5
Case#: 5, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.741G>A
LegacyVariant:
ClinVar: No
CAID: CA414919022
gnomAD:
23
Case#: 23, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6496C>T
LegacyVariant:
ClinVar: 10096
CAID: CA255013
gnomAD:
19
Case#: 19, male, 48 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4342C>T
LegacyVariant:
ClinVar: No
CAID: CA414918542
gnomAD:
18
Case#: 18, male, 15 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 20%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3325C>T
LegacyVariant:
ClinVar: No
CAID: CA414897253
gnomAD:
144
Case#: 144, male, 14 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4320_4325delTAGAAA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
22
Case#: 22, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6496C>T
LegacyVariant:
ClinVar: 10096
CAID: CA255013
gnomAD:
13 3 M 31 c.5335C.T p.R1779* Hmz 5.4 ,1 3 - -
Case: 13, M, 3 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 5.4, VWF:Ag (U/dl): <1, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Homozygous
9 2.5 M 28 c.4975C.T p.R1659* Hmz 7 1.5 9 - -
Case: 9, M, 2.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 7, VWF:Ag (U/dl): 1.5, Bleeding Score: 9
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4975C>T (p.Arg1659*), Exon 28, Homozygous
3 22 F 8 c.970C.T p.R324* Hmz ,1 ,1 4 - -
Case: 3, F, 22 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 4
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.970C>T (p.Arg324*), Exon 8, Homozygous
66 5 F 28 c.3862C.G p.L1288V Htz 1.4 2.3 6 - -c.3931C.T p.Q1311*c.3951C.T p.A1317Ac.4027A.G p.I1343V
Case: 66, F, 5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.4, VWF:Ag (U/dl): 2.3, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3862C>G (p.Leu1288Val), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
c.3951C>T (p.Ala1317Ala), Exon 28
c.4027A>G (p.Ile1343Val), Exon 28
Heterozygous
82 2 M 15 c.1830C.A p.Y610* Hmz 1.4 ,1 6 - -
Case: 82, M, 2 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.4, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1830C>A (p.Tyr610*), Exon 15, Homozygous
6 24 F 9 c.1093C.T p.R365* Hmz 1 ,1 22 - +
Case: 6, F, 24 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1, VWF:Ag (U/dl): <1, Bleeding Score: 22
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1093C>T (p.Arg365*), Exon 9, Homozygous
1 10 M 3 c.100C.T p.R34* Hmz ,1 ,1 11 - +
Case: 1, M, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 11
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.100C>T (p.Arg34*), Exon 3, Homozygous
65 10 M 28 c.3789G.A p.S1263S Hmz 2.1 1.4 5 - -c.3797C.T p.P1266Lc.3835G.A p.V1279Ic.3931C.T p.Q1311*c.3951C.T p.A1317A
Case: 65, M, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.1, VWF:Ag (U/dl): 1.4, Bleeding Score: 5
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3789G>A (p.Ser1263Ser), Exon 28
c.3797C>T (p.Pro1266Leu), Exon 28
c.3835G>A (p.Val1279Ile), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
c.3951C>T (p.Ala1317Ala), Exon 28
Homozygous
25 26 M 14 c.1693C.Tp.Q565* Hmz 2.5 ,1 6 - -
Case: 25, M, 26 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1693C>T (p.Gln565*), Exon 14, Homozygous
8 2 F 10 c.1117C.T p.R373* Hmz 4.5 ,1 11 - -
Case: 8, F, 2 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 4.5, VWF:Ag (U/dl): <1, Bleeding Score: 11
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1117C>T (p.Arg373*), Exon 10, Homozygous
21 22 M 50 c.8145C.Ap.C2715* Hmz 8 4.9 9 - -
Case: 21, M, 22 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 8, VWF:Ag (U/dl): 4.9, Bleeding Score: 9
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.8145C>A (p.Cys2715*), Exon 50, Homozygous
10 42 M 31 c.5335C.T p.R1779* Htz ,1 ,1 34 + -
Case: 10, M, 42 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 34
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Heterozygous
18 8 M 47 c.7300C.T p.R2434* Hmz 8 4.6 8 - +
Case: 18, M, 8 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 8, VWF:Ag (U/dl): 4.6, Bleeding Score: 8
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7300C>T (p.Arg2434*), Exon 47, Homozygous
Note: Look over exon
62 5 F 50 c.8145C.Ap.C2715* Hmz 3.5 2.6 15 - +
Case: 62, F, 5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3.5, VWF:Ag (U/dl): 2.6, Bleeding Score: 15
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.8145C>A (p.Cys2715*), Exon 50, Homozygous
29 0.8 F 45 c.7558C.T p.Q2520* Hmz 1.6 1.8 3 + +
Case: 29, F, 0.8 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.6, VWF:Ag (U/dl): 1.8, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7558C>T (p.Gln2520* ), Exon 45, Homozygous
15 29 M 31 c.5335C.T p.R1779* Hmz 1.8 ,1 16 + -
Case: 15, M, 29 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.8, VWF:Ag (U/dl): <1, Bleeding Score: 16
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Homozygous
23 10 F 18 c.2430C.Ap.C810* Htz 3.1 ,1 8 + +
Case: 23, F, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3.1, VWF:Ag (U/dl): <1, Bleeding Score: 8
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2430C>A (p.Cys810*), Exon 18, Heterozygous
12 16 F 31 c.5335C.T p.R1779* Hmz 6 ,1 16 + -
Case: 12, F, 16 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 6, VWF:Ag (U/dl): <1, Bleeding Score: 16
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Homozygous
20 10 M 45 c.7603C.T p.R2535* Hmz ,1 ,1 8 + -
Case: 20, M, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 8
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7603C>T (p.Arg2535*), Exon 45, Homozygous
A 30‐year‐old male patient
Case#: Patient B, Male, Age 30, Chinese
Disease Assertion: VWD3
FamilyInfo: Consanguineous marriage between parents. Parents had 2 daughters and a son. One daughter died (1 year old) due to bleeding disorder. Mother's VWF:Ag 58% and VWF:RCo 36%. Family pedigree in Figure 2 (a). Both parents were heterozygous carriers of the variant.
Parental Genotype: Both Heterozygous
CasePresentingHPOs: HP:0003645
(Prolonged partial thromboplastin time)
CaseHPOFreeText: Hematoma in the lower extremity, VWF:Ag: 0.5%, VWF:RCo: 0.1%, FVIII:C 1.2%, APTT: 72.0 s
CaseNotHPOs:
CaseNotHPOFreeText: PT: 13.6 s, TT: 14.9s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8, F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4:c.6450C>A
ClinVar: N/A
CAID: CA383491381 CAID
gnomAD:N/A
A 23‐year‐old female
Case#: Patient A, Female, Age 23, Chinese
Disease Assertion: VWD3
FamilyInfo: Family pedigree in figure 1(a). Consanguineous marriage between parents. Parents had a boy who died (1 year old) due to heavy nose bleeds. Parents were heterozygous carriers for the variant.
Parental Genotype: Both parents were heterozygous
CasePresentingHPOs: HP:0000132, HP:0003645, HP:0008151
(Menorrhagia, Prolonged partial thromboplastin time, Prolonged prothrombin time)
CaseHPOFreeText: Scalp hematoma, FVIII:C: 1.3%, VWF:Ag: 3.6%, VWF:RCo: <1.0%, PT: 15.9 s, APTT: 62.7 s
CaseNotHPOs: N/A
CaseNotHPOFreeText: TT: 14.9 s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8,F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4(VWF):c.4696C>T (p.Arg1566Ter)
ClinVar:100382 ClinVarID
CAID: CA228639
gnomAD: MAF of 0.00001762 (2/113480 alleles) in the European (Non- Finnish) population.
Case: P88, Chinese, female, 4yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 11; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 3.0, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 6.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: 1 c.1591C>T (p.Gln531Ter)
HGVS: NM_000552.5:c.1591C>T (p.Gln531Ter)
ClinVarID: NA
CAID: CA383498290; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383498290
gnomAD: absent
Variant 2: c.6678dupC - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P38, Chinese, female, 14yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 1.3, VWF:RCo (%) = 1.0, FVIII:C (%) = 4.5, VWF:CB (%) = 0.7, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 0.6, FVIII:C/VWF:Ag = 3.5
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2684A>G (p.Gln895Arg)
HGVS: NM_000552.5:c.2684A>G (p.Gln895Arg)
ClinVarID: NA
CAID: CA383519914; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383519914
gnomAD: NA
Variant 2: c.3043G>T (p.Glu1015Ter)
HGVS: NM_000552.5:c.3043G>T (p.Glu1015Ter)
ClinVarID: NA
CAID: CA383514739; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383514739
gnomAD: absent
Case: P77, Chinese, female, 10yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 7; VWF:Ag (%) = 3.0, VWF:RCo (%) = 2.7, FVIII:C (%) = 6.8, VWF:CB (%) = 2.1, VWFpp (%) = 3.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 2.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.6771C>A (p.Cys2257Ter)
HGVS: NM_000552.5:c.6771C>A (p.Cys2257Ter)
ClinVarID: NA
CAID: CA383489897; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383489897
gnomAD: absent
Variant 2: c.8116-2delA - unregistered variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P33, Chinese, female, 35yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.0, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 10.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.813C>G (p.Tyr271Ter)
HGVS: NM_000552.5:c.813C>G (p.Tyr271Ter)
ClinVarID: NA
CAID: CA383508522; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508522
gnomAD: MAF = 0.0001088 (2/18380 alleles) in the East Asian popualtion; https://gnomad.broadinstitute.org/variant/12-6184562-G-C
183< 1< 13−−20Mc.1992insC/c.5557C>Tp.C665LfsX13/p.R1853X16/3215/16N/PD
Case: Patient 18, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 20, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1992insC (p.Cys665LeufsX13), Exon 16
c.5557C>T (p.Arg1853X), Exon 32
Intron 40 VNTR 15/16
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
203< 1< 16−14Mc.103T>C/c.4975C>Tp.C35R/p.R1659X3/2814/16N/PD
Case: Patient 20, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 6, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.103T>C (p.Cys35Arg), Exon 3
c.4975C>T (p.Arg1659X), Exon 28
Intron 40 VNTR 14/16
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
173< 1< 14−−18Fc.7333delG/c.7703C>Ap.E2445RfsX16/p.S2568X43/4517/18N/N
Case: Patient 17, F, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 18, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 4, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detecteddid not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7333delG (p.Glu2445ArgfsX16), Exon 43
c.7703C>A (p.Ser2568X), Exon 45
Intron 40 VNTR 17/18
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
Case#: 21011, Age 54, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#2111.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NP_000543.2:p.Ser83Ter (c.246_247insT)
ClinVar: N/A
CAID: PA1139532036 CAID
gnomAD: N/A
Case#: 27032, Age 49, Female, Blood Type O+
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members of Family#2716. The other member has the same variant, but is only a carrier.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 8, VWF:Ag:31, VWF:RCo: 22.7, FVIII:C: 72, VWF:CB: 38
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2518G>T (p.Glu840Ter)
ClinVar: N/A
CAID:CA383520331 CAID
gnomAD: N/A
Case#: 06024, Age 36, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient is the only member of Family#0617.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 1, VWF:Ag:35, VWF:RCo:25, FVIII:C:69, VWF:CB: 27
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression:N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.7300C>T (p.Arg2434Ter)
ClinVar: 100464 ClinVar
CAID: CA228781 CAID
gnomAD: MAF of 0.0001298 (2/15414 alleles) in the European (non-Finnish) population. gnomAD
Case#: 32002, Age 49, Female, Blood Type +
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3202.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 34, VWF:RCo: 30, FVIII:C: 53, VWF:CB: 29
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 3
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.7408C>T (p.Gln2470Ter)
ClinVar: 100469 ClinVar
CAID: CA228790 CAID
gnomAD: MAF of 0.00002891 (1/34590 alleles) in the Latino population.
T065M/15220.010.020.01c.3303C>Ap.Cys1101*25Homozygous
Case: T065, M, 15
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 22 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3303C>A (p.Cys1101*), Exon 25, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T018F/18120.040.000.03c.7399C>T, c.8418_8419insTCCCp.Gln2467*, p.Ser2807 fs43/52Compound heterozygous
Case: T018, F, 12
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: HP:0000421
CaseHPOFreeText: Bleeding Score: 12 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.03, inhibitor positive
CaseNotHPOs: has not developed any anaphylactic reactions and/or become refractory to replacement therapy
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7399C>T (p.Gln2467*), Exon 43
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T086M/130.010.020.01c.1A>G, c.2377C>Tp.Met1Val, p.Gln793*2/18Compound heterozygous
Case: T086, M, 1
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 3 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1A>G (p.Met1Val), Exon 2
c.2377C>T (p.Gln793*), Exon 18
Compound Heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T050F/21240.010.000.01c.876delC, c.1255C>Tp.Ser293 fs, p.Gln419*8/11Compound heterozygous
Case: T050, F, 21
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 24 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.876delC (p.Ser293 fs), Exon 8
c.1255C>T (p.Gln419*), Exon 11
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T090M/280.010.040.01c.1117C>T, gene conversion (c.3931C>T, c.4027A>G, c.4079T>C, c.4105T>A)p.Arg373*, p.Gln1311*, p.Ile1343Val, p.Val1360Ala, p.Phe1369Ile10/28Compound heterozygous
Case: T090, M, 2
DiseaseAssertion: VWD type 3
FamilyInfo: inherited heterozygous gene conversion from the father
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1117C>T (p.Arg373*)
Gene Conversion (
c.3931C>T (p.Gln1311*)
c.4027A>G (p.Ile1343Val)
c.4079T>C (p.Val1360Ala)
c.4105T>A (p.Phe1369Ile)
)
Exon 10/28
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
10*ItalyF/30<1—YesSevere4626C→GY1542X28HomozygousRsaI (−)
Case: 10, F, 30, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
4626C→G (Tyr1542X), Exon 28, Homozygous
3*ItalyF/21<1—NoSevere666G→A/823T→AW222X/C275S7/7HeterozygousN.A./BsrI (+)
Case: 3, F, 21, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
666G→A (Trp222X), Exon 7
823T→A (Cys275Ser), Exon 7
Compound Heterozygous
8*ItalyF/7<1—NoMild4013C→G/6385G→TS1338X/E2129X28/37HeterozygousN.A./MnlI (−)
Case: 8, F, 7, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
4013C→G (Ser1338X), Exon 28
6385G→T (Glu2129X), Exon 37
Compound Heterozygous
4ItalyM/55<1—NoSevere1093C→T/1830C→AR365X/Y610X9/15HeterozygousTaqI (−)/DdeI (+)
Case: 4 , M, 55, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
1093C→T (Arg365X), Exon 9
1830C→A (Tyr610X), Exon 15
Compound Heterozygous
18*IranM/212—YesSevere1930G→TE644X15HomozygousHaeII (+)
Case: 18, M, 21, Iranian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: Yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): 2, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
1930G→T (Glu644X), Exon 15, Homozygous
37IndiaF/29<1—NoMild1896G→A/3212G→TW642X/C1071F15/24HeterozygousMaeIII (+)/N.A.
Case: 37, F, 29, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: No
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
1896G→A (Trp642X), Exon 15
3212G→T (Cys1071Phe), Exon 24
Compound Heterozygous
Case#: Elayaperumal_2018_V-281, M, 2 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity, no family history of bleeding
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 9, VWF:Ag of 0, FVIII:C of 3.5%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.4696C>T (p.Arg1566*)
HGVS: NM_000552.3:c.4696C>T
ClinVarID: 100382
CAID: CA228639
gnomAD: MAF of 0.00001762 (2/113480 alleles, European non-Finnish) https://gnomad.broadinstitute.org/variant/12-6127888-G-A
MultipleGeneVariants: n/a
Case#: Elayaperumal_2018_V-260 , M, 3y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: consanguinity reported. No family history of bleeding
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 9, VWF:Ag of 0, FVIII:C of 7.4%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.665G>A (p.Trp222*)
HGVS: NM_000552.3:c.665G>A
ClinVarID: not found
CAID: CA383509511
gnomAD: not found
MultipleGeneVariants: n/a
p.(Val510 = ) variant
PMID: 33134807
Gene: VWF
HGNCID:12726
Case: Female patient from the French Caribbean island of Martinique
DiseaseAssertion: VWF Type 3
FamilyInfo: The proband had a combination of two variants p.(Val510+) and p.(Pro21452145Thrfs*5) in a heterozygous state. Her biological profile indicated VWD3: VWF:Ag = 1 to 5%, VWF:RCo = 5%, FVIII:C = 2 to 3%, VWFpp = 6%, and a total absence of multimers assessed by electrophoresis. She was usually treated with plasma-derived VWF concentrates. Interestingly, the VWFpp level in this patient was higher than expected for typical VWD3. The sister who died from a nonhemorrhagic cause had the same clinical-biological profile.
ParentalGenotype(s): The mother had a normal biological assessment and was asymptomatic without any bleeding. Sequencing of the mother's VWF gene revealed a single variant on exon 37: resulting in the nucleotide change c.6432dup / a.a. change p.(Pro2145THRfs*5) which results in a stop codon. This molecular abnormality favors VWD3, even though the mother is asymptomatic. The father experienced excessive bleeding only as a result of trauma or surgery. Sequencing of the father's VWF gene led to the identification of one potential causative variant: p.(Val510 = ), on exon 13 with a nucleotide change c.1530G>A. A second sister of the proband has a clinical and biological phenotype similar to that of her father.
CasePresentingHPOs:HP:0012147, HP:0030132, HP:0030129
CaseHPOFreeText: The proband presented with severe hemorrhagic manifestations.
CaseSubsequentTesting:N/A
GenotypingMethod:NGS
PreviouslyPublished: No
SupplementalData: The prediction softwares used (SpliceSiteFinder-like, MaxEntScan, GeneSplicer, NSPLICE, ESEFinder, RESCUE-ESE, and EX-SKIP) regarding c.1530G > A (p.(Val510 = )) interpreted the appearance of a donor site at 6 base pairs at the end of exon 13 which could potentially alter splicing. This synonymous mutation could therefore have an effect on VWF messenger ribonucleic acid processing, causing a shift in the reading frame and the appearance of a termination codon deletion of two codons. The ACMG predicted that this variant would probably be pathogenic.
VariantEvidence: An additional 21 patients from Martinique were identified with the p.(Val510=) variant. Median age was 63 years (interquartile range [IQR], 45–77) and 65% were female. The striking feature in these patients was a significantly increased VWFpp/VWF:Ag ratio with a median of 5.62 (IQR, 4.36–6,14). This ratio could be calculated only for the 14 patients for whom the VWFpp level was measured. An increased VWFpp/VWF:Ag ratio (> 2.2) is indicative of an accelerated clearance of VWF. Addition testing in four patients involved DDAVP infusion compared to a patient with a VWD1 mutation that does not cause a clearance defect. The results showed accelerated VWF clearance compared to the control. The author propose to classify patient with the p.(Val510=) variant as Type 1C, a rare subtype that removes VWF more quickly than normal in the blood.
Compound Heterozygote:
GeneName:VWF
Variant: NM_00055.2.5:c.6432dup. (Pro2145Thrfs*5)
ClinVarID1330387
gnomAD:N/A
GeneName: VWF
Variant:NM_000552.3:c.1530G>A, p.(Val510=)
CAIDCA6403368
gnomAD: 0.000001240
8 M/46 <1 7 No 19 c.4576C>Ta/c.6973T>Aa p.Q1526Xa/p.C2325Sa 28/40 Heterozygous
Case: 8, M, 46, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 7, Bleeding Score: 19
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4576C>T (p.Gln1526X), Exon 28
c.6973T>A (p.Cys2325Ser), Exon 40, B1 Domain
Compound Heterozygous
C
Case3: Patient ID C, Male, 12 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Hematoma
CaseNotHPOs: HP:0000967, HP:0000979, HP:0000978, HP:0004406, HP:0000225, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, easy bruising, recurrent epistaxis, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemhorrage after dental, hemhorrage after trauma, ear bleeding
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify a;; coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGA2B
Variant: NM_000419.3:c.1233C>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399803781
gnomAD: N/A
PreviouslyPublished: PMID: 12424194
Family L
Case15: Family L (patient found in the GT database as well) gender and age are not specified here
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000225(Epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
PreviouslyPublished: Reference numbers 26,27 in this article
CW
Case12: Patient CW (can be found in GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0031364, HP:0000979, HP:0000967, (Ecchymosis, Purpura/petechiae)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: <1% of normal GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.480C>G (p.Ser160_102del)
LegacyVariant: N/A
ClinVar: 2892 (Arg584Ter)
CAiD: CA115834 and CA399805892
gnomAD: MAF in the East Asian population is 0.0002176 for the Arg584Ter variant and MAF in the East Asian population is 0.00005507 for the other variant https://gnomad.broadinstitute.org/variant/17-42463013-G-C
PreviouslyPublished: Reference number 23 in this article
NR
Case19: Patient NR (found in the GT database as well) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: Menorrhagia HP:0000132
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A Undetectable
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.2941C>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399790399
gnomAD: N/A
PreviouslyPublished: Reference numbers 32,22 in this article
17
Case17: Patient MO (patient found in the GT database as well) gender and age are not specified here
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000132 (Bruising, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
PreviouslyPublished: Reference numbers 29 and 30 in this article
NA
Case13: Patient NA
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study
Gene: ITGA2B
Variant: There is a typo in this article, the article states Glu500Ter however it is Gln. NM_000419.3:c.1591C>T (p.Gln531Ter)
LegacyVariant: (p.Gln500Ter)
ClinVar: N/A
CAiD: CA399802478
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case20b: GT20b, Female, 23 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Family information available in Table1 (sister of proband GT20a)
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0002239, HP:0000132
(Bruising, purpura, ecchymosis, gastrointestinal bleeding, menorrhagia)
CaseHPOFreeText: Post traumatic bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399801310
gnomAD: MAF in Latino population: 0.00003983 https://gnomad.broadinstitute.org/variant/17-42456075-G-A
Supplementary Tables 1 and 2 combined information:
Case26: GT26, Male, 13 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364
(Bruising, purpura, ecchymosis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (Gln778Pro) and NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: 225393 (p.Gln778Pro)
CAiD: CA290947544 (p.Gln778Pro) and CA8602626 (p.Gln891Ter)
gnomAD: MAF in East Asian population: 0.0001087 https://gnomad.broadinstitute.org/variant/17-42453691-T-G
Supplementary Tables 1 and 2 combined information:
Case29: GT29, Female, 16 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132, HP:0000978, HP:0000979, HP:0031364, HP:0000225
(Menorrhagia, bruising, purpura, ecchymosis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case22: GT22, Female, 16 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000132 (Menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case4: GT4, Female, 22 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.2671C>T (p.Gln891Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602626
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case41: GT41, Male, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed 10-20% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1736G>A (p.Trp579Ter) and NM_000212.2:c.1784_1802delinsGTCACA
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400032429 (p.Trp579Ter) and CA915940255 (c.1784_1802delinsGTCACA)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case8: GT8, Male, 9 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1651C>T (p.Arg551Trp) and NM_000419.3:c.2236G>T (p.Glu746Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802348 (p.Arg551Trp) and CA399798321 (p.Glu746Ter)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case23: GT23, Female, 11 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225, HP:0000132
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding, menorrhagia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed a small response to ADP, no response to collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGB3
Variant: NM_000212.2:c.1980C>A (p.Tyr660Ter) and NM_000212.2:c.2147G>T (p.Gly716Val)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400032983 (p.Tyr660Ter) and CA400033923 (p.Gly716Val)
gnomAD: N/A
Supplementary Tables 1 and 2 combined information:
Case40: GT40, Male, 5 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421
(Bruising, purpura, ecchymosis, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.962G>T (p.Gly321Val)
LegacyVariant: N/A
ClinVar: 2892 (p.Arg584Ter)
CAiD: CA115834 (p.Arg584Ter) and CA399804765 (p.Gly321Val)
gnomAD: MAF for p.Arg584Ter in East Asian population 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Tables 1 and 2 combined information:
Case3: GT3, Female, 12 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Not available per supplementary table 1
ParentalGenotype: Parents are not consanguineous, no other genotype information available
CasePresentingHPOs: HP:0000978, HP:0000979, HP:0031364, HP:0000421, HP:0000225
(Bruising, purpura, ecchymosis, epistaxis, gingival bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Showed <5% of αIIbβ3 expression measured by flow cytometry
PlateletAggregation: Platelet aggregation showed no response to ADP and collagen but normal response to ristocetin
CasePreviousTesting: All exons from ITGA2B and ITGB3 genes were amplified by PCR using intronic primers. DNA sequencing was determined by Sanger sequencing.
Gene: ITGA2B
Variant: NM_000419.3: c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in East Asian population: 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
The propositus
Case1: Female, age and ethnicity is previously described in Ruan et al, 1993, but access not available to this article
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: The propositus' twin brother was also affected
ParentalGenotype: Article mentions, "Thus the two affected members are double heterozygote having inherited two different abnormal GPIIb alleles, one from the father and the other from the mother"
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding time > 15 minutes
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Absent or reduced platelet GPIIb and GPIIIa assessed by Western blotting
PlateletAggregation: Absent platelet aggregation in response to ADP, epinephrine, and collagen and normal aggregation in response to ristocetin
CasePreviousTesting: PCR was used to amplify the defective segment of the GPIIb gene
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: c.9644C>T
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case64: GT67, Male, 61 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Affected brother who is now dead (this is all the information we are provided with)
ParentalGenotype: N/A
CasePresentingHPOs:
(Gingival bleeding, epistaxis, bleeding after dental extraction )
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.1618C>T (p.Gln540Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913184940 and CA399802411
gnomAD: MAF in the African population is 0.000 https://gnomad.broadinstitute.org/variant/17-42457504-G-A
Supplementary Table S1 & S2 Proband and Variant Information:
Case56: GT57, Female, 10, Argentinian/European
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421, HP:0000967
(Epistaxis, petechia)
CaseHPOFreeText: Hematomas
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.571T>G (p.Phe191Val) and NM_000419.3:c.961G>T (p.Phe191Alafs*32)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805699 and CA399804768
gnomAD: N/A
Supplementary Table S1 & S2 Proband and Variant Information:
Case65: GT68, Male, 62 years old, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Occasional spontaneous bleeding and frequency decreased with age
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and "LR deletion" which is the only specification we are given
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376
gnomAD: MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C
Supplementary Table S1 & S2 Proband and Variant Information:
Case22: GT25, Male, 81, French
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002239
Gastrointestinal bleeding
CaseHPOFreeText: Life-long bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)
PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)
CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 and CA399801310
gnomAD: MAF in the European (non-Finnish) population 0.000008791 http://gnomad.broadinstitute.org/variant/17-42457994-G-C and MAF in Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
The patient is a 2-year-old female from China
Case1: Female, 3 years old, Chinese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A (No information about the family was available since the child was adopted)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000421 (Epistaxis)
CaseHPOFreeText: Mucocutaneous hemorrhages, prolonged bleeding time
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: Protein expression was estimated by flow cytometry and western blot analysis. The analysis revealed less than 10% of surface expression of alphaIIbbeta3 relative to control platelets. (See Fig 2)
PlateletAggregation: Platelet aggregation in response to ADP, collagen, adrenaline, and arachidonic acid was less than 5% that of control platelets, and no clot retraction was observed. Ristocetin-induced platelet agglutination and plasma fibrinogen content were within the normal range.
CasePreviousTesting: Sequencing for mutations was carried out by direct sequencing of PCR overlapping fragments of reversed transcribed αIIb and β3 mRNA.
Gene: ITGA2B
Variant: NM_000419.3:c.2829C>T (p.Pro943Leu), NM_000419.3:c.2621T>G (p.Ile874Ser), NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: (p.Ile843Ser) and (p.Arg553Ter) and (p.Pro912Leu)
ClinVar: 2891, 2892
CAiD: CA500263536, CA115831, CA115834
gnomAD: MAF in the European (Finnish) population is 0.4395 https://gnomad.broadinstitute.org/variant/17-42453065-A-C and MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
For the patient with Glanzmann thrombasthenia
Case1: Gender, age, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.262C>T (p.Arg88Ter)
LegacyVariant: (p.Arg62Ter)
ClinVar: N/A
CAiD: CA400020703
gnomAD: MAF in the Other population is 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T
Case18: Patient ME, gender and age are not specified, all of these patients are Caucasian (either Italian or European)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients presented with a current or past history of bleeding and a bleeding time >15 min. Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who bled only after trauma or surgery or had minor symptoms, such as epistaxis. Moderate/severe bleeders were defined as those with a history of spontaneous or life threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusions
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 1
PlateletAggregation: See Table 1
CasePreviousTesting: To identify point mutations responsible for GT, we have sequenced all coding regions of Ib and 3 genes and intron/exon boundaries.
Gene: ITGA2B
Variant: NM_000419.3:c.2929C>T (p.Arg977Ter)
LegacyVariant: (p.Arg946Ter)
ClinVar: N/A
CAiD: CA8602528
gnomAD: MAF in the South Asian population is 0.00003266 https://gnomad.broadinstitute.org/variant/17-42452041-G-A
GT 21
Case23: GT21, Male, India, age of onset is 33 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.921C>A (p.Tyr307Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025209
gnomAD: N/A
GT 04
Case15: GT04, Female, India, age of onset is 11 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: Menorrhagia HP:0000132
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.262C>T (p.Arg88Ter) and NM_000212.2:c.356G>A (p.Arg119Gln)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400020703 and CA8622925
gnomAD: MAF in the Other population is 0.0001385 https://gnomad.broadinstitute.org/variant/17-45360816-C-T and MAF in the African population is 0.0002470 https://gnomad.broadinstitute.org/variant/17-45360910-G-A
GT 07
Case16: GT07, Male, India, age of onset is 3 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.153del (p.Trp51CysfsTer5)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940728
gnomAD: N/A
GT 55
Case34: GT55, Male, India, age of onset is 21 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGB3
Variant: NM_000212.2:c.921C>A (p.Tyr307Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400025209
gnomAD: N/A
4
Case4: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0000978, HP:0000132, HP:0000421, HP:0000979
(Easy bruising, menorrhagia, epistaxis, purpura)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGB3
Variant: NM_000212.2:c.1303G>T (p.Glu435Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400028645
gnomAD: N/A
13
Case12: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGA2B
Variant: NM_000419.3:c.1555C>T (p.Gln519Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802559
gnomAD: N/A
3
Case3: Gender or age not specified, Thai ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Parental information available in Table 2
ParentalGenotype: Father: p.Arg782Ter/WT and Mother: Unavailable
Note: No parental consanguinity
CasePresentingHPOs: N/A
CaseHPOFreeText: The article does not mention specific bleeding phenotypes for each of the 4 probands in the article, rather, there is a general statement that says: "The common presentations included recurrent epistaxis, bleeding in oral cavity, and easy-bruising spontaneously or after trauma"
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinEpression: General statement from the article that states that flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression for all probands.
PlateletAggregation: The platelet aggregation test was typically defective with all physiological agonists except ristocetin, for all patients.
CasePreviousTesting: Whole exome sequencing was performed on the 30 exons of ITGA2B and 15 exons in ITGB3. PCR and direct sequencing were then performed in the DNA samples of the patients and their available parents to verify the presence of the identified mutations.
Gene: ITGA2B
Variant: NM_000419.3:c.2344C>T (p.Arg782Ter) and NM_000419.3:c.2915dup (p.Leu973Alafs*63)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399796586 (p.Arg782Ter) and CA8602531 (p.Leu973Alafs*63)
gnomAD: MAF for (p.Leu973Alafs*63) in East Asian population 0.0001088 http://gnomad.broadinstitute.org/variant/17-42452054-C-CG
Recently, we reported the case of an 8-year-old boy with a variant form of GT
Case1: Male, 8 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Sister had no bleeding tendency (all the information given in the previously published article cited in this annotation)
ParentalGenotype: Parental mutations shown in Fig. 3 A and B
CasePresentingHPOs: HP:0000421
(Epistaxis)
CaseHPOFreeText: Tonsilar bleeding
CaseNotHPOs: HP:0000979
(Purpura)
CaseNotHPOFreeText: N/A
ProteinExpression: Western blotting indicated that the proband's platelets contained no normal GPIIb, but showed a trace amount of an abnormal GPIIb (-6% with respect to the GPIIb level in a normal individual).
PlateletAggregation: Decreased aggregation in response to ADP, collagen and epinephrine but a normal ristocetin-induced aggregation (this information was obtained from the previously published article cited at in this annotation)
CasePreviousTesting: Genomic DNA fragments containing exons of the GPIIb gene were amplified by PCR
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter) and NM_000419.3:c.2602-3C>G
LegacyVariant: N/A
ClinVar: 2892 and 2893
CAiD: CA115834 and CA10575472
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A and MAF in the East Asian population is 0.00006523 https://gnomad.broadinstitute.org/variant/17-42453087-G-C
PreviouslyPublished: PMID: 1891767
F5P1
Case1: Patient F1P1, Male, 11 years old, Tunisian
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: Table 1 states there is a family history of bleeding (we have minimal to no specific info on this)
ParentalGenotype: Mother and father are heterozygous for mutation
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: GT diagnosis was based on absent platelet aggregation induced by ADP, collagen, and TRAP and subnormal or cyclical ristocetin induced agglutination
CasePreviousTesting: Using PCR they successfully amplified 20 DNA fragments for the ITGA2B gene (covering more than 48% of the ITGA2B gene constituting 30 exons) and15 DNA fragments of theITGB3gene (covering 15 exons)
Gene: ITGA2B
Variant: NM_000419.3:c.2702C>A (p.Ser901X) another variant this patient has is g.13944G>A --> I am noting this as Unknown Variant as I will need guidance curating this one
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399792888
gnomAD: N/A
F2P1
Case2: Patient F2P1, Male, 34 years old, Tunisian
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: Table 1 states there is a family history of bleeding (we have minimal to no specific info on this)
ParentalGenotype: Mother and father are heterozygotes for the mutation here
CasePresentingHPOs, : HP:0000225, HP:0004406, HP:0000978,HP:0000790
(Gingival bleeding, recurrent epistaxis, easy bruising, hematuria)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: GT diagnosis was based on absent platelet aggregation induced by ADP, collagen, and TRAP and subnormal or cyclical ristocetin induced agglutination
CasePreviousTesting: Using PCR they successfully amplified 20 DNA fragments for the ITGA2B gene (covering more than 48% of the ITGA2B gene constituting 30 exons) and15 DNA fragments of theITGB3gene (covering 15 exons)
Gene: ITGA2B
Variant: NM_000419.3:c.2702C>A (p.Ser901X) another variant this patient has is g.13944G>A --> I am noting this as Unknown Variant as I will need guidance curating this one
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399792888
gnomAD: N/A
Patient 1
Case1: Male, 14 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type 1
FamilyInfo: Sister is also heterozygous for this mutation but shows no bleeding symptoms
ParentalGenotype: Both parents are heterozygous for this mutation
Note: There is parental consanguinity
CasePresentingHPOs: HP:0000967, HP:0000225, HP:0000421
(Petechiae, ginigival bleeding, epistaxis)
CaseHPOFreeText: Haematoma,
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis revealed 3.8 % platelet surface presentation of the αIIbβ3 complex for patient 1 and αIIb was not detected and β3 was significantly reduced in Western blots. Platelets from GT patients showed less than 5 % relative levels of the integrin subunit IIb and 5–9 % fibrinogen compared to controls.
PlateletAggregation: Article states agonist-induced platelet aggregation and binding of exogenous fibrinogen was pathological, too but does not mention specific agonists used or response to ristocetin
CasePreviousTesting: Molecular genetic analysis was done; however, no other information mentioned. In addition, the global proteome of highlight purified washed platelets was quantified by liquid chromatography-mass spectrometry and targeted MS-methods.
Gene: ITGA2B
Variant: NM_000419.3:c.175del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940266
gnomAD: N/A
047–1008
Case#: 047-1008
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1336C>T
LegacyVariant:
ClinVar: No
CAID: CA255038
gnomAD:
047–1007
Case#: 047-1007
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1093T>G
LegacyVariant:
ClinVar: No
CAID: CA414916885
gnomAD:
c.1336C>T
Case#: 11
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.1336C>T (p.Arg446Ter)
ClinVar: 10145 https://www.ncbi.nlm.nih.gov/clinvar/variation/10145/
CAID: CA255038
gnomAD: Not reported
c.5953C>T
Case#: 23
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.5953C>T (p.Arg1985Ter)
ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/
CAID: CA255191
gnomAD: Not reported
c.4692delC
Case#: 19
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.4692del (p.Leu1566Ter)
ClinVar: NA
CAID: CA1139532037
gnomAD: NA
IG1
Case#: IG1, Italy
DiseaseAssertion: Hemophilia A, severe (Table 1)
FamilyInfo: Table 1 - female relative(s) tested
ParentalTesting: No
CasePresentingHPOs: HP:0003125
(Reduced factor VIII activity)
CaseHPOFreeText: FVIII:C <1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Entire FVIII coding region, flanking splicing sites and promoter sequence were amplified. Mutational analyses included DHPLC followed by sequencing.
Gene: F8
Variant: NM_000132.3:c.98G>A p.(Trp33Ter)
LegacyVariant: c.207G>A p.(Trp14Ter) [based on Antonarakis, 1998; PMID: 9450896]
ClinVar: No
CAID: CA414920533
gnomAD: Not reported
35.
Case#: 35
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.223C>T
LegacyVariant:
ClinVar: No
CAID: CA340993
gnomAD:
36.
Case#: 36
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.535G>T
LegacyVariant:
ClinVar: No
CAID: CA414440319
gnomAD:
Table 1
Case#: Cz16, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3(F8):c.5953C>T (p.Arg1985Ter)
ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/
CAID: CA255191
gnomAD: Not reported
c.5805T>A
Case#: 8
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5805T>A (p.Tyr1935Ter)
ClinVar: NA
CAID: CA414906924
gnomAD: Not Reported
2-year-old male MPS1-H child
Case#: Male, 2-year old
DiseaseAssertion: MPS1-H
FamilyInfo: Not provided
CasePresentingHPOs: Not provided
CaseHPOFreeText: NA
CaseNotHPOs: Not provided
CaseNotHPOFreeText: NA
CaseEnzymeAssay: MPS1-H fibroblasts exhibited no activity of IDUAα (0.01 ± 0.02 nmol/mg/min); iPSC clones were devoid of IDUAα activity
CaseUrineGAGs: Not provided
CaseERT: Don't know
CaseBMT: Don't know
Variant1: NM_000203.5(IDUA):c.1073_1093del (p.His358_Thr364del)
Variant1ClinVarID:557260
Variant1CAID:
Variant2: NM_000203.4(IDUA):c.1205 G>A (p.Trp402Ter)
Variant2ClinVarID:11908
Variant2CAID:
ParentalGenotype: Not provided
PreviouslyPublished: Authors reference [30]: PMID: 31678774 DOI: 10.1016/j.scr.2019.101604
A 30-year-old male patient
Case: Patient from family B, a 30-year-old male consanguineous Chinese patient
DiseaseAssertion: Type 3 von Willebrand disease
FamilyInfo: Patient's parents were cousins, both heterozygous carriers, who had also had a son and two daughters, of which one daughter died at 1 year old due to unspecified bleeding disorder
ParentalGenotype(s): Heterozygous carriers, no details given as far as specific genotypes
CasePresentingHPOs:
CaseHPOFreeRext: "hematoma in the lower extremity," "The VWF:Ag, VWF:RCo, and FVIII:C were decreased to be 0.5%, 0.1%, and 1.2%, respectively," and APTT was prolonged (PT: 13.6 s, APTT: 72.0 s, TT: 14.9 s)
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: PT and TT were within normal range
CasePreviousTesting: N/A
GenotypingMethod: NGS was performed targeting all exons and intronic flanking regions of the F8 (OMIM: * 300841, NM_000132.3), F9 (OMIM: * 300746, NM_000133.3), and VWF (OMIM: * 613160, NM_000552.4) genes; Some exons of VWF gene could not be discriminated from its highly homologous pseudogene, and these exons were sequenced by Sanger sequencing
Gene: VWF
Variant: Homozygous VWF c.6450C>A (p.Cys2150Ter) nonsense mutation
HGVS: NM_000552.5:c.6450C>A
ClinVarID: NR
CAID: CA383491381
gnomAD: NR
Case#: Elayaperumal_2018_V-283, M, 3 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: no consanguinity, no family history
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 12, VWF:Ag of 0, FVIII:C 4.3%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.6321G>A (p.Trp2107*)
HGVS: NM_000552.3:c.6321G>A
ClinVarID: not reported
CAID: CA383491677
gnomAD: not reported
MultipleGeneVariants: not reported
V‐144
Case#: Elayaperumal_2018_V-144, M, 1 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: consanguinity, family history of bleeding
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 7, VWF:Ag of 0, FVIII:C of 5.9%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.1117C>T (p.Arg373*)
HGVS: NM_000552.3:c.1117C>T
ClinVarID: 100175
CAID: CA228261
gnomAD: MAF of 0.0001309 (4/30550 alleles, South Asian population) https://gnomad.broadinstitute.org/variant/12-6180502-G-A
MultipleGeneVariants:
Note: previously reported in LOVD
V‐115
Case#: Elayaperumal_2018_V-115, female, 1 year old (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: consanguinity
ParentalGenotype: not reported. family history of bleeding.
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 13. VWF:Ag of 0. FVIII:C of 1.9%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF only.
Gene: VWF
Variant: homozygous c.6321G>A (p.Trp2107*)
HGVS: NM_000552.3:c.6321G>A (p.Trp2107*)
ClinVarID: not found
CAID: CA383491677
gnomAD: not found
MultipleGeneVariants: not reported
VWD3-4‡8.3<4.05<1.0436c.319C>T§c.6151A>T§p.Gln107Terp.Arg2051TerD1D4Stop gainedStop gainedHeterozygousHeterozygous
Case: Croatian adult patient
DiseaseAssertion: VWD3
FamilyInfo: No variant detected in a family member with VWD3.
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Reduced VWF:Ag of <4.0%, VWF:GPIbM of 8.3%, FVIII:C of 5% and VWF:CBA below 1%.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Not specified.
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.6151A>T
HGVS: NM_000552.4:c.6151A>T (c.6151A>T)
ClinVarID: Not available
CAID: CA383492290
gnomAD: Not available
1.
Case1: Male, now deceased
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0002239
(Gastrointestinal bleeding)
CaseHPOFreeText: Severe bleeding when young
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific at all
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) Codon change confirmed from PMID: 20492470 and NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 and CA399801310
gnomAD: MAF in European non Finnish population 0.000008791 http://gnomad.broadinstitute.org/variant/17-42457994-G-C and MAF in Latino population 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
21
Case21: Male, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Mild bleeding tendency (See Table 1 for Clinical and Biological data for selected genotyped patients
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.2421G>A (p.Trp807Ter)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399796017
gnomAD: N/A
13.
Case13: Female, African, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.1357C>T (p.Arg453Ter)
LegacyVariant: N/A
ClinVar: 631773
CAiD: CA399803529
gnomAD: N/A
A 3-year-old girl
Case1: Female, 3 year old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: An analysis of family members indicated that the Gln517Stop and Arg553Stop mutations were located on different alleles and inherited from the patient’s mother and father, respectively
CasePresentingHPOs: HP:0004406, HP:0002248, HP:0000978, HP:0000225
(Recurrent epistaxis, hematemesis, easy bruising, gingival bleeding)
CaseHPOFreeText: Petechial hemorrhages
CaseNotHPOs: HP:0001945, HP:0002014, HP:0005261
Fever, diarreah, hemarthrosis
CaseNotHPOsFreeText: N/A
ProteinExpression: A flow cytometry evaluation revealed marked reduction in glycoprotein IIb/IIIa (See Table 1 for Patient's Lab results)
PlateletAggregation: Patients platelets did not aggregate in response to ADP, epinephrine, arachidonic acid, or collagen but platelets had normal ristocetin induced aggregation
CasePreviousTesting: Molecular genetic analysis of ITGA2B was performed which revealed mutations
Gene: ITGA2B
Variant: NM_000419.3:c.1642C>T (p.Gln548Ter) and NM_000419.3:c.1750C>T (Arg584Ter)
LegacyVariant: Gln517Ter and Arg553Ter
ClinVar: 2892
CAiD: CA399802364 and CA115834
gnomAD: MAF in the East Asian population is 0.0002176
The probands are two brothers, 18
Case1: Male, 18 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Figure 4 for family pedigree of patients carrying the 288delC mutation in GPIIb
ParentalGenotype: Heterozygous for variant
CasePresentingHPOs: HP:0000978 (Bruising)
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analysis shown in Fig 1
PlateletAggregation: Platelets failed to aggregate either spontaneously or in response to ADP, adrenaline, collagen or arachidonic acid, but they showed agglutination in the presence of ristocetin
CasePreviousTesting: ITGA2B and ITGB3 both were sequenced
Gene: ITGA2B
Variant: NM_000419.3:c.291del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940464
gnomAD: N/A
Supplementary Table S1:
Case14: GT15, French, gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.2095-19T>A and NM_000419.3:c.2770C>T
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940312 and CA399792054
gnomAD: N/A
Supplementary Table S1:
Case35: GT41a, Canadian/Chinese, gender and age not specified here
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.91del (p.Ala31ProfsTer2) and NM_000419.3:c.2915dup (p.Leu973AlafsTer63)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA913203486 and CA8602531
gnomAD: MAF in the East Asian population is 0.0001088 https://gnomad.broadinstitute.org/variant/17-42452054-C-CG for the variant (p.Leu973Alafs*63)
6CabGT-6
Case6: (Proband, CabGT-6), Male, age not specified, Caucasian
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed <5% surface expression of GPIIIa and GPIIb
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.1413C>G (p.Tyr471Ter) and NM_000419.3:c.2800G>T (p.Val934Phe)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA290950376 (p.Tyr471Ter) and CA290946484 (p.Val934Phe)
gnomAD MAF in the European (non-Finnish) population is 0.000008791 https://gnomad.broadinstitute.org/variant/17-42457994-G-C
13
Case2: Female, 41 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: "This mutation was confirmed in the proband and parents."
CasePresentingHPOs: HP:0000225 (Gingival bleeding)
CaseHPOFreeText: Site of bleeding: Skin
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: See Table 1 (information provided)
PlateletAggregation: See Table 1 (information provided)
CasePreviousTesting: Screened mutations in ITGA2B and ITGB3 by multiplex polymerase chain reaction (PCR) amplification (MPCR) and conformation-sensitive gel electrophoresis
Gene: ITGA2B
Variant: NM_000419.3:c.1750C>T (p.Arg584Ter)
LegacyVariant: N/A
ClinVar: 2892
CAiD: CA115834
gnomAD: MAF in the East Asian population is 0.0002176 https://gnomad.broadinstitute.org/variant/17-42457372-G-A
Case 1
Case1: Female, 9 years old, Japanese
DiseaseAssertion: Macrothrombocytopenia
FamilyInfo: Information given in Table 1 and Fig 2
ParentalGenotype: Mother: ITGA2B (p.Arg422Ter heterozygous) and Father: ITGA2B (p.Gly991Cys heterozygous) See Table 1 for this information
Sequencing of parental DNA indicated parental mutations. CasePresentingHPOs: HP:0000979, HP:0000421, HP:0000978
(Purpura, epistaxis, bruising)
CaseHPOFreeText: Hemorrhage after dental
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometric analysis showed that surface αIIbβ3 expression in platelets (was markedly impaired 3-11%)
PlateletAggregation: N/A
CasePreviousTesting: Sequence analysis of entire coding regions of exons and exon-intron boundaries of ITGA2B and ITGB3 gene of the patient revealed two novel mutations in ITGA2B.
Gene: ITGA2B
Variant: NM_000419.3:c.3064G>T (p.Gly1022Cys) and NM_000419.3:c.1357C>T (p.Arg453Ter)
LegacyVariant: (p.Gly991Cys legacy nomenclature for p.Gly1022Cys) and (p.Arg422Ter legacy nomenclature for p.Arg453Ter)
ClinVar: 631773
CAiD: CA399787943 and CA399803529
gnomAD: N/A
The patient
Case1: Male, 7 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See pedigree Fig 5
ParentalGenotype: Parents heterozygous for the mutation proband has
CasePresentingHPOs:
(Petechia, bruising
CaseHPOFreeText: Mucocutaneous hemorrhages
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: There was a lack of platelet surface expression of the GPIIb-IIIa complex as shown by Western blotting
PlateletAggregation: Platelets fail to aggregate spontaneously or in response to agonists, although they agglutinate in response to ristocetin
CasePreviousTesting: Screening of mutations in both ITGA2B and ITGB3 was carried out by single stranded conformational polymorphism (SSCP) analysis
Gene: ITGA2B
Variant: NM_000419.3:c.1882C>T (p.Arg628Ter)
LegacyVariant: (p.Arg597Ter)
ClinVar: N/A
CAiD: CA399801310
gnomAD: MAF in the Latino population is 0.00003983 http://gnomad.broadinstitute.org/variant/17-42456075-G-A
The propositus (A.C.S.; II.1) in family 1 is a 22-yearold Portuguese girl
Case1: Female, 22 years old, Portugese
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Also studied were the patient’s mother (I.2),her father (1.1), and her sister (II.2). Of these family members, only her sister has reported excessive bleeding although platelet aggregation tests were normal for all of them. Consanguinity was present as her parents were cousins.
ParentalGenotype: Parents heterozygous for mutation
CasePresentingHPOs: HP:0000967
(Petechia)
CaseHPOFreeText: Mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: <5% surface expression of aIIbb3
PlateletAggregation: Absent with physiologic agonists but agglutination with ristocetin was normal
CasePreviousTesting: We examined each of the 30 exons of the b3 gene and each of the 15 exons of the aIIb gene for migration changes in PCR-SSCP analysis
Gene: ITGB3
Variant:
LegacyVariant:
ClinVar:
CAiD:
gnomAD: N/A
two cases from two additional families (case 3, 11 years and case 4, 11 years).
Case#:two cases from two additional families (case 3, 11 years and case 4, 11 years).
DiseaseAssertion: Stargardt’s Disease
FamilyInfo: NR
ParentalTesting: NR
CasePresentingHPOs: HP:0030500, HP:0011507
CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.
CaseNotHPOs: HP:0007401, HP:0000505
CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases
CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.
GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).
Variant: NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter) and NM_000350.3:c.5461-10T>C
LegacyVariant: c.1906C>T (p.Gln636Ter) and c.5461-10T>C
ClinVar: 265012 and 92870
CAID: CA10588302 and CA220687
gnomeAD: 1:94528164 G / A and 1:94476951 A / G
MultipleGeneVariants:No
PreviouslyPublished: No
AdditionalInfo: Most symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example, in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD
14-year-old patient
Case#: 14-year-old, female, asian (Chinese) patient
DiseaseAssertion: ABCA-4 associated retinal dystrophy
FamilyInfo: The effect of the deep intronic variant on splicing was validated by a minigene assay in our previous study (Tian et al., 2022). Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent
ParentalTesting: Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent
CasePresentingHPOs: HP:0000556
CasePhenotypeFreeText: ABCA4-associated retinal dystrophy
CaseNotHPOs: NR
CaseNotPhenotypeFreeText: NR
CasePreviousTesting:NR
GenotypingMethod:
In the present study, we recruited a 14-year-old female patient diagnosed with ABCA4-RD. Biallelic variants were found in this patient, including the nonsense variant c.1222C>T p.(Arg408Ter) detected by Sanger sequencing and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] identified by next-generation sequencing.
We isolated peripheral blood mononuclear cells (PBMCs) from the patient’s peripheral venous blood and introduced three episomal plasmids containing transcription factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT into PBMCs. The reprogramming iPSC line, named BIOi003-A, showed stabilized morphology (Fig. 1A) and a normal karyotype in culture (Fig. 1B). Then, the endogenous expression of two pluripotent biomarkers, POU5F1 and NANOG, was detected (Table 2). The expression levels were compared with human embryonic stem cell line H1(hESC-H1) and mesenchymal stem cell line P3 (MSC-P3) by qRT-PCR (Fig. 1C). Surface markers SSEA4 and TRA-1–81 were analyzed by flow cytometry (Fig. 1D). the ABCA4 compound heterozygous variants c.(1222C>T;2919-884G>T) p.[Arg408Ter;Phe973LeufsTer3,=] were verified by Sanger sequencing (Fig. 1E). Furthermore, the teratoma assay exhibited the differentiation capacity of this iPSC line in vivo (Fig. 1F). Short tandem repeats (STR) analysis exhibited that the PBMCs and the iPSC line came from the same patient. PCR proved negative for mycoplasma contamination
Variant: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter) and NM_000350.3(ABCA4):c.2919G>T (p.Leu973Phe)
LegacyVariant: c.1222C>T (p.Arg408Ter) and c.2919G>T (p.Leu973Phe)
ClinVar: 99035 and NR
CAID: CA179692 and CA341275270
gnomeAD: 1:94544895 G / A and NR
MultipleGeneVariants: No
PreviouslyPublished:No
AdditionalInfo: One patient was homozygous at the ABCA-4 gene, so there is information about both variants in one annotation because there is only one patient.
Case 2
Case:Patient 2, female, Chinese
DiseaseAssertion:Global delay
FamilyInfo:Patient 2 was the first child of nonconsanguineous Chinese couple born at 38-week gestation. The mother had gestational diabetes mellitus that required insulin therapy.
ParentalGenotype:Not provided
CasePresentingHPOs:HP:0000365, HP:0020049, HP:0000252, HP:0001263, HP:0012171, HP:0000154, HP:0000708, HP:0003763, HP:0002376, HP:0012433.
CaseHPOFreeText:
Patient History
@ birth - Patient 2 presented with mild grade bilateral hearing impairment and left divergent squint diagnosed at birth.
@ Follow-up visit - Patient 2 had microbrachycephaly and global developmental delay. Brain MRI, metabolic screening and array CGH were normal.
@ 1 year - Patient 2 had stereotypical handwashing movement.
There was no clinical or electrical seizure.
Patient 2 has craniofacial features like microbrachycephaly, wide mouth, divergent squint, and behavioral phenotype.
@ 1.5 years - Patient 2 had bruxism and developmental regression. Patient 2 also had loss of some motor and social skills.
CaseNotHPOs:HP:0001250
CaseNotHPOFreeText:Patient 2 has no seizures.
CasePreviousTesting:Not provided
PreviouslyPublished:Not previously published
GenotypingMethod:Not provided
Gene:MECP2 (MN_004992.3) (NP_004983.1)
Variant:c. 808C>T (p. Arg270*)
HGVS:Not provided
ClinVarID:Not found
CAID:CA172577
gnomAD:Not found
MultipleGeneVariants:NA
In this study, we report a 4-month-old boy with T−B+NK− SCID due to an unreported nonsense mutation in exon 2 of the IL2RG gene. The patient was derived from a twin pregnancy, and his twin brother was asymptomatic with no immune defects. In order to confirm the pathogenic effect of the detected novel variant on the protein structure, a modeling process was performed.
Case: Patient, Male, 4 months old <br /> DiseaseAssertion: SCID <br /> FamilyInfo: third child of non-consanguineous parents; has twin brother that is asymptomatic with no immune defects; no family history of primary immunodeficiencies <br /> CasePresentingHPOs: HP:0002014, HP:0020099, HP:0030148 <br /> CaseHPOFreeText: diarrhea, norovirus infection, heart murmur <br /> CaseNotHPOs: increased CRP <br /> CasePreviousTesting: N/A <br /> Gene: IL2RG <br /> Variant: NM_000206(IL2RG): <br /> ClinVar: <br /> CAID: <br /> gnomAD: <br /> SupplementalData:
DICER1 syndrome encompasses a variety of benign and malignant manifestations including multinodular goitre
Gene: DICER1 PMCID: PMC8451242 PMID: 34552563 Pathogenic Inheritance Pattern: Autosomal Dominant MultipleDiseaseEntities Disease Entity: DICER1 syndrome, multinodular goitre, cystic nephroma, anaplastic renal sarcoma, Wilms tumour, differentiated thyroid carcinoma, gynandroblastoma, ciliary body medulloepithelioma, embryonal rhabdomyosarcoma, pineoblastoma, pituitary blastoma, kidney cyst, pulmonary cyst, Sertoli-Leydig Cell Tumor. Mutation: Germline MultipleGeneVariants Variant & Clinvar IDs: c.3452_3453del (485534), c.316del (no ClinVar ID), c.171_172insAC (no ClinVar ID), c.3434del (no ClinVar ID), c.988C>T (933007), c.5388dup (no ClinVar ID) Zygosity: None provided. Case: At time of operation, the goitre patients living in Denmark were ages 21, 12, 21, 8, 14, and 16. Four underwent total thyroidectomies, and two underwent partial thyroidectomies. The patient originally aged 21 previously had a kidney cyst at age 14 and a pulmonary cyst at an unknown age. The patient aged 14 at time of partial thyroidectomy later manifested a Sertoli-Leydig Cell Tumor at age 15. All six patients were female. CasePresentingHPO: None provided. CasePreviousTesting: thyroidectomy gnomAD: ENSG00000100697.10, https://gnomad.broadinstitute.org/gene/ENSG00000100697 Mutation Type: Frameshift, Nonsense