Case#: F5, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 105; VWF:RCo = 90; VWF:GPIbM = 87; 0.86; 0.82; 0.96

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[I1372S];[=]

HGVS: c.4115T>G (p.Ile1372Ser)

CAID: CA228535

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019303-A-C?dataset=gnomad_r4

Case#: F18, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 95; VWF:RCo = 30; VWF:GPIbM = 70; 0.32; 0.73; 2.31

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308C];[=]

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

CAID: CA114125

gnomAD: absent from gnomad v4.1.0

Case#: F17, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 30; VWF:RCo = 8; VWF:GPIbM = 23; 0.27; 0.75; 2.81

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308C];[=]

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

CAID: CA114125

gnomAD: absent from gnomad v4.1.0

Case#: F16, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 48; VWF:RCo = 13; VWF:GPIbM = 48; 0.27; 1.00; 3.65

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308C];[=]

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

CAID: CA114125

gnomAD: absent from gnomad v4.1.0

Case#: F15, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: loss of high and intermediate MWMs, VWF:Ag = 43; VWF:RCo = 12; VWF:GPIbM = 30; 0.28; 0.70; 2.56

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308C];[=]

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

CAID: CA114125

gnomAD: absent from gnomad v4.1.0

Case#: F4, I:3

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 34; VWF:RCo = 21; VWF:GPIbM = 31; 0.62; 0.92; 1.49

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308L];[=]

HGVS: c.3923G>T (p.Arg1308Leu)

CAID: CA6402650

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019495-C-A?dataset=gnomad_r4

Case#: F4, I:2

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 40; VWF:RCo = 25; VWF:GPIbM = 38; 0.63; 0.95; 1.52

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1308L];[=]

HGVS: c.3923G>T (p.Arg1308Leu)

CAID: CA6402650

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019495-C-A?dataset=gnomad_r4

Case#: F3, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 45; VWF:RCo = 38; VWF:GPIbM = 45; 0.84; 1.00; 1.19

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F13, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 69; VWF:RCo = 50; VWF:GPIbM = 71; 0.72; 1.04; 1.43

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1341Q];[=]

HGVS: c.4022G>A (p.Arg1341Gln)

CAID: CA114129

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case#: F3, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 60; VWF:RCo = 57; VWF:GPIbM = 59; 0.95; 0.98; 1.03

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F2, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 68; VWF:RCo = 66; VWF:GPIbM = 61; 0.97; 0.90; 0.93

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F12, II:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 52; VWF:RCo = 18; VWF:GPIbM = 52; 0.34; 1.00; 2.92

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1341Q];[=]

HGVS: c.4022G>A (p.Arg1341Gln)

CAID: CA114129

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case#: F2, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: all mutimers present, VWF:Ag = 30; VWF:RCo = 29; VWF:GPIbM = 24; 0.97; 0.81; 0.84

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[P1266L];[=]

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

CAID: CA114170

gnomAD: https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case#: F11, I:1

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 35; VWF:RCo = 5; VWF:GPIbM = 27; 0.14; 0.78; 5.44

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

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

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

Case#: F10, II:3

DiseaseAssertion: Type 2 VWD

CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 53; VWF:RCo = 13; VWF:GPIbM = 37; 0.25; 0.69; 2.82

CasePreviousTesting: Not clearly described

Gene: VWF

Variant: p.[R1306W];[=]

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

CAID: CA114123

gnomAD: absent from gnomad v4.1.0

Case: Patient 7 (Family B), male, 81yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 165, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.6, VWF:Ag U/dL = 166.4, VWF:CB U/dL = 30.0, VWF:CB ratio = 0.18, VWF:RCo U/dL = 112.0, VWF:RCo ratio = 0.67, Platelet VWF U/dL = NA, FVIII U/dL = 136.0, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 17 (Family E), female, 24yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 65, PFA 100 sec = >300, SPA % = 22.5, MADR mg/mL = 0.15, VWF:Ag U/dL = 35.9, VWF:CB U/dL = 15.6, VWF:CB ratio = 0.44, VWF:RCo U/dL = 14.4, VWF:RCo ratio = 0.40, Platelet VWF U/dL = 140.3, FVIII U/dL = 35.9, BAT F/M = 13

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID: NA

gnomAD: absent

Case: Patient 4 (Family A), male, 43yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 163, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 42.8, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.25, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.58, Platelet VWF U/dL = 132.7, FVIII U/dL = 47.1, BAT F/M = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 5 (Family B), male, 26yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 176, PFA 100 sec = >300, SPA % = 8, MADR mg/mL = 0.6, VWF:Ag U/dL = 17.6, VWF:CB U/dL = 9.2, VWF:CB ratio = 0.52, VWF:RCo U/dL = 10.4, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 76.6, FVIII U/dL = 38.8, BAT F/M = 8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 19 (Family F), male, 44yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 116, PFA 100 sec = >300, SPA % = 15.7, MADR mg/mL = 0.3, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.48, VWF:RCo U/dL = 11.4, VWF:RCo ratio = 0.71, Platelet VWF U/dL = 130, FVIII U/dL = 27.7, BAT F/M = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 21 (Family H), male, 40yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 158, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.45, VWF:Ag U/dL = 32.5, VWF:CB U/dL = 14.7, VWF:CB ratio = 0.45, VWF:RCo U/dL = 18.7, VWF:RCo ratio = 0.59, Platelet VWF U/dL = 130, FVIII U/dL = 39.0, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 13 (Family C), male, 37yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 132, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 51.9, VWF:CB U/dL = 10.6, VWF:CB ratio = 0.20, VWF:RCo U/dL = 25.2, VWF:RCo ratio = 0.48, Platelet VWF U/dL = 133.4, FVIII U/dL = 34.5, BAT F/M = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: Patient 15 (Family C), female, 14yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 126, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.45, VWF:Ag U/dL = 35.0, VWF:CB U/dL = 4.0, VWF:CB ratio = 0.11, VWF:RCo U/dL = 12.7, VWF:RCo ratio = 0.38, Platelet VWF U/dL = 141, FVIII U/dL = 46.0, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P9, female, 28yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: bleeding score = 7; VWF:Ag (%) = 35, VWF:RCo(%) = 24, VWF:RCo/VWF:Ag ratio = 0.69, VWF:CIIIB (%) = 11, VWF:CIIIB/VWF:Ag ratio = 0.31, VWF:CVIB (%) = 19.2, VWF:CVIB/VWF:Ag ratio = 0.54

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5140G>C (p.Ala1714Pro)

HGVS: NM_000552.3:c.5140G>C (p.Ala1714Pro)

ClinVarID: NA

CAID: CA383496428; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383496428

gnomAD: absent

Case: IP-6

DiseaseAssertion: VWD2

FamilyInfo: Mother is unaffected carrier of F8 Asn2129Ser. The VWF deletion of exons 33-34 segregates in 5 other affected male family members including the father and a full brother of IP-6. The patient’s father displayed a significant decrease in VWF:Ag and VWF:RCo, 13% and 7%, respectively, FVIII: C of 18.5% and the VWF:RCo/VWF:Ag ratio of 0.5 pointing out to type 2 VWD.

ParentalGenotype(s): Mother is heterozygous for F8FAsn2129Ser. Father is heterozygous for VWF deletion of exons 33-34.

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag (17%), VWF:RCo (9%) and FVIII:C (1,9%). Bleedings in the oral cavity, ankle joint and hematomas.

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene

GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany). Dosage analysis based on a comparison between deleted and reference wild‐type DNA samples was performed using the Excel‐based software Coffalyser V9.4 (MRC Holland).

PreviouslyPublished: NA

Gene:VWF

Variant: deletion of exons 33-34

HGVS:

ClinVarID:

CAID:

gnomAD:

MultipleGeneVariants:

GeneName: F8

Variant: Asn2129Ser

ClinVarID or CAID:

gnomAD:

Case: Case Report, female, 63yo

DiseaseAssertion: VWD2B

FamilyInfo: sister exhibited thrombocytopenia and mother had suffered from acute subdural hematoma in the context of chronic thrombocytopenia

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0002138, HP:0011854, HP:0001873, HP:0032044, HP:0030132

(Subarachnoid hemorrhage, Hemoperitoneum, thrombocytopenia, Decreased vigilance, Absence of large von Willebrand factor multimers)

CaseHPOFreeText: thrombocytopenia with pregnancy, platelet count fluctuated between 3 and 200 G/l, subarachnoid hemorrhage associated with a subdural hematoma after falling, hemostasis results were normal, meningeal hemorrhage, cephalalgia; FVIII:C: 1.63 IU/ml; VWF:RCo: 0.7 IU/ml; VWF:Ag: 1.8 IU/ml, ratio VWF:Rco/VWF/Ag: 0.39; Ristocetin-induced platelet agglutination could not be performed due to the severe thrombocytopenia

CaseNOTHPOs: NA

CaseNOTHPOFreeText: NA

CasePreviousTesting: tests for autoimmune disease negative

GenotypingMethod: NGS of exon 28 of VWF gene; variant confirmed via Sanger sequencing

PreviouslyPublished: NA

Gene: VWF

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

HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)

ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/

CAID:

gnomAD: absent

Case: P28, Chinese, male, 15yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 17.7, VWF:RCo (%) = 4.9, FVIII:C (%) = 25.5, VWF:CB (%) = 5.1, VWFpp (%) = 45.3, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 1.4, RIPA (0.5 mg/ml, %) = 20.5, PLT(×109/l) = 112

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

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

CAID: NA

gnomAD: absent

Case: P81, Chinese, female, 30yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 7; VWF:Ag (%) = 5.0, VWF:RCo (%) = 5.3, FVIII:C (%) = 6.1, VWF:CB (%) = 6.8, VWFpp (%) = 46.0, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.4, VWFpp/VWF:Ag = 9.2, FVIII:C/VWF:Ag = 1.2, RIPA (1.2 mg/ml, %) = 85.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

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

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

ClinVarID: 308; https://www.ncbi.nlm.nih.gov/clinvar/variation/308/

CAID: NA

gnomAD: absent

Case: P1,Chinese, female, 17yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 8; VWF:Ag (%) = 38.0, VWF:RCo (%) = 35.2, FVIII:C (%) = 59.0, VWF:CB (%) = 33.2, VWFpp (%) = 52.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 1.4, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6860G>A (p.Arg2287Gln)

HGVS: NM_000552.3:c.6860G>A (p.Arg2287Gln)

ClinVarID: NA

CAID: CA6401877; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401877

gnomAD: MAF = 0.005415 (108/19946 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6094770-C-T

Case: P68, Chinese, female, 12yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 14.1, VWF:RCo (%) = 1.3, FVIII:C (%) = 42.3, VWF:CB (%) = 7.3, VWFpp (%) = 16.9, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 1.2, FVIII:C/VWF:Ag = 3.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3830A>G (p.Asp1277Gly)

HGVS: NM_000552.5:c.3830A>G (p.Asp1277Gly)

ClinVarID: NA

CAID: CA383506912; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506912

gnomAD: absent

Case: P3, M/36

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 4, aPTT was 43 seconds, FVIII:C was 22%, VWF:RCo was not determined, and VWF:Ag was 14 IU/dL. The VWF:RCo/VWF:Ag ratio was not available. RIPA showed a loss of intermediate and high molecular weight multimers, VWF multimer analysis was 2, and platelet count was 265 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.3538+1G>A — heterozygous

HGVS: NM_000552.5(VWF):c.3538+1G>A

ClinVar: 100267

CAID: CA228420

gnomAD: absent from gnomad v4.1.0

Case: P7, M/41

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 7, aPTT was 36 seconds, FVIII:C was 36%, VWF:RCo was not determined, and VWF:Ag was 25 IU/dL. The VWF:RCo/VWF:Ag ratio was not applicable. The VWF multimer pattern showed a mild loss of high molecular weight multimers, RIPA was 4 ohms, and the platelet count was 301 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4789C>T, p.R1597W — heterozygous

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

ClinVar: 285

CAID: CA114117

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018629-G-A?dataset=gnomad_r4

Case: P1, M/5

DiseaseAssertion: VWD1

FamilyInfo: No

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 0, aPTT was 41 seconds, FVIII:C was 60%, VWF:RCo was 22 IU/dL, and VWF:Ag was 27 IU/dL, resulting in a VWF:RCo/VWF:Ag ratio of 0.8. RIPA was nearly absent, VWF multimer analysis was not tested, and the platelet count was 250 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.6579G>C, p.W2193C — heterozygous

HGVS: NM_000552.5(VWF):c.6579G>C (p.Trp2193Cys)

ClinVar:

CAID: CA383490665

gnomAD: absent from gnomad v4.1.0

Case: P22, F/5

DiseaseAssertion: VWD2A

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 3, aPTT was 43 seconds, FVIII:C was 47%, VWF:RCo was 122 IU/dL, and VWF:Ag was 20 IU/dL, with a VWF:RCo/VWF:Ag ratio of 0.1. RIPA was normal, VWF multimer analysis was 2, and platelet count was 270 × 10⁹/L.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4825G>A, p.G1609R — heterozygous

HGVS: NM_000552.5(VWF):c.4825G>A (p.Gly1609Arg)

ClinVar: 100395

CAID: CA228665

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6018593-C-T?dataset=gnomad_r4

Case: P21, F/5

DiseaseAssertion: VWD2M

FamilyInfo: Positive family history, no details provided.

ParentalGenotype: NA

CaseHPOFreeText: The bleeding score was 2, aPTT was 53 seconds, FVIII:C was 30%, and VWF:RCo was 25 IU/dL. The VWF:RCo/VWF:Ag ratio indicated a mild loss of high molecular weight multimers. RIPA was 4, VWF multimer analysis was 301, and platelet count was not specified.

CasePreviousTesting: NA

GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.

Gene: VWF

Variant: c.4121G>T, p.R1374L — heterozygous

HGVS: NM_000552.5(VWF):c.4121G>T (p.Arg1374Leu)

ClinVar: 100331

CAID: CA228543

gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6019297-C-A?dataset=gnomad_r4

Case#: Melo-Nava_2007,31, F, 7 y.o. (report), Mestizo Mexican and French ancestry reported

DiseaseAssertion: VWD type 3

FamilyInfo: No consanguinity

ParentalGenotype: NR

CasePresentingHPOs:

CaseHPOFreeText: low 42% VWF:Ag, low FVIII:C 40%, low RIPA 24%, moderate bleeding severity

CaseNotHPOs: abnormal platelet count

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: PCR

Gene: VWF

Variant:

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

ClinVarID: 284

CAID:

gnomAD: Not found

MultipleGeneVariants:

CaseCM006

DiseaseAssertion: HCM

GenotypingMethod: NGS

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.4343A>T

ClinVar: 432912

CAID: CA041680

gnomAD: 0.0001320 European (non Finnish)

https://gnomad.broadinstitute.org/variant/14-23886722-T-A

VariantNEXN: NM_144573.3:c.620A>G

ClinVar: 520305

CAID: CA918690

gnomAD: https://gnomad.broadinstitute.org/variant/1-78392229-A-G

0.00005794 Latino

CaseIII:2: 44 year old male, South Asian

DiseaseAssertion: HCM, septal hypertrophic obstructive cardiomyopathy

FamilyInfo: family history of two sudden cardiac deaths at ages 35 and 19, and three family members with septal hypertrophic obstructive cardiomyopathy

CasePresentingHPOs: HP:0001279, HP:0002094, HP:0001962

"Syncope, Dyspnea, Palpitations"

CasePreviousTesting: screened sarcomeric thin filament protein gene, α-tropomyosin (TPM1), screening of seven other sarcomeric genes: MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, and ACTC

GenotypingMethod: sequences covering all the exons and exon–intron boundaries of TPM1 and seven other sarcomeric genes (MYH7, MYBPC3, TNNT2, TTN, TNNI3, MYL2, MYL3, and ACTC) were synthesized

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.2686G>A

ClinVar: 132908

CAID: CA012857

gnomAD: not found

VariantMYH7: NP_000248.2:p.Ile524Lys

ClinVar: not found

CAID: valid allele but not present in the registry

gnomAD: not found

VariantTPM1: NM_000366.6:c.644C>T

ClinVar: 31883

CAID: CA018243

gnomAD: https://gnomad.broadinstitute.org/variant/15-63354418-C-T

0.000008806 European (non-Finnish)

CaseHCM006: 15 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of sudden cardiac death

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0031295, HP:0011103, HP:0001653 (Exertional dyspnea, Left ventricular hypertrophy, Left atrial enlargement, Abnormality of the left ventricular outflow tract, Mitral regurgitation)

HPOsFreeText: Maximal LV thickness 33 mm

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

Variant: NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)

ClinVar: 164342 https://www.ncbi.nlm.nih.gov/clinvar/variation/164342/

gnomAD: Not in gnomAD

Multiple Gene Variants

(1) NEXN Variant

Variant: NM_144573.3(NEXN):c.835C>T (p.Arg279Cys)

ClinVar: 30994 https://www.ncbi.nlm.nih.gov/clinvar/variation/30994/

gnomAD: 0.006303, http://gnomad.broadinstitute.org/variant/1-78392548-C-T

CaseHCM147: 31 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Family history of Sudden Cardiac Death and Hypertrophic Cardiomyopathy, Has a 9 year old daughter with the same variant but no symptoms

CasePresentingHPOs: HP:0100749, HP:0006698, HP:0031295 (Chest pain, Dilatation of the ventricular cavity, Left atrial enlargement)

HPOsFreeText: Maximal LV thickness 32 mm

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

Variant: NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)

ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

gnomAD: Not in gnomAD

Case#: Male 74 (age when studied)

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0001873, HP:0005110, HP:0001638, HP:0000225, HP:0000978

Thrombocytopenia, Atrial fibrillation, cardiomyopathy, gingival bleeding, easy bruising

CaseNotHPOs: NA

FamilyInfo: Pedigree figure 1. Several affected family members, history of thrombocytopenia.

PlateletAgreggation:Daughter studied: Normal aggregation to epi and ADP, ristocetin not tested.

GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

ClinVar: 50227

CAID: CA143709

Variant: NM_000212.3:c.2245G>C (ITGB3)

GnomAD: Not found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 66%, CD61 (GPIIIa) 65.5%, and CD42b (GPIb) 113%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

Case#: Female, 45 (age of diagnosis)

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0001873, HP:0100646

Thrombocytopenia, Thyroiditis

CaseNotHPOs: NA

FamilyInfo: Pedigree figure 1. Affected sister, family history of thrombocytopenia

PlateletAgreggation: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination

GenotypingMethod: Genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

ClinVar: Not Found

CAID: CA400034288

Variant: NM_000212.3:c.2243A>C (ITGB3)

GnomAD: Not Found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 65%, CD61 (GPIIIa) 58%, and CD42b (GPIb) 116%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

Case#: 64 year old male

Disease: Glazmann's Thrombasthenia Like Syndrome

CasePresentingHPOs: HP:0001873, HP:0000421

Thrombocytopenia, Epistaxis

CaseNotHPOs: HP:0006298

Prolonged bleeding after dental extractions

FamilyInfo: Pedigree figure 1. Mother, affected, thrombocytopenia, son, affected, thrombocytopenia. Daughter normal PLT.

PlateletAgreggation: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA, with normal ristocetin agglutination

GenotypingMethod: genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.

ClinVar: 50233

CAID: CA10575573

Variant: NM_000419.5:c.3076C>T

GnomAD: Not Found

ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 37%, CD61 (GPIIIa) 40%, and CD42b (GPIb) 82%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).

PatientID: 3

KindredID: K-V7/V6

Case: M, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: The proband (ID 1) was affected with retinal hemangioblastoma, bilateral pheochromocytoma, and pancreatic tumor. The daughter (ID 2) was affected with retinal hemangioblastoma and bilateral pheochromocytoma. The son (ID 3) was affected with retinal hemangioblastoma. All three were positive for the D121N (c.361G>A) germline variant of the VHL gene.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Retinal hemangioblastomas, pancreatic tumor and bilateral pheochromocytoma. Diagnosed with VHL type 2.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121N (c.361G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753750, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351753750

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D121N (c.361G>A)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0010797; HP:0001737; HP:0006770 (Renal neoplasm, Multiple renal cysts, Hemangioblastoma, Pancreatic cysts, Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient 7 had a medical history of a left solid renal tumor and multiple renal cysts. They also had central nervous system hemangioblastomas and pancreatic cysts.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.447del)

LegacyVariant: c.661delA

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: CA432421904, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.447del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.447del)

MultipleGeneVariants: N/A

PatientID: 249

KindredID: 95

Case: F, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 244) has a daughter with the variant (patient 245) who was asymptomatic at the time of assessment.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister) was asymptomatic at the time of assessment

CaseNotHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0009711; HP:0002666; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 200

KindredID: 77

Case: F, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 200) has six family members who passed away before diagnosis/ had no DNA sample available. Of the family who passed away before diagnosis: the proband's aunt 1 (patient 202) had a CNS hemangioblastoma at 27; the daughter of aunt 1 (patient 203) had a pheochromocytoma at 31; aunt 2 (patient 205) had a CNS hemangioblastoma at 43, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 48. Of the family for whom no DNA sample was available: the proband's mother (patient 201) had a CNS hemangioblastoma at 51, multiple pancreatic cysts/tumors at 46, and a pheochromocytoma at 25; the grandson of aunt 1 (patient 204) had a pheochromocytoma at age 9; and the son of aunt 2 (patient 206) had a pheochromocytoma at 16 and renal cell carcinoma + multiple pancreatic cysts/tumors at 21.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: The patient presented with a pheochromocytoma and renal cell carcinoma at 36.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Renal cell carcinoma )

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 27

KindredID: 9

Case: F, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: The proband, patient 27, presented at age 36 with a CNS hemangioblastoma, and renal cell carcinoma and multiple pancreatic cysts and tumors at 40.

CaseNotHPOs: HP:0002666, HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 3

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: No family information was provided for this patient. A total of 291 patients from 115 different families were included for analysis. VHL mutation confirmation was verified in at least one patient of each family.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 34. At age 37, they presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0009711; HP:0002666; (Retinal Capillary Hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597, https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 98

KindredID: 33

Case: M, 43Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband's brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

MultipleGeneVariants: N/A

PatientID: 187

KindredID: 72

Case: M, 67Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001732; HP:0001737 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 65, renal cell carcinoma at 54, and multiple pancreatic cysts/tumors at 67.

CaseNotHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 272

KindredID: 106

Case: F, 51Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 272, has a daughter and a father who both passed away before diagnosis/ before they could undergo genetic testing. The proband's daughter (patient 273) had a CNS hemangioblastoma at age 13, and the proband's father (patient 274) had a CNS hemangioblastoma at age 30.

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0010797 HP:0009711; HP:0005584 (Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a retinal angioma at 49, and at 51 presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: Exon 2 Deletion (c.341-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

PatientID: 157

KindredID: 58

Case: M, Age Unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's nephew (son of sister) was asymptomatic at the time of analysis.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0001737; HP:0001732; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

MultipleGeneVariants: N/A

PatientID: 224

KindredID: 83

Case: M, 53Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had the same germline mutation as his sister (the proband). His sister presented with a pheochromocytoma at age 38. His mother had a CNS hemangioblastoma at 52, but no genotyping information is available for her.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 53.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 276

KindredID: 107

Case: M, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 276, presented with a retinal angioma at age 31, and a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 37. The proband has a father who presented with a CNS hemangioblastoma at age 50.

CasePresentingHPOs: HP:0001737; HP:0001732; HP:0010797 HP:0009711 (Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at age 50.

CaseNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 58

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S5 describes 8 patients with small deletions, including this patient.

Variant: p.E160Afs*13(c.479_480delAG)

LegacyVariant: c.691_692delAG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621940

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant; deletion

CivicName: E160FS(c.479_480delAG)

MultipleGeneVariants: N/A

PatientID: 18

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S5 describes 8 patients with frameshift or in-frame deletions, including this patient.

Variant: p.F76del(c.224_226del)

LegacyVariant: c.437_439delTCT

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: F76del(c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: unknown (brother)

KindredID: A

Case: M, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient and his one brother were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797 (retinal capillary hemangioma; pheochromocytoma; hemangioblatoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: 9

KindredID: A

Case: F, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. The father and one uncle were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584 (retinal capillary hemangioma; pheochromocytoma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9)

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A

PatientID: III1(Ca001)

KindredID: C

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient’s grandfather (I-2) presented with hemangioblastoma and possessed the same exon 2 deletion. The patient’s mother also possessed the deletion and had hemangioblastoma. Mother’s sister (II-3) had retinoblastoma, pancreatic cyst and pheochromocytoma, while the mother’s other sibling (II-5) had hemangioblastoma, pancreatic cyst, and clear cell renal carcinoma. The patient’s 2 cousins each possessed the same deletion, but did not exhibit phenotypes (Please see Figure 1. Family C matches with Pedigree B).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0006770; HP:0001737; HP:0002666; HP:0009919 (Hemangioblastoma; clear cell renal cell carcinoma; pancreatic cysts; pheochromocytoma, retinoblastoma)

CaseNotHPOFreeText: Patient did not present with any symptoms.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: large fragment deletion in exon 2

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as GRCh37 chr3:10188300ATATCACACTGCCA>T in paper

MutationType: minus_2_frameshift_variant; deletion

CivicName: Exon 2 (deletion)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 65

Case: Sex unknown, Age unknown, Iranian

DiseaseAssertion: assumed VHL

FamilyInfo: One patient with the given mutation is stated to belong to VHL family 65

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0000107; HP:0005584; HP:0008261 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cyst, renal cell carcinoma, pancreatic islet cell adenoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164* (c.490C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q164* (c.703C>T)

ClinVarID: 223228 https://www.ncbi.nlm.nih.gov/clinvar/variation/223228/

CAID: CA357060 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.490C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q164* (c.490C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 55

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation belonging to VHL family 55

GroupPresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

GroupHPOFreeText: Both (2) patients have retinal angiomas (retinal capillary hemangioma) and CNS hemangioblastomas

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R113* (c.550C>T)

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: CA348491 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.337C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113* (c.337C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 48

Case: M, 25Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: None (Brother 2)

KindredID: ASP (L63P)

Case: M, Age Unknown, Hungarian

DiseaseAssertion: Asymptomatic

FamilyInfo: Family screening showed the presence of the L63P mutation in two out of the three clinically healthy brothers, whereas the mutation was absent in a clinically healthy son. Proband of this family presented with an apparently sporadic pheochromocytoma and the L63P germline mutation of the VHL gene.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L63P (c.188T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as L63P and cDNA change was mapped to c.188T>C.

MutationType: missense_variant;transition

CivicName: L63P (c.188T>C)

MultipleGeneVariants: N/A

PatientID: IP (Proband)

KindredID: C

Case: M, 35Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Index patient presented with cerebellar hemangioblastoma, renal cysts, pancreatic cyst and bilateral renal cell carcinomas. Family members were not available for clinical and genetic screening except a brother whose screening revealed no abnormality.

CasePresentingHPOs: HP:0006880; HP:0005562; HP:0005584; HP:0001737 (Cerebellar hemangioblastoma, Multiple renal cysts, Renal cell carcinoma, Pancreatic cysts)

CaseHPOFreeText: Patient was operated for cerebellar hemangioblastoma at the age of 33 years. Preoperative clinical screening also showed renal cysts. Two years later, a pancreatic cyst and bilateral renal cell carcinomas were found and the patients underwent bilateral nephrectomy with subsequent chronic hemodialysis. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Heterozygous deletion of Exon 3.

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: B

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: Daughter

KindredID: 1

Case: F, 35Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Father and brother presented with the same VHL mutation. Brother presented with a meningioma, pancreatic lesions and bilateral renal cysts all at 38Y. Father presented with cerebellar hemangioblastoma 49Y, retinal hemangioblastoma 64Y, bilateral renal cell carcinoma 51Y and multiple pancreatic neuroendocrine tumors 64Y.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0030405; HP:0000107 (Cerebellar hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst)

CaseHPOFreeText: Cerebellar hemangioblastoma, renal cell carcinoma, multiple pancreatic neuroendocrine tumors and bilateral renal cysts all at 35Y. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.M54Gfs*77 (c.160_161del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189210, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.160_161del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: M54Gfs*77 (c.160_161delAT)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.TF136C (c.407G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065, https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988, https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: R79G (c.235C>G)

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The two patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W(c.194C>G)

GroupProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID:43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID:N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: None (X)

KindredID: 7

Case: Sex and Ethnicity unknown; Age <18Y0M

DiseaseAssertion: Asymptomatic

FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 4

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This is the proband. 3 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: hemangioblastoma, parathyroid nodule, and esophageal carcinoma but the presenting patient is unclear. Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 25 years later but it is unclear if this pertained to all affected family members. Pheochromocytoma diagnosed at age 20. VHL type 2C.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 2

Case: Sex Unknown, 53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This is the proband. 5 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: paraganglioma, hemangioblastoma, lung metastases and spinal hemangioblastoma but the presenting patient is unclear.Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 18 years later but it is unclear if this pertained to all affected family members.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666; HP:0000107 (Pheochromocytoma, Renal cyst)

CaseHPOFreeText: Unilateral pheochromocytoma diagnosed at age 34.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

GroupID: 4325

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 4 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma, retinal capillary hemangioma)

GroupHPOFreeText: 1 of the 4 (1/4) patients were recorded with a hemangioblastoma; 3/4 with retinal angiomas

GroupNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC or pheos

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S65W (c.407C>G)

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 36Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's half brothers both carried the mutation, one was asymptomatic and one had renal cell carcinoma. The patient's mother was found to carry the mutation and had breast cancer. The maternal grandmother also harboured the mutation but was asymptomatic. See Figure 1 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P81S (c.241C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 52Y0M, Danish

DiseaseAssertion: Breast carcinoma

FamilyInfo: The patient had three sons all of whom carried the VHL mutation. Two of the sons were asymptomatic and one had renal cell carcinoma. The affected son also had a P2P mutation and he had a child who was found to have the VHL mutation (P2P). The patient's mother had the mutation but was also asymptomatic. See Figure 1 for family pedigree.

CasePresentingHPOs: HP:0003002 (Breast carcinoma)

CaseHPOFreeText: The patient had breast cancer at age 34.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P81S (c.241C>T)

MultipleGeneVariants: N/A

PatientID: P6

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: P5

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

GroupID: None

KindredID:9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed/Latino

GroupAgeRange: N/A

GroupInfo: Three members of a South American family expressed this c.344delA mutation.

GroupPresentingHPOs: HP:0010797, HP:0009711, HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Pfs*44 (c.344delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70049370 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.344delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115Pfs*44(c.344delA) and P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL,c.c.183C>G (p.Pro61Pro)

PatientID: None

KindredID: 97

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 97

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: No presence of phaeochromocytoma in family

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117* (c.351G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.W117* (c.564G>A)

ClinVarID: N/A

CAID: CA351753679 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.351G%3EA

gnomAD: 0.000003976 https://gnomad.broadinstitute.org/variant/3-10188208-G-A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W117* (c.351G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: Unknown, 36Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText:The patient presented with hemangioblastoma at age 35. One year later he was found to have renal cell carcinoma and pancreatic cysts or tumors.

CaseNotHPOs: HP:0009711, HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA2499306941 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306941

gnomAD:N/A

VariantEvidence: N/A

MutationType: delins

CivicName:V62Efs*68 (c.185_193delTGCTGCGCTinsAGCA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 8

Case: Unknown, 24Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas)

CaseHPOFreeText:The patient presented with hemangioblastoma at age 18. At age 24 the patient had renal cell carcinoma and cysts/tumours of the pancreas.

CaseNotHPOs: HP:0009711, HP:0002666(retinal capillary hemangioma, pheochromocytoma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117S(c.350G>C)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.350G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117S(c.350G>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 41F

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 41F. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y156* (c.468T>G)

LegacyVariant: p.Y156* (c.681T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756053 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.468T>G

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: Y156* (c.468T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 41CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 41CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L153Cfs*6 (c.457delC)

LegacyVariant: FS (c.670delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421920 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.457delC

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: L153fs (c.457delC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3759NCI, 3760NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family IDs 3759NCI and 3760NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.Y112* (c.336C>A)

LegacyVariant: p.Y112* (c.549C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16602183 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.336C>A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: Y112* (c.336C>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 147CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to family ID Family 147CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as a VHL family without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121Mfs*38 (c.361delG)

LegacyVariant: FS (c.574delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421803 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361delG

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: D121fs (c.361delG)

MultipleGeneVariants: N/A

GroupID/ KindredID: 40CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 40CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114C (c.340G>T)

LegacyVariant: p.G114C (c.553G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751376 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G>T

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 146CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to family ID Family 146CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A56Sfs*76 (c.165_166insA)

LegacyVariant: FS (c.378insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524648 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.165_166insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: A56fs (c.165_166insA)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: F, 49Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: CA020207 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.266T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 3

Case: F, 53Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Sister was thought to be sporadic (non familial) in 2001 with a spinal T7 tumor - genetic testing in this paper describes her (the sister, case 3) without any mutations.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53. She had a germline point and 2 somatic point mutations found in the DNA of her CHB. These mutations are discussed further in PMID: 24335534

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24335534 (pt. HGB-25)

SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

Variant: p.D126Rfs*6 (c.375_376insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320316 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320316

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P25L(c.74C>T) and D126Rfs*6(c.375_376insA) and E55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.163delG (p.Glu55Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)