Supplementary Data: Online Table 1a

Case:

CasePresentingHPOs: HP:0001629 (Ebstein anomaly)

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

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

Variant: NM_000257.3(MYH7):c.689T>C (p.Phe230Ser)

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

gnomAD: n/a

Supplementary Data: Online Table 2a

Case:

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

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

Variant: NM_000257.3(MYH7):c.689T>C (p.Phe230Ser)

ClinVar: 236543, https://www.ncbi.nlm.nih.gov/clinvar/variation/263543/

gnomAD: n/a

Variant1: NM_000257.4(MYH7):c.1633G>A (p.Asp545Asn)

ClinVar: 264607 https://www.ncbi.nlm.nih.gov/clinvar/variation/264607/

gnomAD: 0.00001759, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

Variant2: NM_000257.4(MYH7):c.2678C>T (p.Ala893Val)

ClinVar: 177763 https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/

gnomAD: Not in gnomAD

Variant3: NM_000257.3:c.2713T>C (p.Cys905Arg)

CAID: CA389047302 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.2713T%3EC

gnomAD: Not in gnomAD

Variant4: NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608 https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: Not in gnomAD

Variant5: NM_000257.3:c.415G>T (p.Val139Leu)

CAID: CA389052864 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.415G%3ET

gnomAD: Not in gnomAD

Variant6: NM_000257.4(MYH7):c.495G>A (p.Met165Ile)

ClinVar: 524948 https://www.ncbi.nlm.nih.gov/clinvar/variation/524948/

gnomAD: Not in gnomAD

Variant7: NM_000257.3:c.547G>A (p.Gly183Arg)

CAID: CA389052574 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.547G%3EA

gnomAD: Not in gnomAD

Variant8: NM_000257.3:c.5754C>G (p.Asn1918Lys)

CAID: CA389034544 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5754C%3EG

gnomAD: Not in gnomAD

Variant9: NM_000257.3:c.5773C>G (p.Arg1925Gly)

CAID: CA257807342 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.5773C%3EG

gnomAD: Not in gnomAD

Variant10: NM_000257.4(MYH7):c.689T>C (p.Phe230Ser)

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

gnomAD: Not in gnomAD

Variant11: NM_000257.3:c.715_717del (p.Asp239del)

CAID: CA913184869 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.715_717del

gnomAD: Not in gnomAD

Variant12: NM_000257.4(MYH7):c.732+1G>A

ClinVar: 14127 https://www.ncbi.nlm.nih.gov/clinvar/variation/14127/

gnomAD: 0.00005437, https://gnomad.broadinstitute.org/variant/14-23900793-C-T

Variant13: NM_000257.3:c.798T>A (p.Tyr266Ter)

CAID: CA389052023 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.798T%3EA

gnomAD: Not in gnomAD

Variant14: NM_000257.4(MYH7):c.847T>G (p.Tyr283Asp)

ClinVar: 66081 https://www.ncbi.nlm.nih.gov/clinvar/variation/66081/

gnomAD: Not in gnomAD

Variant15: NM_000257.3:c.902T>A (p.Leu301Gln)

CAID: CA389051788 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000257.3%3Ac.902T%3EA

gnomAD: Not in gnomAD

Case362: Female, 0.0833 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

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

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

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

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

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

gnomAD: Not in gnomAD

Case#: 24

DiseaseAssertion: LVNC

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: 5.9 Fathmm, 0 sift, 0.984 polyphen2, 0 GVGD, mutation taster 1, -4.96 provean, -6.07 CADD

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

Variant: NM_000257.4(MYH7):c.689T>C (p.Phe230Ser)

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

CAID: N/A

gnomAD: absent