Case: P26, Chinese, female, 30yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type AB blood, bleeding score = 14; VWF:Ag (%) = 11.3, VWF:RCo (%) = 3.7, FVIII:C (%) = 45.0, VWF:CB (%) = 4.0, VWFpp (%) = 41.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.4, VWFpp/VWF:Ag = 3.7, FVIII:C/VWF:Ag = 4.0

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: P3, Chinese, male, 7yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.0, VWF:RCo (%) = 5.0, FVIII:C (%) = 39.1, VWF:CB (%) = 3.5, VWFpp (%) = 46.8, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 3.6, FVIII:C/VWF:Ag = 3.0

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: P58, Chinese, female, 27yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeText: HP:0012147

(Reduced quantity of VWF)

CaseNOTHPOs: type O blood, bleeding score = 8; VWF:Ag (%) = 17.1, VWF:RCo (%) = 2.3, FVIII:C (%) = 44.3, VWF:CB (%) = 3.7, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.4, FVIII:C/VWF:Ag = 2.6

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4790G>T (p.Arg1597Leu)

HGVS: NM_000552.4(VWF):c.4790G>T (p.Arg1597Leu)

ClinVarID: 100392; https://www.ncbi.nlm.nih.gov/clinvar/variation/100392/

CAID: NA

gnomAD: absent

Case: P17, Chinese, female, 20yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 10; VWF:Ag (%) = 17.6, VWF:RCo (%) = 7.3, FVIII:C (%) = 35.8, VWF:CB (%) = 15.8, VWFpp (%) = 51.9, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 2.9, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3389G>T (p.Cys1130Phe)

HGVS: NM_000552.4(VWF):c.3389G>T (p.Cys1130Phe)

ClinVarID: 100261; https://www.ncbi.nlm.nih.gov/clinvar/variation/100261/

CAID: NA

gnomAD: absent

Case: P31, Chinese, female, 21yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 15; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.7, FVIII:C (%) = 4.1, VWF:CB (%) = 0.8, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.953_954insG - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.4368C>G (p.Tyr1456Ter)

HGVS: NM_000552.4(VWF):c.4368C>G (p.Tyr1456Ter)

ClinVarID: 100350; https://www.ncbi.nlm.nih.gov/clinvar/variation/100350/

CAID: NA

gnomAD: absent

Case: P66, Chinese, male, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 56.0, VWF:RCo (%) = 43.4, FVIII:C (%) = 70.0, VWF:CB (%) = 58.9, VWFpp (%) = 53.6, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)

ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/

CAID: NA

gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1

Case: P32, Chinese, male, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.646G>A (p.Glu216Lys)

HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)

ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/

CAID: NA

gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1

MultipleGeneVariants

Gene: F8

Variant: p.Arg446Ter - Unregistered Variant

Case UZ043: 8 year old male (row 44 supplemental table)

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442

CaseHPOFreeRext: vWF:Ag (%) = 29.3; vWF:GPIbR (%) = 13.6; Act/Ag ratio = 0.46; FVIII:C (%) = 68.1; Platelets (x10^9/L) = 176

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.4021C>T p.Arg1341Trp

HGVS:

ClinVarID: 100316

CAID:

gnomAD: 0.00001859 (30 in 1613842) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019397-G-A?dataset=gnomad_r4

Case: IP #2

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 201; VWF:Ac [IU/dL] = 124; FVIII:C [IU/dL] = 244

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.1309_1326del p.Asp437_Arg442del

HGVS:

ClinVarID: 100179

CAID:

gnomAD: 0.000001239 (2 in 1614154) no homozygotes https://gnomad.broadinstitute.org/variant/12-6064351-AGCGGGTGCACACAGCGTC-A?dataset=gnomad_r4

Case: IP #11 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 27

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.3586T>C p.Cys1196Arg

HGVS:

ClinVarID: 100270

CAID:

gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4

Case: IP #63

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 36

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.4885G>A p.Gly1629Arg

HGVS:

ClinVarID: 100398

CAID:

gnomAD: absent

Case: IP #8 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 61; VWF:CB (IU/dL) = 43

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.4105T>A p.Phe1369Ile

HGVS:

ClinVarID: 100326

CAID:

gnomAD: 0.000006197 (10 in 1613726) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019313-A-T?dataset=gnomad_r4

Case: IP #38 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2B) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 1; FVIII:C [IU/dL] = 27

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.4373G>A p.Cys1458Tyr

HGVS:

ClinVarID: 100351

CAID:

gnomAD: absent

Case: IP #5 in type U VWD sub-cohort (also in row 3 splice variants table 6)

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 20

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

HGVS:

ClinVarID: 1684001

CAID:

gnomAD: absent

MultipleGeneVariants:

Gene: VWF

Variant: c.3539–10T>G

ClinVarID: not found

**gnomAD: absent

Case: IP #31 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] = 32; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 43

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 #34 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] = 19; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 38

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.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: IP #3 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] = 13; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 22

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.2771G>A p.Arg924Gln

HGVS:

ClinVarID: 100240

CAID:

gnomAD: 0.01774 (28642 in 1614096) 297 homozygotes https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

**ClinVarID: 100310

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #27 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] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 22

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 #2 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 43; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 10

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.1117C>T p.Arg373*

HGVS:

ClinVarID: 100175

CAID:

gnomAD: 0.000008055 (13 in 1614004) no homozygotes https://gnomad.broadinstitute.org/variant/12-6071336-G-A?dataset=gnomad_r4

**MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVarID: 296

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #35

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 24

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.4517C>T p.Ser1506Leu

HGVS:

ClinVarID: 100369

CAID:

gnomAD: absent

Case: IP #56

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 60

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.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: IP #27 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 69

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.3673T>G p.Cys1225Gly

HGVS:

ClinVarID: 100272

CAID:

gnomAD: absent

Case: IP #40

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 57

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.4690C>T p.Arg1564Trp

HGVS:

ClinVarID: 811702

CAID:

gnomAD: 0.000006818 (11 in 1613330) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018728-G-A?dataset=gnomad_r4

Case: Patient 8 (Family D), male, 49yo

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 A, Platelet count x103/μl = 252, PFA 100 sec = 175, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 54.3, VWF:CB U/dL = 55.1, VWF:CB ratio = 1.01, VWF:RCo U/dL = 51.6, VWF:RCo ratio = 0.94, Platelet VWF U/dL = 60.3, FVIII U/dL = 62.2, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Variant 2: c.3797C>A (p.Pro1266Gln)

HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)

ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/

CAID: NA

gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1

Case: Patient 12 (Family F), female, 50yo

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 A, Platelet count x103/μl = 204, PFA 100 sec = 91, SPA % = 10, MADR mg/mL = 0.45, VWF:Ag U/dL = 108, VWF:CB U/dL = 101.9, VWF:CB ratio = 0.94, VWF:RCo U/dL = 97.7, VWF:RCo ratio = 0.91, Platelet VWF U/dL = 136.4, FVIII U/dL = 107.5, BAT F/M = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3797C>A (p.Pro1266Gln)

HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)

ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/

CAID: NA

gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1

Case: Patient 5 (Family C), female, 50yo

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 = 211, PFA 100 sec = 210, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 40.6, VWF:CB U/dL = 42.8, VWF:CB ratio = 1.1, VWF:RCo U/dL = NA, VWF:RCo ratio = NA, Platelet VWF U/dL = 41.2, FVIII U/dL = 62.8, BAT F/M = 8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 7 (Family C), female, 21yo

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 = 293, PFA 100 sec = >300, SPA % = 6, MADR mg/mL = 0.6, VWF:Ag U/dL = 26.7, VWF:CB U/dL = 27.2, VWF:CB ratio = 1.01, VWF:RCo U/dL = 25.8, VWF:RCo ratio = 0.92, Platelet VWF U/dL = 59.1, FVIII U/dL = 40.9, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 9 (Family D), male, 18yo

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 A, Platelet count x103/μl = 231, PFA 100 sec = 95, SPA % = 0, MADR mg/mL = 0.75, VWF:Ag U/dL = 151.1, VWF:CB U/dL = 175.5, VWF:CB ratio = 1.16, VWF:RCo U/dL = 153.5, VWF:RCo ratio = 0.87, Platelet VWF U/dL = 95.2, FVIII U/dL = 148.2, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3797C>A (p.Pro1266Gln)

HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)

ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/

CAID: NA

gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1

Case 1: Southern Spanish, unrelated patient to Case 2

DiseaseAssertion: VWD1

FamilyInfo: Patient unrelated to families of Case 2, but same two VWF variants found on the same allele

CasePresentingHPOs4: Not reported

CaseHPOFreeText4: Bleeding score of 4

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Normal multimeric assay, VWF:Ag level at 66%, VWF:RCo at 60 U/mL, FVIIIC at 84 U/dL, VWF:RCo/VWF:Ag ratio of 0.9, PFA-100:Col-EPI/Col-ADP of 277s/124s

CasePreviousTesting: Sequencing of exon 28 of VWF gene in 11 families.

Gene: VWF

Variant: c.3797C>T, c.3835G>A

ClinVarID:314, 100288

Case: 2B-11

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.70; AcuStar CB/Ag = 0.83; ELISA CB/Ag = 1.07

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-6

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.66; AcuStar CB/Ag = 0.69; ELISA CB/Ag = 0.71

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: Proband 2 (Family 2)

DiseaseAssertion: VWD1

FamilyInfo: 2 family members diagnosed with VWD1

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130, HP:0011871

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

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 19, VWF:Ag % = 13, VWF:RCo % = 12, VIII C/vWF:AG ratio = 1.5, vWF:Rco/vWF:AG ratio = 0.9

CaseNOTHPOs: HP:0030132

(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 1: index case of family 3.

DiseaseAssertion: previous diagnosis of type 1 VWD

FamilyInfo: not provided

ParentalGenotype(s): unknown

CasePresentingHPOs: unknown

CaseHPOFreeRext: unknown

CaseNOTHPOs: unknown

CaseNOTHPOFreeText: unknown

CasePreviousTesting: no

GenotypingMethod: Sanger sequencing of exon 28

PreviouslyPublished: n/a

Gene: VWF

Variant: c.3797C>A

HGVS:

ClinVarID: 100279

CAID:

gnomAD: AF = 0.0005419 (874/1612906) https://gnomad.broadinstitute.org/variant/12-6019621-G-T?dataset=gnomad_r4

Supplementary Data: S2 Table

Case 4: Spanish, 67yo, 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, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.1324C>T (p.Arg442Cys)

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

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/14-23898247-G-A

Supplementary Data: S2 Table

Case 12: Spanish, 83yo, 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, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.3236G>A (p.Arg1079Gln)

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

gnomAD: 0.000007073, https://gnomad.broadinstitute.org/variant/14-23891398-C-T

Supplementary Data: S2 Table

Case 11: Spanish, 27yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.5359G>C (p.Glu1787Gln)

ClinVar: 427207, https://www.ncbi.nlm.nih.gov/clinvar/variation/427207/

gnomAD: n/a

Supplementary Data: S2 Table

Case 3: Spanish, 17yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, PCR, Sanger Sequencing

Variant: NM_000257.3(MYH7):c.1207C>G (p.Arg403Gly)

ClinVar: 505562, https://www.ncbi.nlm.nih.gov/clinvar/variation/505562/

gnomAD: n/a

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in two HCM probands

Variant: NM_000257.4(MYH7):c.2539A>G (p.Lys847Glu)

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

gnomAD: Not in gnomAD

DiseaseAssertion: Hypertrophic Cardiomyopathy

VariantPreviousTesting: ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, and TTR were all tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 760 HCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one proband

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

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

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

DiseaseAssertion: Cardiomyopathy

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

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of the 305 PanCM probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

VariantAddInfo: Seen in one PanCM proband

Variant: NM_000257.4(MYH7):c.3157C>T (p.Arg1053Trp)

ClinVar: 181382 https://www.ncbi.nlm.nih.gov/clinvar/variation/181382/

gnomAD: Not in gnomAD

Supplementary Data: Online Table 1a

Case:

CaseHPOFreeText: heart transplant

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.495G>A (p.Met165Ile)

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

gnomAD: n/a

Supplementary Data: Online Table 2b

Case 4:

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 1: 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

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

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

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 2a

Case:

CasePresentingHPOs: HP:0010316 (Ebstein anomaly)

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

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

Variant: NM_000257.3(MYH7):c.847T>G (p.Tyr283Asp)

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

gnomAD: n/a

Supplementary Data: Online Table 2b

Case 3:

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 1: 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

Variant 2: NM_000257.3(MYH7):c.1633G>A (p.Asp545Asn)

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

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23897049-C-T

variants asserted to be in cis

Supplementary Data: Online Table 2a

Case:

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

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

Variant: NM_000257.3(MYH7):c.4075C>T (p.Arg1359Cys)

ClinVar: 178082, https://www.ncbi.nlm.nih.gov/clinvar/variation/178082/

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/14-23887513-G-A

Supplementary Data: Table S3

Case 135:

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

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.4010G>A (p.Arg1337Gln)

ClinVar: 181238, https://www.ncbi.nlm.nih.gov/clinvar/variation/181238/

gnomAD: 0.0001207, https://gnomad.broadinstitute.org/variant/14-23887578-C-T

Supplementary Data: Table 2

Case 3:

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: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

Variant - paternal: 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 2:

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: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

Variant - maternal: 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 M:

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, MYBPC3)

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

CaseMYH7-19: 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.2539A>G (p.Lys847Glu)

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

gnomAD: Not in gnomAD

CaseAJV: 17 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.

CasePresentingHPOs: HP:0001639, HP:0006536 (Hypertrophic cardiomyopathy, Obstructive lung disease)

HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,

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.1954A>G (p.Arg652Gly)

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

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)

ClinVar: 180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/

gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A

CaseMYH7-11: 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.3325A>G (p.Lys1109Glu)

ClinVar: 492984 https://www.ncbi.nlm.nih.gov/clinvar/variation/492984/

gnomAD: Not in gnomAD

CaseVIII: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM, 1 other relative without phenotypes

CasePresentingHPOs: HP:0001712, HP:0001639, HP:0011103 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Cosegregation confirmed for MYH7

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.4402G>A (p.Glu1468Lys)

ClinVar: 235033 https://www.ncbi.nlm.nih.gov/clinvar/variation/235033/

gnomAD: Not in gnomAD

Multiple Gene Variants

MYBPC3 Variant

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

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

gnomAD: European (Finnish) 0.02794, Overall 0.006194 https://gnomad.broadinstitute.org/variant/11-47357479-C-T

CaseIV: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM

CasePresentingHPOs: HP:0001712, HP:0001639 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Cosegregation confirmed, one other proband (X) has the same genotype, Late sudden death

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.4402G>A (p.Glu1468Lys)

ClinVar: 235033 https://www.ncbi.nlm.nih.gov/clinvar/variation/235033/

gnomAD: Not in gnomAD

Supplementary Data Table S3

Case: 33

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.5656-4G>A

ClinVar: 516360, https://www.ncbi.nlm.nih.gov/clinvar/variation/516360/

gnomAD: 0.00006011, https://gnomad.broadinstitute.org/variant/14-23883106-C-T

MultipleGeneVariants:

(1) CRYAB Variant

Variant: c.331G>A (p.Gly111Ser) unregistered variant

(2) DES Variant

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

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

gnomAD: 0.009280, https://gnomad.broadinstitute.org/variant/2-220284876-C-T

(3) FKTN Variant

Variant: NM_006731.2(FKTN):c.1336A>G (p.Asn446Asp)

ClinVar: 36138, https://www.ncbi.nlm.nih.gov/clinvar/variation/36138/

gnomAD: 0.01093, https://gnomad.broadinstitute.org/variant/9-108397495-A-G

(4) MYBPC3 Variant

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

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

gnomAD: 0.006194, https://gnomad.broadinstitute.org/variant/11-47357479-C-T

CasePT-110: 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.5326A>G (p.Ser1776Gly)

ClinVar: 177629 https://www.ncbi.nlm.nih.gov/clinvar/variation/177629/

gnomAD: East Asian 3.007e-4, Overall 4.595e-5 https://gnomad.broadinstitute.org/variant/14-23884437-T-C

Multiple Gene Variants:

MYBPC3 Variant:

Variant is reported as below, but the nucleotide sequence is incorrect. Unable to register

Variant: NM_000256.3:c.76A>G (p.Ser236Gly)

CasePT-99: 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.4199C>G (p.Ala1400Gly)

ClinVar: 181248 https://www.ncbi.nlm.nih.gov/clinvar/variation/181248/

gnomAD: Not in gnomAD

CasePT-42: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo: 2 other siblings share the same genotype

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

Variant: NM_000257.3:c.5317C>A (p.Gln1773Lys)

ClinVar: 181277 https://www.ncbi.nlm.nih.gov/clinvar/variation/181277/

gnomAD: Not in gnomAD

CasePT-33: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

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

NotHPOsFreeText: N/A

CaseAddInfo: PT-34 is the proband's sibling in Family 17 with the same genotype

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

Variant: NM_000257.3:c.1615A>G (p.Met539Val)

ClinVar: 181409 https://www.ncbi.nlm.nih.gov/clinvar/variation/181409/

gnomAD: Not in gnomAD

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.1324C>T (p.Arg442Cys)

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

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/14-23898247-G-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.1478T>A (p.Met493Lys)

ClinVar: 192308, https://www.ncbi.nlm.nih.gov/clinvar/variation/192308/

gnomAD: n/a

Table V

Case 902: Italian, Female, 25yo at onset

DiseaseAssertion: HCM

CasePresentingHPOs: HP:0001712, HP:0000821, HP:0006682, HP:0004756 (left ventricular hypertrophy, hypothyroidism, premature ventricular contractions, ventricular tachycardia)

CaseHPOFreeText: maximum left ventricular wall thickness of ≥15 mm, LVWT = 19mm, automatic implantable cardioverter defibrillator, LV ejection fraction = 64%

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_000256.3(MYBPC3):c.2507T>C (p.Met836Thr) written in paper as p.Ile836Thr

ClinVar: 454315, https://www.ncbi.nlm.nih.gov/clinvar/variation/454315/

gnomAD: n/a

Case#: HCM516, male, 23 years,

DiseaseAssertion: HCM

FamilyInfo: Yes, father and mother has HCM

CasePresentingHPOs: syncope, chest tightness (HP:0001279, HP:0031352)

CaseHPOFreeText: inverted T-waves, ST-segment depression, 28mm MLVWT, 67% LVE F, 0.64 E/A ratio, LVOT-PG 44mm

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: sequencing, physical examination, ECG, 3D modeling, statistical analysis

MultipleGeneVariants:

(1) Variant: NM_000257.4(MYH7):c.2631G>A (p.Met877Ile)

ClinVar: 955476 https://www.ncbi.nlm.nih.gov/clinvar/variation/955476/

CAID: N/A

gnomAD: absent

(2) Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

Case#: 6, female, 45 yr at onset, 66 yr at diagnosis

DiseaseAssertion: Myopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0100595, HP:0003202, HP:0003715, HP:0100301 (Camptocormia, skeletal muscle atrophy, myofibrillar myopathy, muscle fiber tubular inclusions)

CaseHPOFreeText: muscle atrophy specifically paraspinal, no clinical signs of the atrophy

CaseNotHPOs: HP:0003701, HP:0000508, HP:0000602, HP:0002015 (proximal muscle weakness, ptosis, ophthalmoplegia, dysphagia)

CaseNotHPOFreeText: No ALS, MG, or Parkinson's disease

CasePreviousTesting: spinal cord imaging, EMG, deltoid muscle, repetitive nerve stimulation, intravenous Prostigmin therapeutic text, screening for anti-ancetylcholine receptor and anti-muscle specific kinase antibodies, left deltoid muscle biopsy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr)

ClinVar: 177697 https://www.ncbi.nlm.nih.gov/clinvar/variation/177697/

CAID: N/A

gnomAD: 0.0001316 (European/non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884434-C-T

CaseHCM4.1: Mixed ancestry

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0000819 (Diabetes mellitus)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was extracted from the probands' blood, followed by sequencing of the coding regions and exon/intron boundaries of 15 genes associated with HCM. From there, they were amplified by PCR ampliication and variants were filtered by pathogenicity. Every unclassified variant was confirmed by Sanger sequencing afterwards.

Variant: NM_000257.3:c.2282C>A (p.Thr761Asn)

ClinVar: 546292 https://www.ncbi.nlm.nih.gov/clinvar/variation/546292/

gnomAD: Not in gnomAD

Case2: Male, 43 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0005110 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Atrial fibrillation)

HPOsFreeText: 0 SCD risk factors, NYHA class is II, Right ventricular wall thickness 14.9 mm

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

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: NM_000257.3:c.2123G>C (p.Gly708Ala)

ClinVar: 42882 https://www.ncbi.nlm.nih.gov/clinvar/variation/42882/

gnomAD: Not in gnomAD

MultipleGeneVariants:

MYBPC3 Variant:

Variant: NM_000256.3:c.1000G>A (p.Glu334Lys)

ClinVar: 177902 https://www.ncbi.nlm.nih.gov/clinvar/variation/177902/

gnomAD: East Asian 3.338e-3, Overall 2.368e-4 https://gnomad.broadinstitute.org/variant/11-47367848-C-T

**TTN Variant

Unknown Variant

Variant: TTN-E23808K

CAID: N/A

gnomAD: N/A

ACTN2 Variant

Unknown Variant

Variant: ACTN2-P32fs

CAID: N/A

gnomAD: N/A

DSC2 Variant

Unknown Variant, as 3 possible mutations can be responsible for this protein change

Variant: DSC2-S574R

CAID: N/A

gnomAD: N/A

LAMA4 Variant

Unknown Variant

Variant: LAMA4-L1040P

CAID: N/A

gnomAD: N/A

SYNEC2 Variant

Unknown Variant, as 3 possible mutations can be responsible for this protein change

Variant: SYNE2-W5861C

CAID: N/A

gnomAD: N/A

CaseARVC-02: Male, 35 year diagnosis, Caucasian, Germany

CasePresentingHPOs: HP:0011663, HP:0001635 (Right ventricular cardiomyopathy, Heart failure)

HPOsFreeText: RVEDD at 61 mm

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband treated with HTx and ICD, Father died of cardiac issues, Brother has heart disease, 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.3715A>G (p.Ile1239Val)

ClinVar: 265831 https://www.ncbi.nlm.nih.gov/clinvar/variation/265831/

gnomAD: Not in gnomAD

CaseMYH7-27: 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.505A>G (p.Arg169Gly)

ClinVar: 177664 https://www.ncbi.nlm.nih.gov/clinvar/variation/177664/

gnomAD: Not in gnomAD

Case#: Consequence 8 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.2539A>G (p.Lys847Glu)

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

CAID: n/a

gnomAD: absent

Case IV-8: Female, Iranian, 36yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0005162 (left ventricular dysfunction)

CaseHPOFreeText: New York Heart Association Class = I, left ventricular ejection fraction = 60%, left ventricular internal end-diastolic diameter = 5.0cm, left ventricular internal end-systolic diameter = 3.1cm, interventricular septum = 0.7cm, posterior wall = 0.7cm, normal sinus rhythm, Normal heart valve function

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG

CaseGenotypingMethod: 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

Case III-10: Female, Iranian, 60yo

DiseaseAssertion: DCM

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0011713, HP:0005162, HP:0005185, HP:0002375 (mitral regurgitation, left bundle branch block, left ventricular dysfunction, systolic dysfunction, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 15-20%, left ventricular internal end-diastolic diameter = 5.6cm, left ventricular internal end-systolic diameter = 4.3cm, interventricular septum = 0.7cm, posterior wall = 0.6cm, Normal heart valve function, grade II diastolic dysfunction

CaseNotHPOFreeText: Ischemic heart disease

CasePreviousTesting: ECG

CaseGenotypingMethod: 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

CasePD/Pathogenic-8: 2 weeks diagnosis

HPOsFreeText: GAA activity 5.0 (nmol · h−1 · mg−1), Mean percentage of normal 7.0%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

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

Variant3: NM_000152.4:c.692+5G>T

ClinVar: 526532 https://www.ncbi.nlm.nih.gov/clinvar/variation/526532/

gnomAD: European (Non-Finnish) 9.003e-6, Overall 4.181e-6 http://gnomad.broadinstitute.org/variant/17-78079698-G-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-8: 6 weeks diagnosis

HPOsFreeText: GAA activity 2.9 (nmol · h−1 · mg−1), Mean percentage of normal 4.1%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.2051C>T (p.Pro684Leu)

ClinVar: 285821 https://www.ncbi.nlm.nih.gov/clinvar/variation/285821/

gnomAD: European (Non-Finnish) 1.631e-4, Overall 8.195e-5 http://gnomad.broadinstitute.org/variant/17-78087027-C-T

Variant2: NM_000152.3: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

CaseLOPD-17: 6 weeks diagnosis

HPOsFreeText: GAA activity 6.5 (nmol · h−1 · mg−1), Mean percentage of normal 9.2%

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.1552-3C>G

ClinVar: 419722 https://www.ncbi.nlm.nih.gov/clinvar/variation/419722/

gnomAD: European (Non-Finnish) 2.713e-4, Overall 1.344e-4 http://gnomad.broadinstitute.org/variant/17-78084737-C-G

CaseAddInfo: Late Onset Pompe Disease

CasePD/Pathogenic-2: 3 weeks diagnosis

HPOsFreeText: GAA activity 8.8 (nmol · h−1 · mg−1), Mean percentage of normal 12.4%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

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

Variant3: NM_000152.4:c.2646+2T>A

ClinVar: 188924 https://www.ncbi.nlm.nih.gov/clinvar/variation/188924/

gnomAD: Not in gnomAD

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-19: 2 weeks diagnosis

HPOsFreeText: GAA activity 2.7 (nmol · h−1 · mg−1), Mean percentage of normal 3.8%

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.1115A>T (p.His372Leu)

ClinVar: 370483 https://www.ncbi.nlm.nih.gov/clinvar/variation/370483/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease

Patient 11 - LOPD

Variant1: NM_000152.4(GAA):c.670C>T (p.Arg224Trp)

ClinVar: 189188, https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/

gnomAD: 0.00002184, http://gnomad.broadinstitute.org/variant/17-78079671-C-T

Variant2: NM_000152.4(GAA):c.2331+2T>A

ClinVar: 371281, https://www.ncbi.nlm.nih.gov/clinvar/variation/371281/

gnomAD: 0.000004033, http://gnomad.broadinstitute.org/variant/17-78090910-T-A

Case44: Male, 10yo at onset, 15yo at enrollment

CasePresentingHPOs: HP:0007340, HP:0003701, HP:0003327, HP:0003236, HP:0002111, HP:0100748, HP:0003458

HPOsFreeText: symmetric muscle weakness of extremities, CK = 3313 IU/L, FVC = 23%, Unspecific myopathic change, DBS GAA activity = 0.1, mixed leukocyte GAA activity = 1.80

CaseNotHPOs: HP:0001627, HP:0002086

NotHPOsFreeText:

CaseAddInfo: 5 years between onset and diagnosis

CasePreviousTesting: clinical history, laboratory data, DBS and ML assays to measure GAA activity, electromyography, muscle pathology analysis

CaseGenotypingMethod: full sequencing of GAA gene

VariantAllele1: NM_000152.4(GAA):c.546G>T (p.Thr182=)

ClinVar: 370637, https://www.ncbi.nlm.nih.gov/clinvar/variation/370637/

gnomAD: n/a

VariantAllele2: NM_000152.4(GAA):c.1316T>A (p.Met439Lys)

ClinVar: 371305, https://www.ncbi.nlm.nih.gov/clinvar/variation/371305/

gnomAD: 3.988e-05, http://exac.broadinstitute.org/variant/17-78082617-T-A

Patient1: Female, northern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: 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

Variant2: NM_000152.4(GAA):c.1927G>A (p.Gly643Arg)

ClinVar: 4023, https://www.ncbi.nlm.nih.gov/clinvar/variation/4023/

gnomAD: 0.00002479, http://gnomad.broadinstitute.org/variant/17-78086713-G-A

Patient7: Female, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1432G>A (p.Gly478Arg)

ClinVar: 551295, https://www.ncbi.nlm.nih.gov/clinvar/variation/551295/

gnomAD: 8.525e-06, http://exac.broadinstitute.org/variant/17-78083849-G-A

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: n/a

Patient5: Female, 0.3mo at ERT start, 3.5yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 40mg/kg/wk, patient had 2 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4(GAA):c.1933G>A (p.Asp645Asn)

ClinVar: 188728, https://www.ncbi.nlm.nih.gov/clinvar/variation/188728/

gnomAD: 0.000008250, http://gnomad.broadinstitute.org/variant/17-78086719-G-A

Patient6: Female, 2.4mo at ERT start, 5.6yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 40mg/kg/wk, patient had 70 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481 + 102_2646 + 31del)

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

gnomAD: n/a

Case1HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 2 pmol/punch/hr, GAA activity at 6% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

Case20HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 9 pmol/spot/hr, GAA activity at 18% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

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 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2459_2461delCTG (p.Ala820del)

ClinVar: 456404 https://www.ncbi.nlm.nih.gov/clinvar/variation/456404/

gnomAD: European (Non-Finnish) 6.492e-5, Overall 3.190e-5 https://gnomad.broadinstitute.org/variant/17-78091524-GGCT-G

CaseAddInfo:

Case4HPOsFreeText: 10 mg/kg GAA treatment, GAA activity at 0.1 pmol/punch/hr, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

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 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 https://gnomad.broadinstitute.org/variant/17-78084529-T-C

CaseAddInfo:

Case17HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.38 umol/g/h, GAA activity at 12.7% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

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 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2242dupG (p.Glu748Glyfs)

ClinVar: 370651 https://www.ncbi.nlm.nih.gov/clinvar/variation/370651/

gnomAD: European (Non-Finnish) 1.767e-5, Overall 7.975e-6 https://gnomad.broadinstitute.org/variant/17-78090813-T-TG

CaseAddInfo:

Case47

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.655G>A (p.Gly219Arg)

ClinVar: 189065 https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: African 4.024e-5, Overall 1.809e-5 http://gnomad.broadinstitute.org/variant/17-78079656-G-A

Variant2: NM_000152.4:c.1979G>A (p.Arg660His)

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

gnomAD: African 2.546e-4, Overall 3.680e-5 http://gnomad.broadinstitute.org/variant/17-78086765-G-A

CaseAddInfo: Infantile Onset Pompe Disease

Case78

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2608C>T (p.Arg870*)

ClinVar: 189009 https://www.ncbi.nlm.nih.gov/clinvar/variation/189009/

gnomAD: European (Non-Finnish) 4.888e-5, Overall 2.662e-5 http://gnomad.broadinstitute.org/variant/17-78092118-C-T

Variant2: 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

CaseAddInfo: Adult Late Onset Pompe Disease

Case42

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2512C>T (p.Gln838*)

ClinVar: 92479 https://www.ncbi.nlm.nih.gov/clinvar/variation/92479/

gnomAD: African 6.177e-5, Overall 3.997e-6 http://gnomad.broadinstitute.org/variant/17-78092022-C-T

Variant2: NM_000152.4:c.2105G>T (p.Arg702Leu)

CAID: 92472 https://www.ncbi.nlm.nih.gov/clinvar/variation/92472/

gnomAD: Not in gnomAD

CaseAddInfo: Infantile Onset Pompe Disease

Patient17: Male

CasePresentingHPOs: HP:0004887, HP:0011471, HP:0001270, HP:0002546

HPOsFreeText: CRIM negative, tracheostomy, heart normalization

CaseNotHPOs: HP:0000365, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: homozygous variants in trans, symptom onset at 2yo, diagnosis and ERT at 6yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1A>G (p.Met1Val)

ClinVar: 188785, https://www.ncbi.nlm.nih.gov/clinvar/variation/188785/

gnomAD: n/a

Patient 12: male

CasePresentingHPOs:

HPOsFreeText: CRIM positive, infusion associated reaction, heart normalization

CaseNotHPOs: HP:0004887, HP:0025156, HP:0002355, HP:0002546, HP:0000365, HP:0001371

CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 3yo, ERT at 4yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

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

gnomAD: 1.663e-05, http://exac.broadinstitute.org/variant/17-78085800-T-C

Patient8: Female

CasePresentingHPOs: HP:0004887, HP:0001270

HPOsFreeText: CRIM positive, tracheostomy partial heart normalization

CaseNotHPOs: HP:0025156, HP:0001371

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 1yo, diagnosis at 9yo, ERT at 10yo. Died due to infusion reaction with ERT.

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 7.041e-05, http://exac.broadinstitute.org/variant/17-78078909-CT-C

Variant2: NM_000152.4(GAA):c.670C>T (p.Arg224Trp)

ClinVar: 189188, https://www.ncbi.nlm.nih.gov/clinvar/variation/189188/

gnomAD: 2.53e-05, http://exac.broadinstitute.org/variant/17-78079671-C-T

CaseP2-GAA: female, ethnicity = North African, country origin = Morocco

CasePresentingHPOs: HP:0010899, HP:0010916, HP:0003236

HPOsFreeText: enzyme activity = 1.41, CPK = 682 U/L, ALT = 68 U/L, AST = 130 U/L, CRIM positive

CaseNotHPOs:

CaseAddInfo: heterozygote, variants in trans. Patient underwent ERT.

CasePreviousTesting: initial and confirmatory DBS, biochemical tests, echocardiography

CaseGenotypingMethod: mutation analyses

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

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

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.236_246delCCACACAGTGC (p.Pro79Argfs)

ClinVar: 371302, https://www.ncbi.nlm.nih.gov/clinvar/variation/371302/

gnomAD: n/a

Family 8 - Patients 8a and 8b

FamilyPresentingHPOs: HP:0007340, HP:0003701, HP:0000467, HP:0003327, HP:0010628, HP:0002015, HP:0003691, HP:0002650, HP:0040081

HPOsFreeText: 8b muscle pathology with mild lysosomal vacuolar myopathy with slight glycogen excess, no metachromatic debris, myopathic muscle unit action potentials

FamilyNotHPOs: HP:0003306

Ethnicity: Iranian

ProbandLabel: 8a, female, 27yo at onset, 32yo at diagnosis

FamilyAddInfo: 8b (male) dx at 40yo, 8a MRC sum score = 82, 8b MRC sum score = 60, 8b is wheelchair bound, both patients required use of NIV

FamilyPreviousTesting: Respiratory Evaluation: 8a FVC = 102%, 8b FVC = 17%, 8a CK = 268 U/L, 8b CK = 199 U/L, muscle pathology (examined only in 8b), DBS enzyme activity (with inhibition) for 8a = 0.11 μmol/L/h, for 8b = 0.15 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.2078dupA (p.Ala694Glyfs)

ClinVar: 180143, https://www.ncbi.nlm.nih.gov/clinvar/variation/180143/

gnomAD: n/a