Case: 2B-9

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.73; AcuStar CB/Ag = 1.09; ELISA CB/Ag = 1.18

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 11325649

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false

CAID:

gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A

Case: 2B-3

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.12; AcuStar CB/Ag = 0.09; ELISA CB/Ag = 0.56

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2M-4

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.44; AcuStar CB/Ag = 0.51; ELISA CB/Ag = 0.73

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-6

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.42

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMIDs: 1537829, 16322474

Gene: VWF

Variant: c.4513G>C (p.Gly1505Arg)

HGVS: NM_000552.5(VWF):c.4513G>C (p.Gly1505Arg)

ClinVarID: 100367; https://www.ncbi.nlm.nih.gov/clinvar/variation/100367/?oq=p.Gly1505Arg[varname]+&m=NM_000552.5(VWF):c.4513G%3EC%20(p.Gly1505Arg)

CAID:

gnomAD: absent

Case: 2B-1

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.41; AcuStar CB/Ag = 0.49; ELISA CB/Ag = 0.40

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2M-7

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.40; AcuStar CB/Ag = 0.55; ELISA CB/Ag = 0.87

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154, 16247740

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.5(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/?new_evidence=false

CAID:

gnomAD: MAF = 0.000008824 in European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A

Case: 2M-6

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.54; ELISA CB/Ag = 0.66

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: P12, Chinese, Male, 11yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 6; VWF:Ag (%) = 15.8, VWF:RCo (%) = 7.3, FVIII:C (%) = 45.5, VWF:CB (%) = 4.1, VWFpp (%) = 50.3, VWF:RCo/VWF:Ag = 0.5, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 3.2, FVIII:C/VWF:Ag = 2.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P16, Chinese, female, 25yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 15; VWF:Ag (%) = 2.1, VWF:RCo (%) = 1.9, FVIII:C (%) = 4.3, VWF:CB (%) = 1.7, VWFpp (%) = 1.5, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1093C>T (p.Arg365Ter)

HGVS: NM_000552.4(VWF):c.1093C>T (p.Arg365Ter)

ClinVarID: 100172; https://www.ncbi.nlm.nih.gov/clinvar/variation/100172/

CAID: NA

gnomAD: absent

Variant 2: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P70, Chinese, female, 51yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 28.3, VWF:RCo (%) = 36.6, FVIII:C (%) = 61.3, VWF:CB (%) = 34.6, VWFpp (%) = 64.5, VWF:RCo/VWF:Ag = 1.3, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.2

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443; https://www.ncbi.nlm.nih.gov/clinvar/variation/100443/

CAID: NA

gnomAD: MAF = 0.1899 (4712/24810 alleles; 465 homozygotes) in the African/African-American population; https://gnomad.broadinstitute.org/variant/12-6103072-C-T?dataset=gnomad_r2_1

Case: P56, Chinese, male, 6yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 13; VWF:Ag (%) = 15.4, VWF:RCo (%) = 7.1, FVIII:C (%) = 43.3, VWF:CB (%) = 2.4, VWFpp (%) = 43.8, VWF:RCo/VWF:Ag = 0.5, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.8, FVIII:C/VWF:Ag = 2.8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P25, Chinese, female, 23yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 15.6, VWF:RCo (%) = 4.4, FVIII:C (%) = 31.0, VWF:CB (%) = 14.2, VWFpp (%) = 47.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 3.1, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P14, Chinese, female, 3yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 5; VWF:Ag (%) = 18.2, VWF:RCo (%) = 7.6, FVIII:C (%) = 29.1, VWF:CB (%) = 17.5, VWFpp (%) = 45.6, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 2.5, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P84, Chinese, female, 36yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 26.6, VWF:RCo (%) = 3.3, FVIII:C (%) = 41.7, VWF:CB (%) = 25.2, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.6, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: IP #14 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 94; VWF:Ac [IU/dL] = 89; FVIII:C [IU/dL] = 126; VWF:CB (IU/dL) = 49

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #64

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 42

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4892G>A p.Gly1631Asp

HGVS:

ClinVarID: 1342155

CAID:

gnomAD: absent

Case: IP #32 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>A p.Arg1374Ser

HGVS:

ClinVarID: 100328

CAID:

gnomAD: absent

Case: IP #4 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 23

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3389G>A p.Cys1130Tyr

HGVS:

ClinVarID: 1684001

CAID:

gnomAD: absent

Case: IP #3 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 52; VWF:Ac [IU/dL] = 41; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2278C>T p.Arg760Cys

HGVS:

ClinVarID: 100208

CAID:

gnomAD: 0.000006196 (10 in 1614050) no homozygotes https://gnomad.broadinstitute.org/variant/12-6046726-G-A?dataset=gnomad_r4

Case: IP #24 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 40

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #35 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4241T>G p.Val1414Gly

HGVS:

ClinVarID: 619752

CAID:

gnomAD: absent

Case: IP #12 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 21; FVIII:C [IU/dL] = 52; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #28 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 11

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case UZ080: 0 year old female (row 81 in supplementary table)

DiseaseAssertion: type 2A/M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442

CaseHPOFreeRext: vWF:Ag (%) = 17.9; vWF:GPIbR (%) = 5.5; Act/Ag ratio = 0.31; FVIII:C (%) = 19.7; Platelets (x10^9/L) = 324

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.4121G>A p.Arg1374His

HGVS:

ClinVarID: 100330

CAID:

gnomAD: 0.000001239 (2 in 1613878) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019297-C-T?dataset=gnomad_r4

Case 16: 1 year old female, study ID UZ052 in supplemental table

DiseaseAssertion: type 3 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442

CaseHPOFreeRext: vWF:Ag (%) = 1.5; vWF:GPIbR (%) = 0.6; Act/Ag ratio = 0.40; FVIII:C (%) = 12.2; Platelets (x10^9/L) = 369

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.421G>A p.Asp141Asn

HGVS:

ClinVarID: 100338

CAID:

gnomAD: 6.195e-7 (1 in 1614092) no homozygotes https://gnomad.broadinstitute.org/variant/12-6110483-A-G?dataset=gnomad_r4

MultipleGeneVariants:

VWF variant

Variant: c.7940C>T p.Thr2647Met p.Thr2647Met

ClinVarID: 100487

gnomAD: 0.004007 (6468 in 1614124) 21 homozygotes https://gnomad.broadinstitute.org/variant/12-5953542-G-A?dataset=gnomad_r4

Case UZ089: 17 year old female (row 90 in supplementary table)

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370

CaseHPOFreeRext: vWF:Ag (%) = 17.7; vWF:GPIbR (%) = 14.2; Act/Ag ratio = 0.80; FVIII:C (%) = 49.8; Platelets (x10^9/L) = 242

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.3359G>C p.Trp1120Ser

HGVS:

ClinVarID: 100256

CAID:

gnomAD: 0.000001239 (2 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6023651-C-G?dataset=gnomad_r4

Case UZ009: 42 year old female (row 10 supplemental table)

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: vWF:Ag (%) = 26.2; vWF:GPIbR (%) = 20.8; Act/Ag ratio = 0.79; FVIII:C (%) = 29.7; Platelets (x10^9/L) = 337

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.6859C>T p.Arg2287Trp

HGVS:

ClinVarID: 100450

CAID:

gnomAD: 0.0004764 (769 in 1614122) 3 homozygotes https://gnomad.broadinstitute.org/variant/12-5985605-G-A?dataset=gnomad_r4

Case 1: 0 y.o. female, study ID UZ083 in Supplemental table

DiseaseAssertion: type 1 VWD presequencing; type 2M VWD postsequencing

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370

CaseHPOFreeRext: vWF:Ag (%) = 17.7; vWF:GPIbR (%) = 14; Act/Ag ratio = 0.79; FVIII:C (%) = 44.5; Platelets (x10^9/L) = 323

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished: If applicable.

Gene: VWF

Variant: c.5087T>G p.Leu1696Arg

HGVS:

ClinVarID: 1684480

CAID:

gnomAD: absent

Case UZ041: 2 year old male

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370

CaseHPOFreeRext: vWF:Ag (%) = 9.9; vWF:GPIbR (%) = 5.7; Act/Ag ratio = 0.6; FVIII:C (%) = 19.9; Platelets (x10^9/L) = 352

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.3380-2A>G p.?

HGVS:

ClinVarID: 1684020

CAID:

gnomAD: absent

Case UZ071: 2 year old female (row 72 in supplemental table)

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440, HP:0040225

CaseHPOFreeRext: vWF:Ag (%) = 16.1; vWF:GPIbR (%) = 3.4; Act/Ag ratio = 0.21; FVIII:C (%) = 17; Platelets (x10^9/L) = 537

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.4517C>T p.Ser1506Leu

HGVS:

ClinVarID: 100369

CAID:

gnomAD: absent

MultipleGeneVariants:

Gene: FGG

Variant: c.571G>A p.Gly191Arg

ClinVarID: 16378

gnomAD: 0.003866 (6239 in 1613896) 21 homozygotes https://gnomad.broadinstitute.org/variant/4-154609725-C-T?dataset=gnomad_r4

Case: Row 4 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.3; VWFpp/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 706C>T R236C

HGVS: c.706C>T p.Arg236Cys

ClinVarID: 1695352

CAID:

gnomAD: absent

Case: Row 9 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.0; VWFpp/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1600G>A D534N

HGVS: c.1600G>A (p.Asp534Asn)

ClinVarID: 1695364

CAID:

gnomAD: absent

Case: Row 18 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.8; VWFpp/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2442+4A>G

HGVS: VWF:c.2442+4A>G

ClinVarID: 1695350

CAID:

gnomAD: absent

Case: Row 7 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.1; VWFpp/VWF:Ag = 1.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1318delT C440A fs*17

HGVS: c.1318del (p.Cys440Alafs*17)

ClinVarID: 1695356

CAID:

gnomAD: absent

Case: Proband 1 (Family 1)

DiseaseAssertion: VWD1

FamilyInfo: 2 family members diagnosed with VWD1

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130

(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 28, VWF:Ag % = 12, VWF:RCo % = 14, VIII C/vWF:AG ratio = 2.3, vWF:Rco/vWF:AG ratio = 1.2

CaseNOTHPOs: HP:0011871, HP:0030132

(Impaired ristocetin-induced platelet aggregation, Absence of large von Willibrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 11992235

Gene: VWF

Variant: c.6536C>T (p.Ser2179Phe)

HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)

ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/

CAID:

gnomAD: absent

Case: Dutch Family Proband (II-1), male

DiseaseAssertion: VWD2A

FamilyInfo: 10 additional affected family members (phenotypic details in Table 4)

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: FVIII:C = 63, vWF:Ag = 59, vWF:pp = 76, pp/Ag = 1.3, vWF:RCo = <15, Rco/Ag = 0.30, RIPA = N; minor or poor response to DDAVP of functional vWF:RCo and vWF:CB with no correction of vWF multimers and BT directly after DDAVP

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 19346881

Gene: VWF

Variant: c.4496T>A (p.Val1499Glu)

HGVS: NM_000552.4(VWF):c.4496T>A (p.Val1499Glu)

ClinVarID: 440408; https://www.ncbi.nlm.nih.gov/clinvar/variation/440408/

CAID:

gnomAD: absent

Case: Proband 3 (S2179F)

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130

(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 26, VWF:Ag % = 6, VWF:RCo % = 6, VIII C/vWF:AG ratio = 4.3, vWF:Rco/vWF:AG ratio = 1.0

CaseNOTHPOs: HP:0011871, HP:0030132

(Impaired ristocetin-induced platelet aggregation, Absence of large von Willibrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 11992235

Gene: VWF

Variant: c.6536C>T (p.Ser2179Phe)

HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)

ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/

CAID:

gnomAD: absent

Case: P3, female, 48yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: bleeding score = 9; VWF:Ag (%) = 35, VWF:RCo(%) = 19, VWF:RCo/VWF:Ag ratio = 0.54, VWF:CIIIB (%) = 25, VWF:CIIIB/VWF:Ag ratio = 0.71, VWF:CVIB (%) = 31, VWF:CVIB/VWF:Ag ratio = 0.89

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/

CAID:

gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1

Case: P4, female, 76yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: bleeding score = 1; VWF:Ag (%) = 36, VWF:RCo(%) = 16, VWF:RCo/VWF:Ag ratio = 0.44, VWF:CIIIB (%) = 32, VWF:CIIIB/VWF:Ag ratio = 0.89, VWF:CVIB (%) = 26, VWF:CVIB/VWF:Ag ratio = 0.72

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/

CAID:

gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1

Case: P1, female, 36yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: bleeding score = 7; VWF:Ag (%) = 22, VWF:RCo(%) = 11, VWF:RCo/VWF:Ag ratio = 0.50, VWF:CIIIB (%) = 19, VWF:CIIIB/VWF:Ag ratio = 0.86, VWF:CVIB (%) = 13, VWF:CVIB/VWF:Ag ratio = 0.59

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.3944G>A (p.Arg1315His)

HGVS: NM_000552.4(VWF):c.3944G>A (p.Arg1315His)

ClinVarID: 100311; https://www.ncbi.nlm.nih.gov/clinvar/variation/100311/

CAID:

gnomAD: MAF = 0.0001633 (1/6124 alleles) in "Other" population; https://gnomad.broadinstitute.org/variant/12-6128640-C-T?dataset=gnomad_r2_1

Variant 2: c.7464C>T (p.Gly2488=)

HGVS: NM_000552.4(VWF):c.7464C>T (p.Gly2488=)

ClinVar: 619755; https://www.ncbi.nlm.nih.gov/clinvar/variation/619755/

gnomAD: MAF = 0.000008799 (1/113644 alleles) in European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6080849-G-A?dataset=gnomad_r2_1

Case: Case 2, age 2-17, Croatian

DiseaseAssertion: VWD1

FamilyInfo:

ParentalGenotypes(s):

CasePresentingHPOs:

CaseHPOFreeText: bleeding score= 3, VWF:GPIbM (%)= 75.7, VWF:Ag (%)=73.5, vWF:GPIbM/vWF:Ag ratio= 1.03, FVIII:C (%): 93, VWF: CBA (%)= 59.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

Gene: VWF

Variant: c.3797C>T (pPro1266Leu)

HGVS: NM_000552.5:c.3797C>T

ClinVar: accession number: VCV000000314.28

CAID:

gnomAD: frequency: 0.0008322, https://gnomad.broadinstitute.org/variant/12-6128787-G-A?dataset=gnomad_r2_1

Case: M771I heterozygous

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: FVIII:C = 20 IU/dL, VWF:RCo = 59 IU/dL, VWF:Ag = 38 IU/dL, VWF:CB = 49 IU/dL, VWF:RCo/VWF:Ag = 1.55

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 16985174

Gene: VWF

Variant: c.2313G>T (p.Met771Ile)

HGVS: NM_000552.4(VWF):c.2313G>T (p.Met771Ile)

ClinVarID: 100211; https://www.ncbi.nlm.nih.gov/clinvar/variation/100211/

CAID:

gnomAD: absent

Case: Patient 11 (Family E), male, 11yo

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 = 220, PFA 100 sec = >300, SPA % = 11.3, MADR mg/mL = 0.3, VWF:Ag U/dL = 28.8, VWF:CB U/dL = 28.4, VWF:CB ratio = 0.98, VWF:RCo U/dL = 23.0, VWF:RCo ratio = 0.80, Platelet VWF U/dL = 54.1, FVIII U/dL = 51.5, BAT F/M = 5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4021C>T (p.Arg1341Trp)

HGVS: NM_000552.4(VWF):c.4021C>T (p.Arg1341Trp)

ClinVarID: 100316; https://www.ncbi.nlm.nih.gov/clinvar/variation/100316/

CAID: NA

gnomAD: MAF = 0.00008674 (3/34586 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6128563-G-A?dataset=gnomad_r2_1

Supplementary Data: Table 2

Case B: proband, Female

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, LMNA)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case K:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) VCL Variant:

Variant: NM_014000.2(VCL):c.688C>T (p.Arg230Cys)

ClinVar: 45620, https://www.ncbi.nlm.nih.gov/clinvar/variation/45620/

gnomAD: 0.00008137, https://gnomad.broadinstitute.org/variant/10-75834566-C-T

CaseDCM-01: Male, 1 year diagnosis, Caucasian, Germany

CasePresentingHPOs: HP:0001644, HP:0001635 (Dilated cardiomyopathy, Heart failure)

HPOsFreeText: LVEDD at 67 mm, LV-Ejection Fraction at 10%, Cardiac Index at 2.6

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband treated with VAD and HTx, No family history of cardiac disease, MYH7 Variant is asserted as de novo, Proband also has a variant in MYL2, Patient is heterozygous for MYH7 variant

CaseGenotypingMethod: Using a Cardiomyopathy gene panel of 46 genes, the proband's DNA was screened for variants. Afterwards, the variants were classified based on pathogenicity and modeled using predictive software.

Variant: NM_000257.3:c.5390T>C (p.Leu1797Pro)

ClinVar: 265799 https://www.ncbi.nlm.nih.gov/clinvar/variation/265799/

gnomAD: Not in gnomAD

Multiple Gene Variants

MYL2 Variant

Variant: NM_000432.3:c.401A>C (p.Glu134Ala)

ClinVar: 43475 https://www.ncbi.nlm.nih.gov/clinvar/variation/43475/

gnomAD: European (Non-Finnish) 3.484e-4, Overall 2.015e-4 https://gnomad.broadinstitute.org/variant/12-111350901-T-G

Supplementary Data: Online Table 3

Case:

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

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

Variant: NM_000257.3(MYH7):c.4076G>A (p.Arg1359His)

ClinVar: 228910, https://www.ncbi.nlm.nih.gov/clinvar/variation/228910/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23887512-C-T

Supplementary Data: Online Table 3

Case:

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

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

Variant: NM_000257.3(MYH7):c.698C>T (p.Ala233Val)

ClinVar: 177858, https://www.ncbi.nlm.nih.gov/clinvar/variation/177858/

gnomAD: n/a

Case: Patient 18, female, 18yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0009053, HP:0002650, HP:0011713, HP:0003458 (axial muscle weakness, distal lower limb muscle weakness, scoliosis, left bundle branch block, EMG: myopathic abnormalities)

HPOsFreeText: respiratory involvement, NIV required from 7yo, normal CK levels

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

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

Variant: NM_000257.4(MYH7):c.5655G>A (p.Ala1885=)

ClinVar: 378215, https://www.ncbi.nlm.nih.gov/clinvar/variation/378215/

gnomAD: absent

Case: Patient 19, female, 33yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0008959, HP:0009053, HP:0008997, HP:0008994, HP:0002650, HP:0003458 (foot drop, Distal upper limb muscle weakness, Distal lower limb muscle weakness, Proximal muscle weakness in upper limbs, Proximal muscle weakness in lower limbs, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: respiratory involvement - restrictive from 25yo, normal CK levels, minicores present on muscle biopsy

CaseNotHPOs: no cardiac involvement

FamilyInfo: family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

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

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

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

gnomAD: absent

Case: 6, femaly, 16yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0008959, HP:0009053, HP:0002650 (axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, scoliosis)

HPOsFreeText: normal CK

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: family history, pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

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

Variant: NM_000257.4(MYH7):c.4807G>C (p.Ala1603Pro)

ClinVar: 190407, https://www.ncbi.nlm.nih.gov/clinvar/variation/190407/

gnomAD: absent

Case: Patient 17, male, 36yo, symptom onset in childhood

CasePresentingHPOs: HP:0003327, HP:0008959, HP:0009053 (axial muscle weakness, Distal upper limb muscle weakness, Distal lower limb muscle weakness)

HPOsFreeText: normal CK levels

CaseNotHPOs: HP:0002650 (scoliosis)

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

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

Variant: NM_000257.4(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: 0.00004598, https://gnomad.broadinstitute.org/variant/14-23882979-T-A?dataset=gnomad_r2_1

Case: Patient 4, male, 22yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0008959, HP:0009053, HP:0001701, HP:0030682 (foot drop, axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, pericarditis, left ventricular noncompaction)

CaseNotHPOs: HP:0003306 (rigid spine)

HPOsFreeText: restrictive respiratory involvement from age 16, CK = 711U/l, minicores present on muscle biopsy, hypertrophy of gastrocnemii

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below; variants in SEPN1 and LMNA rules out

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

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

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

gnomAD: absent

Table III

Case 748: Italian, Female, 16yo

DiseaseAssertion: HCM

FamilyInfo: Family history of HCM and sudden cardiac death

CasePresentingHPOs: HP:0001712, HP:0004756, HP:0005110, HP:0001716 (left ventricular hypertrophy, ventricular tachycardia, atrial fibrillation, Wolff-Parkinson-White syndrome)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, LVWT = 17mm, automatic implantable cardioverter defibrillator, LV ejection fraction = 60%

CasePreviousTesting: echocardiography, Full testing (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1), additional testing: (GLA, LAMP2, PRKAG2), additional genes added with NGS: (TNNC1, MYH6, MYOM1, MYOZ2, ANKRD1, VCL, CALR3, CAV3)

CaseGenotypingMethod: Genomic DNA extracted from peripheral leukocytes, Sanger sequencing (73 samples), Next-gen sequencing (19 samples)

Variant: NM_000257.3(MYH7):c.5287G>A (p.Ala1763Thr)

ClinVar: 177846, https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/

gnomAD: 0.00007423, https://gnomad.broadinstitute.org/variant/14-23884476-C-T

MultipleGeneVariants:

(1) LAMP2 Variant:

Variant: NM_002294.2(LAMP2):c.928G>A (p.Val310Ile)

ClinVar: 9982, https://www.ncbi.nlm.nih.gov/clinvar/variation/9982/

gnomAD: n/a

Supplementary Material 4

Case M-31: 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.4721G>A (p.Arg1574Gln)

ClinVar: 228912, https://www.ncbi.nlm.nih.gov/clinvar/variation/228912/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23885445-C-T

Supplementary Data: S2 Table

Case 156: Spanish, 82yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

Variant: NM_000257.3(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseMYH7-15: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

Variant: NM_000257.3:c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: European (Non-Finnish) 4.657e-5, Overall 2.125e-5 https://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseMYH7-8: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

Variant: NM_000257.3:c.2539A>G (p.Lys847Glu)

ClinVar: 177757 https://www.ncbi.nlm.nih.gov/clinvar/variation/177757/

gnomAD: Not in gnomAD

Case#: Consequence 7 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1608G>T (p.Glu536Asp)

ClinVar: 177671 https://www.ncbi.nlm.nih.gov/clinvar/variation/177671/

CAID: n/a

gnomAD: absent

Case#: Consequence 16 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

CAID: n/a

gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

CaseMYH7-23: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.2225C>A (p.Ala742Glu)

ClinVar: 192310 https://www.ncbi.nlm.nih.gov/clinvar/variation/192310/

gnomAD: Not in gnomAD

CaseWJ: 30 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: One affected relative Brother (index case) died suddenly aged 34 y (MYH7 p.Asp778Val only)

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: Maximum left ventricular hypertrophy at 18 mm

CaseNotHPOs: N/A

NotHPOsFreeText: Sudden cardiac death event

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

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

Variant1: NM_000257.3:c.2333A>T (p.Asp778Val)

ClinVar: 454354 https://www.ncbi.nlm.nih.gov/clinvar/variation/454354/

gnomAD: Not in gnomAD

Variant2: NM_000257.3:c.5452C>T (p.Arg1818Trp)

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

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

CaseMYH7-12: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

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

Variant: NM_000257.3:c.3236G>A (p.Arg1079Gln)

ClinVar: 177826 https://www.ncbi.nlm.nih.gov/clinvar/variation/177826/

gnomAD: European (Non-Finnish) 1.549e-5, Overall 7.073e-6 https://gnomad.broadinstitute.org/variant/14-23891398-C-T

Case N22: Tunisia, Male, 36yo at onset, 37yo at study

DiseaseAssertion: hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001962 (palpitations)

CaseHPOFreeText: left ventricular septum (LVS) ≥15 mm, septum size = 15mm

FamilyInfo: no family history of HCM or sudden cardiac death

CasePreviousTesting: Full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (FLNC, TNNC1), electrocardiogram, echocardiography

CaseGenotypingMethod: PCR, Next-generation sequencing, identified variants confirmed via Sanger Sequencing

Variant: NM_000257.3(MYH7):c.5779A>T (p.Ile1927Phe)

ClinVar: 487639, https://www.ncbi.nlm.nih.gov/clinvar/variation/487639/

gnomAD: 0.00004598, https://gnomad.broadinstitute.org/variant/14-23882979-T-A

Case KMP 15: Eastern Slovakia, Female, 82yo

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: positive family history

CaseHPOFreeText: left ventricular outflow tract obstruction, left ventricular ejection fraction = 60%, New York Heart Association Classification = III, 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.2734A>G (p.Lys912Glu)

ClinVar: 520267, https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/

gnomAD: n/a

Case#: KMP 15, female, 82 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: yes

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 60%; NYHA III.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2734A>G (p.Lys912Glu)

ClinVar: 520267 https://www.ncbi.nlm.nih.gov/clinvar/variation/520267/

CAID: n/a

gnomAD: absent

CasePT-41: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.3749G>C (p.Arg1250Pro)

ClinVar: 181232 https://www.ncbi.nlm.nih.gov/clinvar/variation/181232/

gnomAD: East Asian 5.437e-5, Overall 7.958e-6 https://gnomad.broadinstitute.org/variant/14-23888796-C-G

CasePT-101: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo:

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

Variant: NM_000257.3:c.4353+5G>A

ClinVar: 181255 https://www.ncbi.nlm.nih.gov/clinvar/variation/181255/

gnomAD: African 1.602e-4, Overall 1.769e-5 https://gnomad.broadinstitute.org/variant/14-23886707-C-T

Table 5

Case EO5: Italian

DiseaseAssertion: HCM (early-onset)

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

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

Variant1: NM_000257.3(MYH7):c.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

Variant2: NM_000257.3(MYH7):c.676G>A (p.Ala226Thr)

ClinVar: 372429, https://www.ncbi.nlm.nih.gov/clinvar/variation/372429/

gnomAD: n/a

CaseHCM041: 50 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001712, HP:0100749, HP:0002875, HP:0011103, HP:0031295 (Left ventricular hypertrophy, Chest pain, Exertional dyspnea, Abnormality of the left ventricular outflow tract, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 30 mm

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

Variant: NM_000257.4(MYH7):c.1324C>T (p.Arg442Cys)

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

gnomAD: 0.00005012, http://gnomad.broadinstitute.org/variant/14-23898247-G-A

Case: Patient UK1-IV:1, female, 31yo, Caucasian, Irish ancestry

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0001508, HP:0011471, HP:0002093, HP:0002877, HP:0001620 (toe-walking, scoliosis, poor weight gain, Feeding problem necessitating gastrostomy tube feeding, respiratory impairment, nocturnal hypoventilation, high-pitched voice)

HPOsFreeText: scoliosis required spinal fusion surgery, required nocturnal BiPAP ventilation in adolescence, reduced muscle bulk

Muscle biopsy showed variability in myofiber size, uniformity of type I myofibers on ATPase, moth-eaten appearance of myofibers

CaseNotHPOs:

FamilyInfo: non-consanguineous family

CasePreviousTesting: 32 Illumina genes

CaseGenotypingMethod: NGS (Illumina gene panel) or 32 genes previously associated with congenital myopathies, Sanger sequencing to confirm recessive inheritance

InheritancePattern: autosomal recessive

DiseaseEntity:

Variant 1: NM_000257.3:c.4699C>T (p.Gln1657Ter), maternal

CAID: CA389037829, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389037829

gnomAD: n/a

Variant 2: NM_000257.4(MYH7):c.4664A>G (p.Glu1555Gly), paternal

ClinVar: 181261, https://www.ncbi.nlm.nih.gov/clinvar/variation/181261/

gnomAD: n/a

Case#: 11

DiseaseAssertion: LVNC

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: -5.47 Fathmm, 0 sift, 0.988 polyphen2, GVGD C25, mutation taster 1, -4.54 provean, -4.35 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.2135G>A (p.Arg712His)

ClinVar: 575575 https://www.ncbi.nlm.nih.gov/clinvar/variation/575575/

CAID: N/A

gnomAD: absent

Supplementary Data, Table 2

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.1954A>G (p.Arg652Gly)

ClinVar: 177626, https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: 0.000003978, https://gnomad.broadinstitute.org/variant/14-23896451-T-C

Case IV-5: Male, Iranian, 30yo at diagnosis, 31yo at study, proband

DiseaseAssertion: DCM (initially); paper notes that phenotype is more consisted with hypokinetic non-dilated cardiomyopathy based on guideline from ESC working group on myocardial and pericardial diseases (PMID: 26792875)

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001712, HP:0002375, HP:000516 (left ventricular hypertrophy, hypokinesia, left ventricular dysfunction)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 20-25%, left ventricular internal end-diastolic diameter = 5.7cm, left ventricular internal end-systolic diameter = 5.2cm, interventricular septum = 0.8cm, posterior wall = 0.9cm, normal ECG and normal sinus rhythm, Normal heart valve function

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG, Full testing (https://hyp.is/2c24ajtuEemXQ-fRmGkjTA/www.sciencedirect.com/science/article/pii/S1769721217300484)

CaseGenotypingMethod: WES, targeted exome sequence capture using SureSelectXT Human All Excon v5 kig (Agilent), co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

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

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Supplementary Data: Table S3

Case 56:

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.4717G>A (p.Glu1573Lys)

ClinVar: 222729, https://www.ncbi.nlm.nih.gov/clinvar/variation/222729/

gnomAD: 0.00005967, https://gnomad.broadinstitute.org/variant/14-23885449-C-T

MultipleGeneVariants:

(1) TMPO Variant:

Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)

ClinVar: 44673, https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/

gnomAD: 0.002714, https://gnomad.broadinstitute.org/variant/12-98926856-G-A

Patient14: Male, 59 years report, 40 year onset

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

HPOsFreeText: GAA activity 6.9% from dried blood spot, Respiratory Assistance needed

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

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient20: Male, 22 years report, 12 year onset

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

HPOsFreeText: GAA activity 11.6% from leukocyte, Respiratory Assistance needed

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

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient33: Female, 24 years report, 3 year onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 9.6% from leukocyte

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

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient12: Male, 19 years report, 13 years onset

CasePresentingHPOs: HP:0001324 (Muscle weakness)

HPOsFreeText: GAA activity 9.9% from leukocyte

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

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient1: Italian

CasePresentingHPOs:

HPOsFreeText: non-classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C

CaseLOPD-16: 2.5 weeks diagnosis

HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Multiple interpretations of p.W746C possible, below is considered the most likely

Variant3: NM_000152.4:c.2238G>C (p.Trp746Cys)

ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C

CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 2 and 3 are in cis

Family 6 - Patients 6a and 6b

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0200136, HP:0003691, HP:0003306, HP:0002650, HP:0040081, HP:0002111, HP:0100284

HPOsFreeText: myopathic muscle unit action potentials, 6a muscle pathology with vacuolar myopathy with glycogen excess

FamilyNotHPOs: HP:0010628

Ethnicity: Iranian

ProbandLabel: 6a, male, 12yo at onset, 25yo at diagnosis

FamilyAddInfo: 6b (male) dx at 33yo, 6a MRC sum score = 78, 6b MRC sum score = 79, both patients required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: 6a FVC = 19%, 6b FVC = 38%, 6a CK = 820 U/L, 6b CK = 503 U/L, muscle pathology (examined only in 6a), DBS enzyme activity (with inhibition) for 6a = 0 μmol/L/h, for 6b = 0.21 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.4(GAA):c.1979G>A (p.Arg660His)

ClinVar: 189172, https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/

gnomAD: 3.279e-05, http://exac.broadinstitute.org/variant/17-78086765-G-A

Family 7 - Patient 7

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0003306, HP:0002111, HP:0040081

HPOsFreeText: muscle pathology with vacuolar myopathy with glycogen excess, myopathic muscle unit action potentials

FamilyNotHPOs: HP:0010628, HP:0002015, HP:0003691, HP:0002650

Ethnicity: Iranian

ProbandLabel:

FamilyAddInfo: male, 20yo at onset, 23yo at diagnosis, MRC sum score = 96, patient required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: FVC = 20%, CK = 2,550 U/L, muscle pathology examined, DBS enzyme activity (with inhibition) = 0.1 μmol/L/h, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.2662G>T (p.Glu888Ter)

ClinVar: 578595, https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: 1.65e-05, http://exac.broadinstitute.org/variant/17-78092467-G-T

Family 1 - Patient 1

FamilyPresentingHPOs: HP:0002355, HP:0003701, HP:0040081, HP:0100284

HPOsFreeText: myopathic muscle unit action potentials

FamilyNotHPOs HP:0010628, HP:0002015, HP:0003691, HP:0003306, HP:0002650

NotHPOsFreeText:

Ethnicity: Iranian

ProbandLabel: Patient 1, male

FamilyAddInfo: 2yo at onset, 4yo at diagnosis, MRC sum score not available, consanguineous family

FamilyPreviousTesting: Respiratory evaluation: FVC = 90%, CK = 2,960 U/L,DBS enzyme activity (with inhibition) = 0.3 μmol/L/h, no muscle pathology performed, cardiac evaluations, NCS, EMG

FamilyGenotypingMethod: GAA analyzed with Sanger Sequencing for entire coding region and conserved exon-intron splice junctions, PCR performed for deletion screening

Variant: NM_000152.4(GAA):c.854C>G (p.Pro285Arg)

ClinVar: 225114, https://www.ncbi.nlm.nih.gov/clinvar/variation/225114/

gnomAD: n/a

Case7: Female, 37 years onset, 38 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 40, GAA Activity at ~4.5 pmol/min/mg before ERT and ~5.5 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 16, female

CasePresentingHPOs: HP:0003325

CaseAddInfo: onset and diagnosis at 32yo

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Case#: Patient 12, male

CasePresentingHPOs: HP:0003236

CaseAddInfo: 42yo at onset, 46yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.1438-2A>G

ClinVar: 526521, https://www.ncbi.nlm.nih.gov/clinvar/variation/526521/

gnomAD: n/a

Case#: Patient 3, female

CasePresentingHPOs: HP:0003236

CaseAddInfo: 29yo at onset, 39yo at diagnosis

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

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

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

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

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

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

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

Case6: Female, 22 years onset, 23 years diagnosis, 37 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Case9: Male, 21 years onset, 21.5 years diagnosis, 38 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness, Scapula alata)

CaseAddInfo: Late-Onset Pompe Disease

Case15: Male, 3.5 years onset, 5 years diagnosis, 16 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case7: Male, 11 years onset, 16 years diagnosis, 27 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Patient11: Female, 39yo at diagnosis, 53yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:400, enzyme (μmol/g/h) = 0.41 (3-20), NIV required only after ERT began, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 21yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1548G>A (p.Trp516Ter)

ClinVar: 189025, https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2799+4A>G

ClinVar: 286228, https://www.ncbi.nlm.nih.gov/clinvar/variation/286228/

gnomAD: 8.319e-06, http://exac.broadinstitute.org/variant/17-78092608-A-G