PatientID: 12

KindredID: 12

Case: 32Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Family history unremarkable; Patient was confirmed to have a de novo mutation.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0030424 (hemangioblastoma; retinal capillary hemangioma; renal cyst; epididymal cyst)

CaseHPOFreeText: Aged 32Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. Retinal hemangioblastomas and CNS hemangioblastomas diagnosed at 32Y, renal cysts were also diagnosed at 32Y, while epididymal cysts were diagnosed first at 23Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497423672 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497423672

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

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.E55Rfs*12 (c.163delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

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

MultipleGeneVariants: Somatic, VHL, c.375insA (p.Asp126Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: father

KindredID: F

Case: M, 53Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Family history is said to be positive. Patient’s father had hemangioblastoma of the CNS at 23Y, and pancreatic cysts at 25Y.

CasePresentingHPOs: HP:0010797; HP:0001737 (hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: Patient had hemangioblastoma of the CNS and pancreatic cysts diagnosed at 53Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145* (c.433C>T)

LegacyVariant: p.Q145* (c.646C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 625249 https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q145* (c.433C>T)

MultipleGeneVariants: N/A

PatientID: HGB-25

KindredID: 6

Case: Sex Unknown, 61Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29941223

SupplementalData: N/A

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:minus_1_frameshift_variant

CivicName:CivicName:P25L(c.74C>T)andD126Rfs*6(c.375_376insA)andE55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.375insA (Asn131Ter) Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: None

KindredID: 6

Case: F, 53Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. The patient's sibling was the proband and had the mutation c.349T>G presenting with renal cell carcinoma, retinal angioma, hemangioblastoma, abnormality of the pancreas, and epididymal or ovarian cystadenoma.The patient's mother, aunt, grandmother, brother 1 and 2, and sister 3 all passed before they could undergo genetic testing but had a variety of VHL presentations. The patient's third nephew were confirmed to have this genetic mutation. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

CaseHPOFreeText: The patient presented with abnormality of the pancreas at age 53.

CaseNotHPOs: HP:0002666, HP:0005584, HP:0009711, HP:0010797 (pheochromocytoma, renal cell carcinoma, retinal capillary hemangioma, hemangioblastoma)

CaseNotHPOFreeText: The patient did not have a cystadenoma of the ovary.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.W117G (c.349T>G)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346 https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117G (c.349T>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: M, 53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880; HP:0000107 (Cerebellar hemangioblastoma, Renal cyst)

CaseHPOFreeText: Cerebellum hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183* (c.548C>A)

LegacyVariant: c.761C>A

CaseProblemVariantFreeText: N/A

ClinVarID: 2215, https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: Preoperative hemoglobin: 17.9. Postoperative hemoglobin: 15.1.

MutationType: stop_gained; missense_variant;transversion

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

PatientID: 94

KindredID: 31

Case: F, 56Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 31) has a son who has also genetically confirmed with the mutation. The proband's son presented at age 29 with retinal angioma, renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and multiple pancreatic cysts/tumors at 51, and CNS hemangioblastoma at age 56.

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).

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

Variant: p.E94* (c.280G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 584477; https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: E94* (c.280G>T)

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

GroupID: 26

Case: 61Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0006880; HP:0005584 (cerebellar hemangioblastoma; renal cell carcinoma)

CaseHPOFreeText: patient had cerebellar hemangioblastoma diagnosed at 61Y, and RCC diagnosed at 53Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.N141Mfs*18 (c.422delA)

LegacyVariant: p.N141Mfs*18 (c.421delA)

CaseProblemVariantFreeText: Written in supply. table as c.421delA, this automaps to c.422delA due to redundancy in code

ClinVarID: N/A

CAID: CA432421876 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.421delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N141fs (c.422del) 

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 53Y0M, Korean

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma (see table 3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, NF1, MAX, SDHA/SDHAF2/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70K (c.208G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

CAID: N/A

gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: Sex Unknown, 55Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had family history of VHL disease. Patient’s son presented with epididymal cystadenoma at age 23 and possessed the same mutation. Patient’s daughter had no clinical manifestations but also had the same VHL mutation.

CohortInfo: 16 Chinese patients clinically diagnosed with VHL disease.

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

CaseHPOFreeText: The patient presented with multiple pancreatic cysts or tumors and renal cell carcinoma at age 53 and a hemangioblastoma at age 54.

CaseNotHPOs: HP:0009711, HP:0030424, HP:0002666, HP:0030393 (retinal capillary hemangioma, epididymal cyst, pheochromocytoma, endolymphatic sac tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E94* (c.280G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 584477, https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E94* (c.280G>T)

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)

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

Case#: 25-year old female, juvenile onset

DiseaseAssertion: STGD1

FamilyInfo: Figure 1 shows family pedigree. Table 1 shows clinical features of a Chinese pedigree. Cosegregation analysis was done and shown in Figure 1A, C.

CasePresentingHPOs: HP:0007663, HP:0007722, HP:0007401, HP:0030329, HP:0030610, HP:0003621, HP:0011507, HP:0007984

CaseHPOFreeText: The uncorrected visual acuity of each eye was 20/400, which has progressively decreased for 13 years.

CaseNotHPOs: n/a

CaseNotHPOFreeText: The retinal vessels were normal.

Genotyping Method: Whole Exome Sequencing, Sanger Sequencing

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.3523-2A>G, NM_000350.3(ABCA4):c.5646G>A (p.Met1882Ile)

ClinVar: 866764, 377407

SupplementalData: n/a