Case: 22

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

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

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

Variant 2: NM_000257.4(MYH7):c.3853+7C>T

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

gnomAD: 0.002253, https://gnomad.broadinstitute.org/variant/14-23888685-G-A

Supplementary Data Table S3

Case: 276

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.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

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

(2) NEBL Variant

Variant: NM_006393.2(NEBL):c.109_110del (p.Leu37fs)

ClinVar: 229042 https://www.ncbi.nlm.nih.gov/clinvar/variation/229042/

gnomAD: 0.001673, https://gnomad.broadinstitute.org/variant/10-21185929-TAA-T

Supplementary Data Table S3

Case: 90

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) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.977G>A (p.Arg326Gln)

ClinVar: 42813 https://www.ncbi.nlm.nih.gov/clinvar/variation/42813/

gnomAD: 0.01364, https://gnomad.broadinstitute.org/variant/11-47367871-C-T

Supplementary Data Table S3

Case: 218

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.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYBPC3 Variant

Variant: NM_000256.3(MYBPC3):c.2686G>A (p.Val896Met)

ClinVar: 42652 https://www.ncbi.nlm.nih.gov/clinvar/variation/42652/

gnomAD: 0.02794, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

(2) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

(3) TMPO Variant

Variant: NM_001032283.2(TMPO):c.859G>C (p.Ala287Pro)

ClinVar: 43693 https://www.ncbi.nlm.nih.gov/clinvar/variation/43693/

gnomAD: 0.04732, https://gnomad.broadinstitute.org/variant/12-98938295-G-C

Supplementary Data Table S3

Case: 26

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) FBN1 Variant

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

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

gnomAD: 0.0006449, https://gnomad.broadinstitute.org/variant/15-48782053-A-G

(2) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949, https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.1547, https://gnomad.broadinstitute.org/variant/5-254599-A-T

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: 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

Supplementary Data Table S3

Case: 157

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

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

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

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

MultipleGeneVariants:

(1) SDHA Variant

Variant: NM_004168.4(SDHA):c.1886A>T (p.Tyr629Phe)

ClinVar: 224949 https://www.ncbi.nlm.nih.gov/clinvar/variation/224949/

gnomAD: 0.5249, https://gnomad.broadinstitute.org/variant/5-254599-A-T

Supplementary Data Table S3

Case: 73

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.3825C>A (p.Ser1275Arg)

CAID: CA389041965 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041965

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) NEBL Variant

Variant: NM_006393.2(NEBL):c.109_110del (p.Leu37fs)

ClinVar: 229042 https://www.ncbi.nlm.nih.gov/clinvar/variation/229042/

gnomAD: 0.001673, https://gnomad.broadinstitute.org/variant/10-21185929-TAA-T

(2) NEXN Variant

Variant: NM_144573.3:c.968A>G (p.Glu323Gly)

CAID: CA918784 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA918784

gnomAD: 0.001758, https://gnomad.broadinstitute.org/variant/1-78395104-A-G

(3) PLB1 Variant

Variant: NM_153021.4:c.3967C>A (p.Pro1323Thr)

CAID: CA1588921 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA1588921

gnomAD: 0.04150, https://gnomad.broadinstitute.org/variant/2-28854972-C-A

Supplementary Data Table S3

Case: 296

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.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) DOLK Variant

Current transcript of DOLK has a C at location 17 and a Pro rather than an Ala

Variant: c.17G>C (p.Gly6Ala)

ClinVar: N/A

gnomAD: N/A

(2) MYPN Variant

Variant: NM_032578.3(MYPN):c.2863C>T (p.Arg955Trp)

ClinVar: 192126 https://www.ncbi.nlm.nih.gov/clinvar/variation/192126/

gnomAD: 0.001449, https://gnomad.broadinstitute.org/variant/10-69948821-C-T

(3) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

Supplementary Data Table S3

Case: 252

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

Variant: NM_000257.3:c.1021T>C (p.Phe341Leu)

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

Supplementary Data Table S3

Case: 320

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) NEXN Variant

Variant: NM_144573.3(NEXN):c.995A>C (p.Glu332Ala)

ClinVar: 47915 https://www.ncbi.nlm.nih.gov/clinvar/variation/47915/

gnomAD: 0.01350, https://gnomad.broadinstitute.org/variant/1-78395131-A-C

Supplementary Data Table S3

Case: 374

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.3250G>C (p.Asp1084His)

CAID: CA389044579 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389044579

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) ABCC9 Variant

Variant: NM_000256.3(MYBPC3):c.440C>T (p.Pro147Leu)

CAID: CA6481647 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6481647

gnomAD: Not in gnomAD

Supplementary Data: S2 Table

Case 236: Spanish, 37yo, 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

Variant1: NM_000257.3(MYH7):c.4954G>T (p.Asp1652Tyr)

ClinVar: 43047, https://www.ncbi.nlm.nih.gov/clinvar/variation/43047/

gnomAD: 0.00004774, https://gnomad.broadinstitute.org/variant/14-23885041-C-A

Variant2: NM_000257.3(MYH7):c.4817G>A (p.Arg1606His)

ClinVar: 43039, https://www.ncbi.nlm.nih.gov/clinvar/variation/43039/

gnomAD: 0.00003889, https://gnomad.broadinstitute.org/variant/14-23885349-C-T

Supplementary Data: S2 Table

Case 1: Spanish, 42yo, 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.427C>T (p.Arg143Trp)

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

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

Supplementary Data: S2 Table

Case 195: Spanish, 53yo, 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.958G>A (p.Val320Met)

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

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

Supplementary Data: S2 Table

Case 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

Supplementary Data: S2 Table

Case 82: Spanish, 28yo, 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.745C>G (p.Arg249Gly)

ClinVar: 181322, https://www.ncbi.nlm.nih.gov/clinvar/variation/181322/

gnomAD: n/a

Supplementary Data: S2 Table

Case 139: Spanish, 44yo, 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.2156G>A (p.Arg719Gln)

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

gnomAD: n/a

Supplementary Data: S2 Table

Case 113: 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:c.530C>G

CAID: CA389052613, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052613

gnomAD: n/a

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_001001430.2:c.101C>T

CAID: CA088874, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA088874

gnomAD: 0.00001193, https://gnomad.broadinstitute.org/variant/1-201337322-G-A

Supplementary Data: S2 Table

Case 235: Spanish, 28yo, 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:c.2428T>C

CAID: CA389048429, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389048429

gnomAD: n/a

MultipleGeneVariants:

(1) TTN Variant:

Variant: NM_001256850.1(TTN):c.57107T>C (p.Ile19036Thr)

ClinVar: 179416, https://www.ncbi.nlm.nih.gov/clinvar/variation/179416/

gnomAD: 0.00004835, https://gnomad.broadinstitute.org/variant/2-179454422-A-G

Supplementary Data: S2 Table

Case 159: Spanish, 65yo, 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.2167C>T (p.Arg723Cys)

ClinVar: 14095, https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: 0.00001194, https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Supplementary Data: S2 Table

Case 178: Spanish, 30yo, 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:c.920C>G

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

gnomAD: n/a

Supplementary Data: Table S3

Case 87:

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:c.332C>T

CAID: CA389053057, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389053057

gnomAD: n/a

MultipleGeneVariants:

(1) DMD Variant:

Variant: NM_004011.3:c.3062C>A

CAID: CA10378350, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA10378350

gnomAD: 0.0001133, https://gnomad.broadinstitute.org/variant/X-31893318-G-T

Supplementary Data: Table S3

Case 7:

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.2890G>C (p.Val964Leu)

ClinVar: 42938, https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/

gnomAD: 0.0004383, https://gnomad.broadinstitute.org/variant/14-23893148-C-G

MultipleGeneVariants:

(1) TTN Variant:

Variant: p.Arg12731Ter no ClinVar or CAID

Table 1 and 4

Case 64: Male, 42yo

DiseaseAssertion: HCM

FamilyInfo: negative family history

CaseHPOFreeText: interventricular septum thickness = 18.1mm, left ventricular end diastolic diameter = 51.7mm, left ventricular end systolic diameter = 34.4mm, left ventricular posterior wall thickness = 9.8mm, left atrium = 44mm, left ventricular ejection fraction = 61%

CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)

CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing

Variant: NM_000257.3(MYH7):c.1987C>T (p.Arg663Cys)

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

gnomAD: n/a

Table 1 and 4

Case A37: Female, 40yo

DiseaseAssertion: DCM

FamilyInfo: positive family history

CaseHPOFreeText: interventricular septum thickness = 7.9mm, left ventricular end diastolic diameter = 61.3mm, left ventricular end systolic diameter = 42mm, left ventricular posterior wall thickness = 6.8mm, left atrium = 32.6mm, left ventricular ejection fraction = 48%

CasePreviousTesting: 12-lead ECG, echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing (LMNA, PRKAG2, SCN5A, MYH6)

CaseGenotypingMethod: genomic DNA collected from peripheral whole blood samples, PCR, high-throughput sequencing using PGM Sequencing 400 kit, variants verified via Sanger Sequencing

Variant: NM_000257.3(MYH7):c.77C>T (p.Ala26Val)

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

gnomAD: 0.0005233, https://gnomad.broadinstitute.org/variant/14-23902865-G-A

Supplementary Data: Online Table 2a

Case:

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

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

Variant: NM_000257.3:c.415G>T

CAID: CA389052864, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052864

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.728G>A (p.Arg243His)

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

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/14-23900798-C-T

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

Supplementary Data: Online Table 1a

Case:

CasePresentingHPOs: HP:0001631, HP:0001629 (atrial septal defect, ventricular septal defect)

CaseHPOFreeText: Trisomy 21

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.976G>C (p.Ala326Pro)

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

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

Supplementary Data: 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.2945T>C (p.Met982Thr)

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

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

Supplementary Data: 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.3113T>C

CAID: CA257817954, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA257817954

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

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

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

Variant: NM_000257.3:c.715_717del

CAID: CA913184869, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184869

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:c.798T>A

CAID: CA389052023, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389052023

gnomAD: n/a

Case: Pedigree 4 proband, congenital (abnormalities noticed at 24wks gestation), Yemenite Jewish

CasePresentingHPOs: HP:0012817, HP:0010316 (noncompaction cardiomyopathy, Ebstein anomaly)

HPOsFreeText: clinical severity: moderate to asymptomatic

CaseNotHPOs:

NotHPOsFreeText: skeletal involvement

CasePreviousTesting: none

CaseGenotypingMethod: MYH7 sequencing

Variant: NM_000257.4:c.1859T>C (p.Leu620Pro)

CAID: CA389049669, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049669

gnomAD: n/a

FamilyInfo: father, the paternal grandmother, and paternal uncle had a known history of Ebstein anomaly and NCCM, proband's 2 sisters are healthy with no evidence of cardiomyopathy, 7 other family members diagnosed with Ebstein anomaly and NCCM, but most were asymptomatic, variant segregated with all affected members in heterozygous state, no unaffected members were genotype positive

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

PMID: 32830170

Gene: MYH7

HGNC: 7577

Case12: Female, 60 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One sibling and one child died of SCD in their 30s, with child having confirmed HCM

CasePresentingHPOs: HP:0001639, HP:0030148 (Hypertrophic cardiomyopathy, Heart murmur)

HPOsFreeText: Mixed features of apical and classic HCM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

Variant: NM_000257.3:c.1273G>A (p.Gly425Arg)

ClinVar: 42834 https://www.ncbi.nlm.nih.gov/clinvar/variation/42834/

gnomAD: Not in gnomAD

Case15: Female, 48 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One parent died of cardiomyopathy/sudden death, one offspring had a heart murmur and found to have HCM

CasePresentingHPOs: HP:0001639, HP:0001279, HP:0005162, HP:0003546 (Hypertrophic cardiomyopathy, Syncope, Left ventricular failure, Poor exercise tolerance)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Heart transplantation done

CasePreviousTesting: Probands were only genotyped for MYH7 and MYBPC3 in that order, stopping once a positive finding was detected.

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood. Each gene's coding exons and flanking introns were subject to PCR amplification and sequencing. From there, any variants found were filtered for pathogenicity and low frequencies.

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

Case III-15: Male, 18yo, diagnosed at 16yo

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0012250 (ST segment depression

CaseHPOFreeText: abnormal Q wave, interventricular septum = 15mm, posterior wall of left ventricle = 9mm

CaseNotHPOs: HP:0005135 (abnormal T wave)

CaseNotHPOFreeText: no clinical manifestations

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

Variant: NM_000257.3:c.1172A>C

CAID: CA389051191, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051191

gnomAD: n/a

Case 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

Supplementary Material 4

Case M-10: 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-6: 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-23: 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-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

Supplementary Material 4

Case M-16: 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.2156G>A (p.Arg719Gln)

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

gnomAD: n/a

Supplementary Material 4

Case M-29: 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-20: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

gnomAD: n/a

Case#: HCM443, female, 28 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 46mm LAD, 17mm LVST, 44mm LVEDD, 69% LVEF, 18mm Maxi LVWT, 68mmHg Maxi LVOTG, 103385170 raw RNA-seq reads, 96969874 HQ reads (93.79%), 96.18% mapping rate, 707524 total variant, 33016 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.2221G>T (p.Gly741Trp)

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

CAID: N/A

gnomAD: absent

Case#: HCM431, male, 24 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 57mm LAD, 18mm LVST, 49mm LVEDD, 80% LVEF, 21mm Maxi LVWT, 80mmHg Maxi LVOTG, 95467544 raw RNA-seq reads, 91611504 HQ reads (95.96%), 96.60% mapping rate, 701266 total variant, 33263 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.4066G>A (p.Glu1356Lys)

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

CAID: N/A

gnomAD: absent

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

Case#: HCM456, male, 28 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 51mm LAD, 15mm LVST, 45mm LVEDD, 69% LVEF, 20mm Maxi LVWT, 90mmHg Maxi LVOTG, 124188740 raw RNA-seq reads, 116826920 HQ reads (94.07%), 96.65% mapping rate, 793088 total variant, 35368 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.1207C>T (p.Arg403Trp)

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

CAID: N/A

gnomAD: absent

Case#: HCM491, female, 30 years, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 44mm LAD, 23mm LVST, 32mm LVEDD, 75% LVEF, 28mm Maxi LVWT, 64mmHg Maxi LVOTG, 123213328 raw RNA-seq reads, 115698990 HQ reads (93.90%), 95.97% mapping rate, 756623 total variant, 34040 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.1987C>T (p.Arg663Cys)

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

CAID: N/A

gnomAD: absent

Case#: HCM490, female, 41 yrs, not a smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 44mm LAD, 15mm LVST, 39mm LVEDD, 58% LVEF, 21mm Maxi LVWT, 63mmHg Maxi LVOTG, 109178274 raw RNA-seq reads, 102325212 HQ reads (93.72%), 96.79% mapping rate, 728218 total variant, 33873 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.4130C>T (p.Thr1377Met)

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

CAID: N/A

gnomAD: 0.000008791 European (non-finnish) https://gnomad.broadinstitute.org/variant/14-23887458-G-A

Case#: HCM562, female, 36 yrs, smoker

DiseaseAssertion: HCM

FamilyInfo: None

CasePresentingHPOs: 36mm LAD, 0mm LVST, 36mm LVEDD, 66% LVEF, 21mm Maxi LVWT, 70mmHg Maxi LVOTG, 119176332 raw RNA-seq reads, 113518840 HQ reads (95.25%), 96.63% mapping rate, 782848 total variant, 34382 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.427C>T (p.Arg143Trp)

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

CAID: N/A

gnomAD: 0.0001087 East Asian https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Case#: 8th case, male, 49 years

DiseaseAssertion: SHCM

FamilyInfo: No

CasePresentingHPOs: Mycardial fibrosis (HP:0001685)

CaseHPOFreeText: 630 g heart, IVST to LVWT ratio 1.38, IVST 2.2 cm, LVWT 1.6 cm, hypertrophy of myocardial fibers, stenosis in lumens,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no pathological changes found in major organs besides heart

CasePreviousTesting: N/A

CaseGenotypingMethod: physical examination, ECG, 2D and Doppler echocardiography, histological examinations, genomic DNA extraction, DNA cloning, sequence analysis

Variant: NC_000014.9:g.23429026T>G (Thr446Pro)

ClinVar: absent

CAID: CA257823360

gnomAD: absent

Case#: Case III-2, female, 64 yr, early childhood onset

DiseaseAssertion: None

FamilyInfo: Family C, her mother (II-1) and maternal grandmother (I-1) had late-onset leg weakness (Fig. 1C), her brother (III-4) had severe generalized weakness and was diagnosed with an unspecified muscular dystrophy

CasePresentingHPOs: Gait disturbance, lower limb muscle weakness, hypertension, osteoarthritis, hyperlipidemia, glaucoma, neck flexor weakness, weakness of facial musculature, weakness of long finger extensor muscles, foot dorsiflexor weakness (HP:0001288, HP:0007340, HP:0000822, HP:0002758, HP:0003077, HP:0000501, HP:0003722, HP:0030319, HP:0009077, HP:0009027)

CaseHPOFreeText: mild heel cord contractures, mild eye closure weakness, unable to stand on heels, limb weakness

CaseNotHPOs: Scoliosis, scapular winging, generalized muscle hypertrophy (HP:0002650, HP:0003691, HP:0003720)

CaseNotHPOFreeText: hand or foot deformities, normal knee bend and stand on tiptoes, normal reflexes and sensory

CasePreviousTesting: N/A

CaseGenotypingMethod: neurological examination, serum creatine kinase, nerve conduction studies, concentric needle electromyography, electrocardiogram, echocardiogram, forced vital capacity, muscle biopsy, immunohistochemical analyses, CK 156 unit/L (n < 143), FVC 2.13 L (68%), ECG and echo normal, left ventricular ejection fraction 65%, normal NCS except low-amplitude peroneal and tibial compound muscle action potential, abnormal increase of small polyphasic MUAP in tibialis anterior, no fibrillation potentials, no positive sharp waves, no myotonic discharges

Variant: NM_182476.3(COQ6):c.115G>A (p.Val39Met) & NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 214236 https://www.ncbi.nlm.nih.gov/clinvar/variation/214236/ & 190401 https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

CAID: N/A

gnomAD: 0.00006720 African https://gnomad.broadinstitute.org/variant/14-74417150-G-A & absent

PMID: 32380038

Gene: MYH7

HGNC: 7577

Table 5

Case EO23: 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:c.3973G>A

CAID: CA389041353, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389041353

gnomAD: n/a

Variant2: NM_000257.3(MYH7):c.2804A>T (p.Glu935Val)

ClinVar: 181207, https://www.ncbi.nlm.nih.gov/clinvar/variation/181207/

gnomAD: n/a

Table 5

Case LO13: Italian

DiseaseAssertion: HCM (late-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(MYH7):c.1816G>A (p.Val606Met)

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

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

Case: Patient 16, female, 39yo, symptom onset in adulthood

CasePresentingHPOs: HP:0030237, HP:0003327, HP:0003701, HP:0002460, HP:0003458 (hand muscle weakness, axial muscle weakness, proximal muscle weakness, distal muscle weakness, EMG: myopathic abnormalities)

HPOsFreeText: normal CK values

CaseNotHPOs: HP:0002650 (scoliosis)

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.3:c.1780C>A

CAID: CA389049833, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389049833

gnomAD: absent

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

CaseMYH7-5: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.2155C>T (p.Arg719Trp)

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

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

CaseMYH7-1: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.2803G>A (p.Glu935Lys)

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

gnomAD: Not in gnomAD

CaseMYH7-3: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.2504A>C (p.Lys835Thr)

CAID: CA389048271 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.2504A%3EC

gnomAD: Not in gnomAD

Case2: female, 16 years old

DiseaseAssertion: Myopathy

FamilyInfo:

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0003722, HP:0001371, HP:0009027, HP:0012515

"Toe walking, Scoliosis, Neck flexor weakness, Flexion contractures, Foot dorsiflexor weakness, Hip flexor weakness"

CaseHPOFreeText: Presented with toe-walking at age 5 years and required bilateral tendo-Achilles releases at ages 7 and 13 years. A progressive scoliosis required surgical stabilization at age 12 years. At age 13 years neck movements were markedly restricted in all directions except extension, and there were mild flexion contractures at the hips, knees and ankles. There was marked neck flexion weakness, moderate weakness of hip extension and ankle dorsiflexion, and mild weakness of shoulder abduction, hip flexion and knee flexion/extension. While walking her upper body was angled forward, there was external rotation of the feet and mild foot-drop. The axial involvement in this case largely spares the lumbar musculature and is restricted to the upper thoracic and neck regions.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Serum creatine kinase was 308 iu/l (24–215). There was moderate restrictive lung disease (as determined by formal pulmonary function testing) at age 12 years (FVC 55% of predicted). Electromyography, sural nerve biopsy and cardiac investigations (EKG and echocardiogram) were normal. A quadriceps muscle biopsy taken at age 13 years demonstrated congenital fiber type disproportion. There was type 1 fiber predominance (82%), marked type 1 hypotrophy and type 2 fiber hypertrophy. Muscle MRI scan at age 12 years showed selective fatty infiltration of spinalis muscles in the upper thoracic and cervical regions. Unreported heterozygous variants in RYR1 (p.Asn4200Ser), COL6A3 (p.Ser2829Pro) and TTN (p.Gly4604Glu) were detected, but were all present in a healthy parent. In addition, Sanger sequencing was normal for ACTA1, SEPN1, LMNA, TPM3, TPM2, TNNT1 and MYOZ2.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was found by whole exome sequencing studies, and confirmed by Sanger sequencing. This change was absent in parental DNA samples.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

Case1: female, 32 years old

DiseaseAssertion: Myopathy

FamilyInfo: Neither parent presents with MYH7 mutation

CasePresentingHPOs: HP:0002828, HP:0040083, HP:0003722, HP:0012515, HP:0009027, HP:0001371

"Multiple joint contractures, Toe walking, Neck flexor weakness, Hip flexor weakness, Foot dorsiflexor weakness, flexion contractures"

CaseHPOFreeText: Generalized weakness that is most notable in the distal musculature, presented with toe walking age 2 years, required multiple Achilles tendon lengthening surgeries between ages 11–14 years. From age 19 years patient developed progressive weakness and contractures. At age 32 years, patient could walk only short distances and had prominent contractures of the finger flexors, neck flexors, and tendo-Achilles. There was marked weakness of neck flexion, shoulder abduction, hip flexion and ankle dorsiflexion and moderate weakness of wrist/hand flexors and mild weakness of knee flexion/extension. Facial and ocular muscle function was normal.

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Muscle MRI of the thigh reveals involvement of many muscles including sartorius, quadriceps, and adductors, with relative sparing of biceps femoris. Muscle MRI of the distal lower extremity shows fatty infiltration in the soleus and lateral gastrocnemius with relative sparing of the medial gastrocnemius. Electromyography (EMG) showed myopathic features and serum CK was mildly elevated. Cardiac evaluation (via EKG and echocardiogram) was unremarkable. At age 32 years, based on formal pulmonary function testing, patient exhibited moderate restrictive lung disease (forced vital capacity 63% of predicted). A quadriceps muscle biopsy performed at age 11 years showed non-specific myopathic changes while a gastocnemius biopsy performed at age 32 years showed prominent mini-cores, increased internalized nuclei (~40% of fibers), type I fiber predominance, mildly increased endomysial fibrosis and focal fatty replacement. Sanger sequencing was normal for RYR1 (full exonic sequencing), SEPN1, LMNA, and COL6A1/2/3.

GenotypingMethod: A heterozygous MYH7 p.Leu1597Arg (c.4790T>G) missense change was detected in the patient and not found in either parent.

Variant: NM_000257.4:c.4790T>G (MYH7)

ClinVar: not found

CAID: CA389037627

gnomAD: not found

PMCID: 6447666

Gene: MYH7

HGNC: 7577

PMID: 23711808

Gene: MYH7

HGNC: 7577

Direct gene sequencing of β-myosin heavy chain (MYH7), myosin binding protein-C (MYBPC3), and cardiac troponin T (TNNT2) was performed in 136 unrelated Chinese HC patients. Clinical evaluations were conducted. In total, 32 mutations were identified in 36 patients (27%), including 10 novel ones. Distribution of mutations was 56% (MYBPC3), 31% (MYH7), and 13% (TNNT2), respectively. Double mutations were identified in 3% patients.

PMID: 23580644

Gene: MYH7

HGNC: 7577

We find in agreement with earlier studies that the R403Q mutation in a mouse α-MHC backbone results in a gain of function, a model that has been widely accepted as the primary cause leading to hypertrophic cardiomyopathy. However, we find that this enhancement does not extend to the R403Q mutation in a mouse β-MHC backbone. Our results do not necessarily imply a universal mechanism for FHC mutations in the β-myosin heavy chain.

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

CaseMYH7-39: 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.952A>C (p.Thr318Pro)

CAID: CA389051682 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000257.3%3Ac.952A%3EC

gnomAD: Not in gnomAD

CaseMYH7-26: 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-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

CaseMYH7-35: 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.1324C>T (p.Arg442Cys)

ClinVar: 177897 https://www.ncbi.nlm.nih.gov/clinvar/variation/177897/

gnomAD: East Asian 5.012e-5, Overall 2.121e-5 https://gnomad.broadinstitute.org/variant/14-23898247-G-A

CaseMYH7-32: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 3 other probands share this genotype

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.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

CaseMYH7-29: 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.2093T>C (p.Val698Ala)

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

gnomAD: Not in gnomAD

CaseC: 13 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Three affected relatives (5 possibly affected), Mother died 44 y with heart failure, Brother SCD 16 y

CasePresentingHPOs: HP:0001639, HP:0005110 (Hypertrophic cardiomyopathy, Atrial fibrillation)

HPOsFreeText: Maximum left ventricular hypertrophy at 20 mm

CaseNotHPOs: N/A

NotHPOsFreeText: Sudden cardiac death event

CaseAddInfo: Heart transplant was required

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

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.818G>A (p.Arg273His)

ClinVar: 161312 https://www.ncbi.nlm.nih.gov/clinvar/variation/161312/

gnomAD: Latino 2.275e-4, Overall 9.182e-5 https://gnomad.broadinstitute.org/variant/11-47369411-C-T

Supplemental data table e-1

Case: MYH7 Case 1

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 29300372

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.1358G>A (p.Arg453His)

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

gnomAD: n/a

Supplemental data table e-1

Case: MYH7 Case 2

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 27282841

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.5459G>A (p.Arg1820Gln)

ClinVar: 419278, https://www.ncbi.nlm.nih.gov/clinvar/variation/419278/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23884304-C-T

Country: Portugal

DiseaseAssertion: Hypertrophic Cardiomyopathy

GenotypingMethod: Genetic testing was performed at the discretion of participating centers and laboratories. All variants were classified by pathogenicity based on ClinVar interpretations and populations frequency.

PreviousTesting: All nine sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, ACTC1, TPM1, CSRP3) were compared with others likely being done depending on the submitting center/lab.

VariantAddInfo: 7 individuals inc. carriers reported

Variant: NM_000257.4(MYH7):c.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

Case#: 16, female, diagnosed as fetus,

DiseaseAssertion: LVNC

FamilyInfo: yes

CasePresentingHPOs: cyanosis, Ebstein anomaly of the tricuspid valve, Ventricular septal defect, coarctation of aorta, congestive heart failure (HP:0000961, HP:0010316, HP:0001629, HP:0001680, HP:0001635)

CaseHPOFreeText: -5.47 Fathmm, 0 sift, 0.001 polyphen2, 0 GVGD, mutation taster 1, -3.64 provean, -5.15 CADD,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no extracardiac abnormalities

CasePreviousTesting: N/A

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

Variant: absent

ClinVar: absent

CAID: CA389051391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051391

gnomAD: absent

Case#: 27

DiseaseAssertion: LVNC

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: 1.96 Fathmm, 0 sift, 0.997 polyphen2, C65 GVGD, mutation taster 1, -4.85 provean, -5.29 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.2078T>G

ClinVar: absent

CAID: CA389049168

gnomAD: absent

Case#: 18, female, diagnosed at 4 days,

DiseaseAssertion: LVNC

FamilyInfo: yes

CasePresentingHPOs: heart murmur, Ebstein anomaly of the tricuspid valve, Ventricular septal defect, coarctation of aorta, Congestive heart failure (HP:0030148, HP:0010316, HP:0001629, HP:0001680, HP:0001635)

CaseHPOFreeText: -5.47 Fathmm, 0 sift, 0.001 polyphen2, 0 GVGD, mutation taster 1, -3.64 provean, -5.15 CADD,

CaseNotHPOs: N/A

CaseNotHPOFreeText: no extracardiac abnormalities

CasePreviousTesting: N/A

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

Variant: NM_000257.3:c.1085T>G

ClinVar: absent

CAID: CA389051391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389051391

gnomAD: absent

Case4: Male, 26 years report, Netherlands

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

HPOsFreeText: Positive EPS inducibility

CaseNotHPOs: HP:0001639, HP:0001635 (Hypertrophic cardiomyopathy, Congestive heart failure)

NotHPOsFreeText: ECG Depolarization abnormality, Cardiac transplant

CaseAddInfo:

CasePreviousTesting: No variants were in any of DSP, PKP2, DSG2, DSC2, and JUP. Patients were tested for variants in ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1.

CaseGenotypingMethod: 92 patients underwent panel sequencing of the specific genes listed above, and 45 were subject to Whole Exome Sequencing to locate variants. Afterwards, all variants were verified by PCR amplification and Sanger sequencing and filtered for pathogenicity.

Variant: NM_000257.3:c.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

gnomAD: South Asian 3.266e-5, Overall 1.194e-5 https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Case3: Male, 37 years report, Netherlands

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

HPOsFreeText: Positive EPS inducibility

CaseNotHPOs: HP:0001639, HP:0001635, HP:0001711 (Hypertrophic cardiomyopathy, Congestive heart failure, Abnormality of the left ventricle)

NotHPOsFreeText: ECG Depolarization abnormality, Cardiac transplant

CaseAddInfo:

CasePreviousTesting: No variants were in any of DSP, PKP2, DSG2, DSC2, and JUP. Patients were tested for variants in ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1.

CaseGenotypingMethod: 92 patients underwent panel sequencing of the specific genes listed above, and 45 were subject to Whole Exome Sequencing to locate variants. Afterwards, all variants were verified by PCR amplification and Sanger sequencing and filtered for pathogenicity.

Variant: NM_000257.3:c.5536C>T (p.Arg1846Cys)

ClinVar: 161321 https://www.ncbi.nlm.nih.gov/clinvar/variation/161321/

gnomAD: East Asian 5.441e-5, Overall 1.208e-5 https://gnomad.broadinstitute.org/variant/14-23884227-G-A