Case#: 02042, Age 41, Male, Blood Type: O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Family#: 0215; 5 Members of the family were included in the study. 1 was diagnosed type 3 (patient 02039) and the other 4 were carriers for VW

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:Ag: 25, VWF:RCo: 21, FVIII:C:77, VWF:CB: 27

CaseNotHPOs:

CaseNotHPOFreeText: Bleeding score 1

Protein Expression:

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.1109G>A

ClinVar: N/A

CAID:CA6403559

CAID

gnomAD: MAF of 0.000008802 (1/113608 alleles) in the European (non-Finnish population). gnomAD

Case#: 02074, Age 37, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #0228.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 24, VWF:RCo: 21, FVIII:C: 111, VWF:CB: 29

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4(VWF):c.3426T>C (p.Cys1142=), NM_000552.4:c.6254G>T (p.Cys2085Phe), and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)

ClinVar: 256668 and 619934 ClinVar ClinVar2

CAID: CA6402757, CA383492060, and CA658683073

CAID1

CAID2

gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).

Case#: 27032, Age 49, Female, Blood Type O+

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#2716. The other member has the same variant, but is only a carrier.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:31, VWF:RCo: 22.7, FVIII:C: 72, VWF:CB: 38

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2518G>T (p.Glu840Ter)

ClinVar: N/A

CAID:CA383520331 CAID

gnomAD: N/A

Case#: 06012, Age 10, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is member of Family# 0609, which includes 3 individuals. All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 10, VWF:Ag: 13, VWF:RCo:14, FVIII:C:40, VWF:CB:13

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3363G>T (p.Arg1121Ser)

ClinVar: N/A

CAID: CA383511875 CAID

gnomAD: N/A

Case#: 02064, Age 32, Male, Blood type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is a part of family # 0224. There are 3 other members of the family (02065, 02066, 02067). All members of the family have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 13, VWF:Ag: 4.7, VWF:RCo: 5, FVIII:C: 16, VWF:CB:6

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene:VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308

ClinVar

CAID: CA114160

CAID1

gnomAD: N/A

Case#: 27024, Age 56, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2713.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:5.3, VWF:RCo:6, FVIII:C:38, VWF:CB:4.2

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 06024, Age 36, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#0617.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 1, VWF:Ag:35, VWF:RCo:25, FVIII:C:69, VWF:CB: 27

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.7300C>T (p.Arg2434Ter)

ClinVar: 100464 ClinVar

CAID: CA228781 CAID

gnomAD: MAF of 0.0001298 (2/15414 alleles) in the European (non-Finnish) population. gnomAD

Case#: 02058, Age 64, Female, Blood type A+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Patient is the only member of family #0221.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 19, VWF:Ag: 7.3, VWF:RCo: 5.9, FVIII:C: 19, VWF:CB: 6.3

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His)

ClinVar: 308 ClinVar

CAID: CA114160 CAID

gnomAD: N/A

Case#: 03035, Age 51, Male (Table S3)

Disease Assertion: VWD1

FamilyInfo: A part of family #03150 along with two other patients.

Parental Genotype: Not listed

CasePresentingHPOs: Not listed

CaseHPOFreeText: Bleeding Score 4, VWF:Ag: 34, VWF:RCo: 26, FVIII:C: 43, VWF:CB 33

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression:N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 32002, Age 49, Female, Blood Type +

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 3202.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 34, VWF:RCo: 30, FVIII:C: 53, VWF:CB: 29

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 3

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.7408C>T (p.Gln2470Ter)

ClinVar: 100469 ClinVar

CAID: CA228790 CAID

gnomAD: MAF of 0.00002891 (1/34590 alleles) in the Latino population.

Case#: 06007, Age 54, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD

FamilyInfo: Two total patients were documented from family# 0606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 28, VWF:RCo: 26.1, FVIII:C: 56, VWF:CB: 23

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding Score 5

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.1156+2T>C (intronic)

ClinVar: N/A

CAID: CA383504978 CAID

gnomAD: N/A

Case#: 18001, Age 50, Male, Blood Type B+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient one of 3 members of Family#1801. All of the patients have the same variant.

Parental Genotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:10, VWF:RCo:6.1, FVIII:C:17, VWF:CB:8.2

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations

Gene: VWF

Variant: NM_000552.4:c.3614G>A (p.Arg1205His) and NM_000552.4:c.6989T>G (p.Val2330Gly)

ClinVar: 308 ClinVar1

CAID: CA114160 and CA6401808 CAID1 CAID2

gnomAD: MAF of 0.000008823 (1/113342 alleles) in the European (non-Finnish population) (CA6401808) gnomAD

Case#: 36008, Age 34, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#3606.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag: 34, VWF:RCo:14, FVIII:C: 37, VWF:CB: 25

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.2771G>A(p.Arg924Gln) and NM_000552.4:c.3390C>T (p.Cys1130=)

ClinVar: 627186 ClinVar

CAID: CA228368 and CA478101454 CAID1 CAID2

gnomAD: MAF of 0.01866 (2411/ 129182 alleles) in the European (non-Finnish) population (CA228368). gnomAD

Case#: 02052, Age 25, Male, Blood type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only family member of family # 0220

Parental Genotype: Not listed

CasePresentingHPOs:N/A

CaseHPOFreeText: Bleeding Score: 11, VWF:Ag: 15, VWF:RCO:12, FVIII:C:20, VWF:CB: 16

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Protein Expression: N/A

CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.

Gene: VWF

Variant: NM_000552.4:c.1625C>G (p.Ala542Gly) and NM_000552.4:c.6187C>T (p.Pro2063Ser)

ClinVar: 381621 and 100436 ClinVar1

ClinVar2

CAID: CA6403319 and CA202650 CAID1

CAID2

gnomAD: MAF of 0.001355 (48/ 35418 alleles) in the Latino population (CA6403319). MAF of 0.04854 (1486/ 30616 alleles) in the South Asian Population (CA202650).

gnomAD1

gnomAD2

Case: 24-year-old Caucasian woman with a rare variety of type 2M VWD

DiseaseAssertion: 2M VWD

FamilyInfo: family history was negative for easy bruisability, bleeding, or clotting disorder but maternal grandmother had lung cancer.

CaseNOTHPOFreeText: Von Willebrand factor antigen 45% on 9/12/17 and 37% on 9/19/17 with the ratio of VWF activity to the antigen is less than 0.7

ParentalGenotype(s):Unknown

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0000978 (Bruising susceptibility).

**CaseHPOFreeText: ** loss of weight over the last six months, The complete blood count, comprehensive metabolic panel, factor VIII, prothrombin time and partial thromboplastin time, D-Dimer, and antithrombin activity were normal. Her von Willebrand factor activity was much lower compared to the antigen.

CasePreviousTesting: None

GenotypingMethod: Patient have not been genotyped

PreviouslyPublished: N/A

Variant: N/A

ClinVarID: N/A

gnomAD: N/A

**Gene: ** VWF Inheritance mode autosomal dominant variety with normal, high molecular weight multimers

Case: P71, Chinese, female, 23yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 57.9, VWF:RCo (%) = 55.6, FVIII:C (%) = 71.3, VWF:CB (%) = 69.7, VWFpp (%) = 66.9, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 1.2

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4850A>G (p.Lys1617Arg)

HGVS: NM_000552.3:c.4850A>G (p.Lys1617Arg)

ClinVarID: NA

CAID: CA6402448; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402448

gnomAD: MAF = 0.0002507 (5/19942 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6127734-T-C

Case: P7, Chinese, female, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 5.4, VWF:RCo (%) = 5.3, FVIII:C (%) = 28, VWF:CB (%) = 4.1, VWFpp (%) = 4.8, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.2, RIPA (1.2 mg/ml, %) = 73.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.711C>G (p.Cys237Trp)

HGVS: NM_000552.3:c.711C>G (p.Cys237Trp)

ClinVarID: NA

CAID: CA383509260; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383509260

gnomAD: absent

Variant: c.1109+47T>A - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P10, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 2; VWF:Ag (%) = 4.2, VWF:RCo (%) = 3.8, FVIII:C (%) = 30.1, VWF:CB (%) = 3.5, VWFpp (%) = 4.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 7.4, RIPA (1.2 mg/ml, %) = 40.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.7199delA (p.Asn2400Thrfs*4) - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.8155+5G>C - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P6, Chinese, male, 57yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type AB blood, bleeding score = 15; VWF:Ag (%) = 18.5, VWF:RCo (%) = 5.8, FVIII:C (%) = 39.0, VWF:CB (%) = 4.9, VWFpp (%) = 36.4, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3920T>G (p.Leu1307Arg)

HGVS: NM_000552.5:c.3920T>G (p.Leu1307Arg)

ClinVarID: NA

CAID: CA383506205; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506205

gnomAD: absent

Case: P72, Chinese, female, 25yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 31.1, VWF:RCo (%) = 10.5, FVIII:C (%) = 44.8, VWF:CB (%) = 5.4, VWFpp (%) = 73, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 8.7, PLT(×109/l) = 181

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3939G>C (p.Trp1313Cys)

HGVS: NM_000552.4(VWF):c.3939G>C (p.Trp1313Cys)

ClinVarID: 287; https://www.ncbi.nlm.nih.gov/clinvar/variation/287/

CAID: NA

gnomAD: absent

Case: P77, Chinese, female, 10yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 7; VWF:Ag (%) = 3.0, VWF:RCo (%) = 2.7, FVIII:C (%) = 6.8, VWF:CB (%) = 2.1, VWFpp (%) = 3.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 2.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.6771C>A (p.Cys2257Ter)

HGVS: NM_000552.5:c.6771C>A (p.Cys2257Ter)

ClinVarID: NA

CAID: CA383489897; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383489897

gnomAD: absent

Variant 2: c.8116-2delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P34, Chinese, female, 34yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 13; VWF:Ag (%) = 20.2, VWF:RCo (%) = 6.9, FVIII:C (%) = 32.9, VWF:CB (%) = 4.8, VWFpp (%) = 54.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.7, FVIII:C/VWF:Ag = 1.6, RIPA (0.5 mg/ml, %) = 65.1, PLT(×109/l) = 153

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3916C>T (p.Arg1306Trp)

HGVS: NM_000552.4(VWF):c.3916C>T (p.Arg1306Trp)

ClinVarID: 288; https://www.ncbi.nlm.nih.gov/clinvar/variation/288/

CAID: NA

gnomAD: absent

Case: P61, Chinese, female, 34yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 57.6, VWF:RCo (%) = 57.8, FVIII:C (%) = 76.2, VWF:CB (%) = 67.4, VWFpp (%) = 62.7, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-128G>A

HGVS: NM_000552.3:c.-128G>A

ClinVarID: NA

CAID: CA603092904; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA603092904

gnomAD: MAF = 0.001182 (1/846 alleles) in Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6233714-C-T

Case: P27, Chinese, female, 3yo

DiseaseAssertion: VWD2N

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 6; VWF:Ag (%) = 9.5, VWF:RCo (%) = 8.9, FVIII:C (%) = 6.5, VWF:CB (%) = 6.9, VWFpp (%) = 10.8, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.7, VWF: FVIIIB (%) = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.2396G>A (p.Cys799Tyr)

HGVS: NM_000552.5:c.2396G>A (p.Cys799Tyr)

ClinVarID: NA

CAID: CA232300402; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232300402

gnomAD: absent

Variant 2: c.3197_3201del - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P36, Chinese, male, 56yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.1, VWF:CB (%) = 0.9, VWFpp (%) = 0.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P83, Chinese, male, 5yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with mild haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 44.5, VWF:RCo (%) = 36.7, FVIII:C (%) = 12.6, VWF:CB (%) = 49.2, VWFpp (%) = 35.2, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 0.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6104G>A (p.Gly2035Asp)

HGVS: NM_000552.3:c.6104G>A (p.Gly2035Asp)

ClinVarID: NA

CAID: CA6402069; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6402069

gnomAD: MAF = 0.005613 (112/19954 alleles; 2 homozygotes) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6103733-C-T

Multiple Gene Variants

Gene: F8

Variant: c.943G>T (p.Ala315Ser)

HGVS: NM_000132.3:c.943G>T (p.Ala315Ser)

ClinVarID: NA

CAID: CA414917823; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA414917823

gnomAD: absent

Case: P29, Chinese, male, 10yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.9, VWF:RCo (%) = 5.9, FVIII:C (%) = 37.8, VWF:CB (%) = 17.4, VWFpp (%) = 31.3, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3943C>T (p.Arg1315Cys)

HGVS: NM_000552.4(VWF):c.3943C>T (p.Arg1315Cys)

ClinVarID: 100310; https://www.ncbi.nlm.nih.gov/clinvar/variation/100310/

CAID: NA

gnomAD: absent

Case: P22, Chinese, male, 22yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 1.4, VWF:RCo (%) = 1.2, FVIII:C (%) = 5.1, VWF:CB (%) = 1.3, VWFpp (%) = 1.0, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 3.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P42, Chinese, male, 10yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 41.9, VWF:RCo (%) = 33.9, FVIII:C (%) = 54.7, VWF:CB (%) = 46.8, VWFpp (%) = 34.6, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.-672C>T

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P33, Chinese, female, 35yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.0, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 10.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.813C>G (p.Tyr271Ter)

HGVS: NM_000552.5:c.813C>G (p.Tyr271Ter)

ClinVarID: NA

CAID: CA383508522; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508522

gnomAD: MAF = 0.0001088 (2/18380 alleles) in the East Asian popualtion; https://gnomad.broadinstitute.org/variant/12-6184562-G-C

Case#: 1, female, 44yo

DiseaseAssertion: VWD1

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0007420, HP:0000132, HP:0004846, HP:0012147, HP:0030129, HP:0030130 (spontaneous hematomas, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·47, VWF:RCo (0·55–2 iu/ml) pre = 0·5, FVIII:C (0·55–2 iu/ml) pre = 0·16, FVIII:C/VWF:Ag ratio = 0·32, VWF:FVIII binding (>20%) = 7%, VWF:FVIII binding/VWF:Ag (>0·7) = 0·15, patient died after motor vehicle accident

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: N/A

CasePreviousTesting: RFLP; confirmatory sequencing

Gene: VWF

Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation

Case#: 3, female, 19yo

DiseaseAssertion: VWD1

FamilyInfo: brother diagnosed with VWD

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978; HP:0000132, HP:0004846, HP:0012147, HP:0030129 (Bruising susceptibility, Menorrhagia, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Type O blood, VWF:Ag (0·55–2 iu/ml) pre = 0·14, VWF:RCo (0·55–2 iu/ml) pre = 0·15, FVIII:C (0·55–2 iu/ml) pre = 0·1, FVIII:C/VWF:Ag ratio = 0·71, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, spinal surgery with VWF concentrate and adequate haemostasis

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: N/A

CasePreviousTesting: RFLP; confirmatory sequencing

Gene: VWF

Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation

Case#: 4, male, 23yo

DiseaseAssertion: VWD1

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0004846, HP:0012147, HP:0030129 (Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Haemarthrosis in teens, Delayed bleeding after tonsillectomy (DDAVP given prior to procedure), VWF:Ag (0·55–2 iu/ml) pre = 0·35, VWF:RCo (0·55–2 iu/ml) pre = 0·32, FVIII:C (0·55–2 iu/ml) pre = 0·12, FVIII:C/VWF:Ag ratio = 0·34, VWF:FVIII binding (>20%) = n/a, VWF:FVIII binding/VWF:Ag (>0·7) = n/a, Surgery to repair a syringomyelia defect with VWF concentrate and no bleeding complications

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

ProteinExpression: N/A

CasePreviousTesting: RFLP; confirmatory sequencing

Gene: VWF

Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T

Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation

Case: 2M-2

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.01; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.41

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1409710

Gene: VWF

Variant: c.3970G>A (p.Gly1324Ser)

HGVS: NM_000552.5(VWF):c.3970G>A (p.Gly1324Ser)

ClinVarID: 300; https://www.ncbi.nlm.nih.gov/clinvar/variation/300/?new_evidence=false

CAID:

gnomAD: MAF = 0.00003267 in South Asian population; https://gnomad.broadinstitute.org/variant/12-6128614-C-T

Case: 2A-5

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.24

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 1537829

Gene: VWF

Variant: c.4789C>T (p.Arg1597Trp)

HGVS: NM_000552.5(VWF):c.4789C>T (p.Arg1597Trp)

ClinVarID: 285; https://www.ncbi.nlm.nih.gov/clinvar/variation/285/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-8

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.99; AcuStar CB/Ag = 1.35; ELISA CB/Ag = 1.02

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 16985174

Gene: VWF

Variant: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.5(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/?new_evidence=false

CAID:

gnomAD: MAF (European, Finnish) = 0.003667; 1 homozygote; https://gnomad.broadinstitute.org/variant/12-6128787-G-A

Case: 2A-7

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.27; AcuStar CB/Ag = 0.10; ELISA CB/Ag = 0.39

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID:1673047

Gene: VWF

Variant: c.4883T>C (p.Ile1628Thr)

HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-1

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.49; AcuStar CB/Ag = 0.29; ELISA CB/Ag = 0.33

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMID: 8435341

Gene: VWF

Variant: c.4541T>G (p.Phe1514Cys)

HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)

ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false

CAID:

gnomAD: absent

Case: Patient 9 (Family B), male, 71yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147

(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 56, PFA 100 sec = >300, SPA % = 22, MADR mg/mL = 0.3, VWF:Ag U/dL = 81.2, VWF:CB U/dL = 25.9, VWF:CB ratio = 0.32, VWF:RCo U/dL = 33.75, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 146.2, FVIII U/dL = 52, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/

CAID: NA

gnomAD: absent

Case: Patient 3 (Family B), male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)

CaseHPOFreeText: blood group O, Platelet count x103/μl = 204, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 23.4, VWF:CB U/dL = 21.1, VWF:CB ratio = 0.9, VWF:RCo U/dL = 17.2, VWF:RCo ratio = 0.74, Platelet VWF U/dL = 42.6, FVIII U/dL = 60.5, BAT F/M = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.3797C>T (p.Pro1266Leu)

HGVS: NM_000552.4(VWF):c.3797C>T (p.Pro1266Leu)

ClinVarID: 314; https://www.ncbi.nlm.nih.gov/clinvar/variation/314/

CAID: NA

gnomAD: MAF = 0.003667 (92/25086 alleles; 1 homozygote) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128787-G-A?dataset=gnomad_r2_1

Variant 2: c.7085G>T (p.Cys2362Phe)

HGVS: NM_000552.4(VWF):c.7085G>T (p.Cys2362Phe)

ClinVarID: 315; https://www.ncbi.nlm.nih.gov/clinvar/variation/315/

CAID: NA

gnomAD: absent

Case#: Male, 31<br /> DiseaseAssertion: VWD 2N<br /> FamilyInfo: A younger brother with mild HA, sister with normal VWF levels, no other famile members with bleeding disorders<br /> ParentalGenotype: <br /> CasePresentingHPOs: HP:0000421 (epistaxis), HP:0007420 (spontaneous hematoma)<br /> CaseHPOFreeText: Soft tissue bleeding, VWF:Ag 80%, VWF:RCo 60%, normal VWF multimer pattern<br /> CaseNotHPOs:<br /> CaseNotHPOFreeText: <br /> CasePreviousTesting: Genotyping using Next Gen screening, by Sanger sequence screening of all 26 exons of F8 gene, by a multiplex ligation-dependent probe affinity assay, and by a VWF:FVIII binding assay<br /> Gene: VWF<br /> Variant: c2390T>G in exon 18<br /> ClinVar:<br /> CAID: gnomAD:

Case#: p.D1283Y, Female, Age 85, Caucasian

Disease Assertion: VWD2M

FamilyInfo: Single affected family member with similar bleeding score

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: VWF:RCo/ VWF:Ag ratio 0.34, bleeding score 12, VWF:RCo 12 IU/dL, VWF:Ag 25 IU/dL

CaseNotHPOs: HP:0040240

(Increased Ratio of VWF Propeptide to VWF antigen)

CaseNotHPOFreeText: Normal multimer distribution

Protein Expression: N/A

CasePreviousTesting: VWF Sequencing

Gene: VWF

Variant: NM_000552.4:c.3847G>T (p.Asp1283Tyr)

ClinVar: N/A

CAID: CA383506819

CAID

gnomAD: N/A

Case: T3-2, female, 11yo

DiseaseAssertion: VWD3

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 13, VWF:Ag (IU/mL) = 0.01; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.01

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.1897T>C (p.Cys633Arg)

HGVS: NM_000552.5:c.1897T>C (p.Cys633Arg)

ClinVarID: n/a

CAID: CA383496953; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496953

gnomAD: absent

Case: 2B, male, 55yo

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: O+, bleeding score = 17, VWF:Ag (IU/mL) = 0.40; VWF:RCo (IU/mL) = 0.13; FVIII:C (IU/mL) = 0.46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A (p.Val1316Met)

HGVS: NM_000552.5(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/?new_evidence=false

CAID:

gnomAD: absent

Case: 2M, female, 25yo

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeText: Blood type: A+, bleeding score = 7, VWF:Ag (IU/mL) = 0.11; VWF:RCo (IU/mL) = 0.03; FVIII:C (IU/mL) = 0.39

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: qRT-PCR

PreviouslyPublished:

Gene: VWF

Variant: c.4145T>C (p.Leu1382Pro)

HGVS: NM_000552.5:c.4145T>C (p.Leu1382Pro)

ClinVarID: n/a

CAID: CA383504407; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383504407

gnomAD: absent

Case: Index Patient (IP), Female, 26 years old; described as from a genetically isolated population (not further specified), consistent with elevated homozygosity rates in that population. DiseaseAssertion: Type 3 VWD, confirmed by VWF:Ag <4 IU/dL (virtual absence of VWF). FamilyInfo: NA — no relatives' bleeding history or genotype reported ParentalGenotype(s): NA (not tested/not reported) CasePresentingHPOs: HP:0000421 (Epistaxis — frequent nosebleeds), HP:0000132 (Menorrhagia — heavy, prolonged, led to iron-deficiency anemia), HP:0001934 (Persistent bleeding after trauma — bleeding following injury), HP:0012147 (Reduced quantity of VWF; VWF:Ag <4 IU/dL), HP:0030129 (Impaired VWF:RCo-type activity; VWF:GPIbM <4 IU/dL) CaseHPOFreeText: Easy bruising (no matching HPO code in the approved list); FVIII:C 2.0 IU/dL (nv 70–157); referred to Hemophilia Centre at age 1 for bleeding complications; declined recommended lifelong prophylaxis due to injection discomfort, later underwent prophylaxis with plasma-derived VWF/FVIII concentrates and on-demand treatment (tranexamic acid, oral contraceptives, replacement therapy). Supporting functional evidence from patient-derived endothelial colony-forming cells (ECFCs): virtual absence of VWF mRNA (RQ ~0.04–0.05 vs. 1.00 in healthy controls, across 4 primer/probe sets); VWF secretion into ECFC medium 6.2% ± 0.4% of healthy controls (p<0.0001); near-total absence of Weibel-Palade bodies on immunofluorescence (only 1–3 small WPBs seen in some cells vs. normal stick-shaped WPBs in controls); altered intracellular trafficking of angiopoietin-2 (WPB inflammatory cargo) in the absence of WPBs. CaseNOTHPOs: NA CaseNOTHPOFreeText: NA CasePreviousTesting: Routine testing (Sanger sequencing of coding exons, ~50 bp flanking intronic regions, promoter, 5'/3'-UTR, plus MLPA) was negative — patient was "mutation-negative" prior to this study. Not genome-wide; targeted to VWF only, but comprehensive: this study's NGS covered the entire 176 kb VWF locus (all 52 exons, full intronic regions, promoter) at 30x coverage, going well beyond standard exon+flanking-intron approaches specifically to find deep intronic variants. GenotypingMethod: Illumina NovaSeq 6000 NGS (2×150 bp reads) of the whole VWF genomic region; variant annotation via Ensembl VEP with SpliceAI, PolyPhen-2, SIFT; splice effect independently confirmed with Neural Network Splicing, ASSP, and MaxEnt/HSF prediction tools. Functional validation via patient-derived ECFCs: RT-qPCR of VWF mRNA (4 primer/probe sets), cDNA sequencing, VWF:Ag ELISA of ECFC secretion, immunofluorescence microscopy, and whole-transcriptome RNA-seq. PreviouslyPublished: NA — no indication this patient was reported elsewhere; paper explicitly frames this variant/mechanism as a first report. Gene: VWF Variant: Novel homozygous deep intronic variant, intron 8, creating a new donor splice site that outcompetes the native donor site, causing inclusion of a 118-bp pseudoexon, frameshift, premature stop codon, and nonsense-mediated decay of the transcript. HGVS: NM_000552.5:c.997+118T>G (confirmed via ClinGen Allele Registry Community Standard Title; not explicitly stated in the paper's main text, which only gives cDNA/genomic coordinates without a transcript version). Genomic: g.6073501A>C (GRCh38/hg38; note the T>G/A>C discrepancy reflects VWF being transcribed from the minus strand of chr12). ClinVarID: NA CAID: CA3275979827 gnomAD: NA

Case-Individual:

Case: 50-year old male of consanguinous parents

DiseaseAssertion: severe Type 1 Von Willebrand Disease, previously misclassified as Type 3

Family Info: Proband's parents and offspring had the same mutation, but at the heterozygous level; all asymptomatic

Parental Genotype: N/A

CasePresentingHPOs: HP:0000421, HP:0030140, HP:0006298, HP:0005261

Epistaxis, oral cavity bleeding, severe hemorrhagic complications after tooth extractions (HP is called Prolonged bleeding after dental extraction), hemarthrosis (joint bleeding)

CaseHPOFreeRext: Lifelong history of severe bleeding, frequent hematomas, bleeding from minor wounds (possibly HP:0030138, excessive bleeding from superficial cuts), impaired hemostatic picture, extremely high ISTH bleeding score (proband's was 30 whereas males usually range from 0-3)

CaseNOTHPOs: N/A

CaseNOTHPOFreeText: N/A

CasePreviousTesting: N/A

GenotypingMethod: Sequencing reactions were performed in an ABI3130 XL Genetic Analyzer; digital droplet polymerase chain reaction (ddPCR) assays were performed (in multiplex); in vitro expression also performed, then electrophoresis system used to run Western blot

Gene: VWD

HGVS: NM_000552.5:c.2269_2270del

Variant: Gene null homozygous c.2269_2270del mutation

ClinVarID: 100207

CAID: CA228313

gnomAD: MAF of 0.000002542 (3 of 1180022 alleles) in the European non-Finnish population

Case: Patient 32, Family K (Table 1.), F/17, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Carribean), Patient 29 (F/33, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = 79, VWF:Ag (IU/dL) = 49, VWF:Act (IU/dL) = 37

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.2365A > G, p.(Thr789Ala)

HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)

ClinVarID: 256659

CAID: CA6403090

gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044368-T-C?dataset=gnomad_r4

Variant: c.2385T > C, p.(Tyr795 =)

HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)

ClinVarID: 256660

CAID: CA6403087

gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

Case: Patient 39, Family S (Table 1.), F/76, Afro-Caribbean

DiseaseAssertion: VWD2A (IIA)

FamilyInfo: Patient 40 (F/38, Afro-Caribbean), Patient 41 (M/63, Afro-Caribbean) and Patient 52 (F/48, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 3, FVIII:C (IU/dL) = 74, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 12

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: deletion of exons 9-10

HGVS: NM_000552.5:c.1030_1317del (p.Gly344_Arg439del)

ClinVarID:

CAID: CA3260663889

gnomAD:

Variant: c.4138A > G, p.(Ile1380Val)

HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)

ClinVarID: 310063

CAID: CA6402595

gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4

Variant: c.4304A > G, p.(Asn1435Ser)

HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)

ClinVarID: 310062

CAID: CA6402552

gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.4628C > G p.(Ser1543Cys)

HGVS: NM_000552.5:c.4628C>G (p.Ser1543Cys)

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

Case: Patient 9, Family F (Table 1.), F/76, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 8 (M/86, Afro-Caribbean) and Patient 28 (F/55, Afro-Caribbean) also from Family F. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =11, FVIII:C (IU/dL) = 40, VWF:Ag (IU/dL) = 30, VWF:Act (IU/dL) = 28

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group B-

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.1530G > A, p.(Val510 =) p.

HGVS: NM_000552.5:c.1530G>A (p.Val510=)

ClinVarID:

CAID: CA6403368

gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4

Variant: c.1892C > T, p.(Ala631Val)

HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)

ClinVarID: 422844

CAID: CA6403245

gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4

Variant: c.2220G > A, p.(Met740Ile)

HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)

ClinVarID: 100206

CAID: CA201316

gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4

Variant: c.2451T > A, p.(His817Gln)

HGVS: NM_000552.5:c.2451T>A (p.His817Gln)

ClinVarID: 100224

CAID: CA228345

gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4

Variant: c.3426T > C, p.(Cys1142 =)

HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)

ClinVarID: 256668

CAID: CA6402757

gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?dataset=gnomad_r4

Variant: c.3445T > C, p.(Cys1149Arg)

HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)

ClinVarID: 309

CAID: CA228410

gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4

Variant: c.3485C > T, p.(Pro1162Leu)

HGVS: NM_000552.5(VWF):c.3485C>T (p.Pro1162Leu)

ClinVarID: 256669

CAID: CA6402756

gnomAD: MAF of 0.2076 (7087/34136 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4

Variant: c.3486A > G, p.(Pro1162 =)

HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)

ClinVarID: 256670

CAID: CA6402755

gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Variant: c.6554G > A, p.(Arg2185Gln)

HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443

CAID: CA228748

gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4

Case: Patient 45, Family V (Table 1.), M/51, Afro-Caribbean

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 5, FVIII:C (IU/dL) = 45, VWF:Ag (IU/dL) = 96, VWF:Act (IU/dL) = 59

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood group O+

CasePreviousTesting:

GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).

PreviouslyPublished: NA

Gene: VWF

Variant: c.4196G > A, p.(Arg1399His)

HGVS: NM_000552.5:c.4196G>A (p.Arg1399His)

ClinVarID: 293

CAID: CA114133

gnomAD: MAF of 0.01540 (456/29604 alleles) in Ashkenazi Jewish population https://gnomad.broadinstitute.org/variant/chr12-6019222-C-T?dataset=gnomad_r4

Variant: c.4414G > C p.(Asp1472His)

HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)

ClinVarID: 256679

CAID: CA6402534

gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4

Case: Patient IV-4, Female (mother of proband V-2) DiseaseAssertion: Type 2A VWD, based on history of abnormal bleeding, low plasma VWF:Ag and activity, and lack of plasma HMW VWF multimers. FamilyInfo: Mother of proband V-2; part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): Not described (her own parents' genotype status not reported in extracted text — see Figure 1). CasePresentingHPOs: HP:0000421 (Epistaxis), HP:0000132 (Menorrhagia), HP:0012147 (Reduced quantity of VWF; VWF:Ag 21.7 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 5.0 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0011871 (Impaired RIPA; 3.0%), HP:0003645 (Prolonged partial thromboplastin time; APTT 46.1 sec) CaseHPOFreeText: Anemia (secondary to menorrhagia; no matching HPO code in the approved list); FVIII:C not tested (N/A); TT 18.1 sec and PT 14.1 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet VWF multimer status NOT tested for this patient ("Platelet samples were not available from IV-4") — do not assume the "normal platelet multimers" finding reported for the other four affected members applies here. CasePreviousTesting: Targeted confirmation of the familial VWF variant (not described as independent full 52-exon screening for this individual specifically); not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband (Applied Biosystems 310 DNA analyzer). PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA

Case: Patient IV-2 (daughter of III-3; first cousin of proband's mother IV-4) DiseaseAssertion: Type 2A VWD, based on low plasma VWF:Ag and activity and lack of plasma HMW VWF multimers. FamilyInfo: Daughter of III-3 (proband's granduncle); first cousin of IV-4 (proband's mother); part of 5-affected-member pedigree (Fig. 1). ParentalGenotype(s): Father (III-3) heterozygous for the variant, affected. Mother's genotype not reported. CasePresentingHPOs: HP:0012147 (Reduced quantity of VWF; VWF:Ag 30.4 U/dL), HP:0030129 (Impaired VWF:RCo; VWF:Rco 8.4 U/dL), HP:0030132 (Absence of large VWF multimers — plasma), HP:0003645 (Prolonged partial thromboplastin time; APTT 45.8 sec) CaseHPOFreeText: Described only generically as having "abnormal bleedings" / "similar clinical symptoms" — no itemized bleeding symptoms given specifically for this individual. FVIII:C 50.0 U/dL — at the exact lower limit of normal (nv 50-150), notably higher than the other affected members. RIPA not tested (N/A). TT 15.6 sec and PT 13.8 sec both within normal range. CaseNOTHPOs: NA CaseNOTHPOFreeText: Platelet-associated VWF multimers normal (HMW multimers present) per the group finding covering this patient. CasePreviousTesting: Targeted confirmation of the familial VWF variant; not genome-wide. GenotypingMethod: Sanger sequencing/allele-specific analysis, same platform as proband. PreviouslyPublished: NA Gene: VWF Variant: Same novel heterozygous in-frame 6-bp deletion, exon 28, ΔD1529V1530 (VWF A2 domain) HGVS: c.4585_4590del (p.Asp1529_Val1530del) ClinVarID: NA CAID: NA gnomAD: NA

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

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

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

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

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

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

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

gnomAD: n/a

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

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0005135 (abnormal T wave)

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

CaseNotHPOs: HP:0012250 (ST segment depression)

CaseNotHPOsFreeText: no clinical manifestation, abnormal Q wave

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

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

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

gnomAD: n/a

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

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

CaseNotHPOs: HP:0005135 (abnormal T wave)

CasePreviousTesting: same as proband

CaseGenotypingMethod: same as proband

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

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

gnomAD: n/a

Case1:

DiseaseAssertion: Hypertrophic cardiomyopathy

CaseHPOFreeText: severe congestive heart failure

GenotypingMethod: bi-directional Sanger sequencing

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

ClinVar: 181176

CAID: CA011922

gnomAD: not found

CaseMYH7-8: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

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

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

gnomAD: Not in gnomAD

CaseMYH7-7: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

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

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

gnomAD: Not in gnomAD

CaseMYH7-9: Japan, Asian

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

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

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

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

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

gnomAD: Not in gnomAD

Case120682: 62 year old Caucasian female

DiseaseAssertion: LVNC

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

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText:pulmonary hypertension

CasePreviousTesting: 41 cardiomyopathy-associated genes

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

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

ClinVar: 14127

CAID: CA016715

gnomAD: 0.00005437 East Asian

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

Supplementary Material 4

Case M-18: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

gnomAD: n/a

Supplementary Material 4

Case M-2: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.611G>A (p.Arg204His)

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

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

Supplementary Material 4

Case M-8: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

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

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

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

Supplementary Material 4

Case M-25: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3:c.2596T>C

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

gnomAD: n/a

Supplementary Material 4

Case M-14: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

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

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

Supplementary Material 4

Case M-22: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.2333A>G (p.Asp778Gly)

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

gnomAD: n/a

Supplementary Material 4

Case M-15: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

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

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

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

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

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

Supplementary Data: Table S3

Case 140:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

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

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

CaseGenotypingMethod: WES, variant enrichment analysis

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

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

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

MultipleGeneVariants:

(1) SDHA Variant:

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

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

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

(2) TTN Variant:

Variant: p.32991_32992del no ClinVar or CAID

Supplementary Data: Table S3

Case: 63

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

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

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

CaseGenotypingMethod: WES, variant enrichment analysis

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

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

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

MultipleGeneVariants:

(1) TTN Variant:

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

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

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

Supplementary Data: Table S3

Case 35:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

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

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

CaseGenotypingMethod: WES, variant enrichment analysis

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

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

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

Case153: Female, 0.083 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 46%, LVDD-Z score at 0.795

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: Sister also has LVNC

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

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

Variant: NM_000257.3:c.1342G>A (p.Glu448Lys)

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

gnomAD: Not in gnomAD

Case361: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 38%, LVDD-Z score at 0.977

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.896-1G>A

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

gnomAD: Not in gnomAD

Case333: Male, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 10%, LVDD-Z score at -0.4

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.668C>T (p.Ala223Val)

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

gnomAD: Not in gnomAD

Case250: Male, 0.04 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

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

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.2030A>T (p.Glu677Val)

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

gnomAD: Not in gnomAD

Case427: Female, 1.5 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

FamilyInfo: Father has DCM

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

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

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

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo:

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

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

Variant: NM_000257.3:c.2821C>T (p.Arg941Cys)

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

gnomAD: Not in gnomAD

Case392: Male, 0.083 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

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

HPOsFreeText: Left Ventricular Ejection Fraction at 29%, LVDD-Z score at 2.1428

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.944A>G (p.Gln315Arg)

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

gnomAD: Not in gnomAD

Case378: Female, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

FamilyInfo: Sister has LVNC

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo:

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

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

Variant: NM_000257.3:c.1859T>C (p.Leu620Pro)

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

gnomAD: Not in gnomAD

Case298: Female, 6 years onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (Left ventricular noncompaction)

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

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history

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

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

Variant: NM_000257.3:c.2710C>T (p.Arg904Cys)

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

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

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

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: No

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric cancer,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: WES, Sanger sequencing,

Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)

ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/

CAID: N/A

gnomAD: absent

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

DiseaseAssertion: hypertrophic cardiomyopathy, dilated cardiomyopathy

FamilyInfo: Yes, one affected

CasePresentingHPOs: N/A

CaseHPOFreeText: Gastric cancer,

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: WES, Sanger sequencing,

Variant: NM_000257.3(MYH7):c.4522_4524delGAG (p.Glu1508del)

ClinVar: 43023 https://www.ncbi.nlm.nih.gov/clinvar/variation/43023/

CAID: N/A

gnomAD: absent

Case KMP 4: Eastern Slovakia, Female, 69yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

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

CaseNotHPOFreeText: left ventricular outflow tract obstruction

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

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

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

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

gnomAD: n/a

Case KMP 16: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 39-40%, New York Heart Association Classification = I, implantable cardioverter defibrillator

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

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

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

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

gnomAD: n/a

Case KMP 8: Eastern Slovakia, Female, 60yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: no family history

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

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

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

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

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

gnomAD: n/a

MultipleGeneVariants:

(1) SCN5A Variant:

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

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

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

Case KMP 11: Eastern Slovakia, Female, 57yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: positive family history

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

CaseNotHPOFreeText: left ventricular outflow tract obstruction

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

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

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

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

gnomAD: n/a

Case7: Female, 13 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0001279 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Syncope)

HPOsFreeText: 2 SCD risk factors, NYHA class is II, Right ventricular wall thickness 12 mm

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

Variant reported as below, but no SNP corresponds to the variant.

Variant: NP_000248.2:p.R719E

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

MYOM1 Variant:

Variant: NM_003803.3:c.2507G>T (p.Gly836Val)

CAID: CA8874590 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_003803.3:c.2507G%3ET

gnomAD: East Asian 5.044e-4, Overall 3.707e-5 https://gnomad.broadinstitute.org/variant/18-3129517-C-A

AKAP9 Variant:

Variant: NM_005751.4:c.11590T>C (p.Cys3864Arg)

CAID: CA368165252 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_005751.4:c.11590T%3EC

gnomAD: Not in gnomAD

Case1: Male, 27 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

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

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

TTN Variants:

Unknown Variant

Variant1: TTN-S3872fs

CAID: N/A

gnomAD: N/A

Unknown Variant

Variant2: TTN-S6350A

CAID: N/A

gnomAD: N/A

Unknown Variant

Variant3: TTN-P10663R

CAID: N/A

gnomAD: N/A

ACTN2 Variant

Unknown Variant

Variant: ACTN2-P32fs

CAID: N/A

gnomAD: N/A

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.2722C>G (p.Leu908Val)

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

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

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.428G>A (p.Arg143Gln)

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

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

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.611G>A (p.Arg204His)

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

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

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

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

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

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

Supplementary Data, Table 2

Case: Australian

DiseaseAssertion: HCM

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm

CasePreviousTesting: electrocardiography, echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1)

CaseGenotypingMethod: DNA isolated from peripheral blood or buccal swabs, PCR, Sanger sequencing, segregation analysis, haplotype analysis of MYBPC3 and MYH7

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

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

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

Table 1 and 4

Case A36: Female, 49yo

DiseaseAssertion: HCM

FamilyInfo: positive family history

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

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

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

Variant: NM_000257.3:c.2654A>C

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

gnomAD: n/a

Table 1 and 4

Case A12: Female, 21yo

DiseaseAssertion: HCM

FamilyInfo: positive family history

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

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

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

Variant: NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp)

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

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

Supplementary Data Table S3

Case: 210

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) MYH6 Variant

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

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

gnomAD: Not in gnomAD

(2) VCL Variant

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

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

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

Supplementary Data Table S3

Case: 329

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

Variant1: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

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

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

Variant2: NM_000257.4(MYH7):c.4472C>G (p.Ser1491Cys)

ClinVar: 43020 https://www.ncbi.nlm.nih.gov/clinvar/variation/43020/

gnomAD: 0.01265, https://gnomad.broadinstitute.org/variant/14-23886409-G-C

Supplementary Data Table S3

Case: 154

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

MultipleGeneVariants:

(1) FBN1 Variant

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

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

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

(2) JUP Variant

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

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

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

Supplementary Data Table S3

Case: 204

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

Supplementary Data Table S3

Case: 145

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

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

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

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

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

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

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

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

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

MultipleGeneVariants:

(1) SDHA Variant

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