PatientID: 4

KindredID: 3

Case: M, 45Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL disease was described for this patient. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0000107; HP:0001737; HP:0000787 (cerebellar hemangioblastoma; spinal hemangioblastoma; renal cyst; pancreatic cysts; nephrolithiasis)

CaseHPOFreeText: At 40Y, Patient 4 was diagnosed with spinal and cerebellar hemangioblastomas, as well as multiple renal and pancreatic cysts. He was diagnosed with VHL disease type 1. At 43Y, renal cysts and stones were discovered. A year later, more spinal hemangioblastomas and renal stones were found. A year later, cerebellar lesions, as well as renal and pancreatic cysts were reported (see table 1).

CaseNotHPOs: HP:0002088; HP:0001392; HP:0005264; HP:0001743 (abnormal lung morphology; abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the lungs, liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.N90del (c.268_270del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524783, https://reg.genome.network/redmine/projects/registry/genboree_registry/by_caid?caid=CA645524783

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: N90del (c.268_270del)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 51Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: Patient 2 (the patient’s brother) presented with the same mutation and was diagnosed with VHL at age 45. The two brothers had very similar VHL clinical manifestations including cerebellar hemangioblastomas, renal cell carcinoma, and cysts in the pancreas. However, patient 1 had testicular and epididymal cysts, as well as lesions in the spine, which were absent in Patient 2. No other family history was noted. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0005584; HP:0009713; HP:0006880; HP:0000107; HP:0001737; HP:0030424; HP:0033608; HP:0000541; HP:0012215 (renal cell carcinoma; spinal hemangioblastoma; cerebellar hemangioblastoma; renal cyst; pancreatic cysts; epididymal cyst; pulmonary nodule; retinal detachment; testicular microlithiasis)

CaseHPOFreeText: At 44Y, Patient 1 exhibited cerebellar and spinal hemangioblastomas, as well as retinal detachment. He also had renal cell carcinoma in both kidneys and multiple cysts in one kidney, testis, and pancreas. He also reported a history of headaches and vertigo, leading to a diagnosis of VHL disease type 1. At 49Y, multiple nodules were found in his lungs and a year later, a nodule in the testis and scrotal lithiasis were detected. At 51Y, renal cell carcinoma was identified in the left kidney and his left epididymis was enlarged. Patient continued to present with left testicular and scrotal lithiasis, right retinal detachment, and multiple nodules in both lungs. However, tMutation:Germlinehe lung phenotype was asymptomatic (see table 1).

CaseNotHPOs: HP:0001392; HP:0005264; HP:0001743 (abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

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.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/Av

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: 28

KindredID: 28

Case: M, 34Y0M, Korean

DiseaseAssertion: Paraganglioma

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: The patient presented with paraganglioma (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.P103L (c.308C>T))

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1488386, https://www.ncbi.nlm.nih.gov/clinvar/variation/1488386/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P103L (c.308C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 6

Case: Sex Unknown, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive. Patient's son who was confirmed to have this mutation presented with hemangioblastoma at age 12. 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 first sister and third nephew were confirmed to have this genetic mutation. The first sister presented with abnormality of the pancreas at age 53. The nephew had hemangioblastoma and retinal angioma at age 13. Additional familial phenotypes can be found in Table 1.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0009711 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with hemangioblastoma at age 36. At age 40 he/she presented with pancreatic cysts or tumours. At age 44 the patient had retinal angioma, renal cell carcinoma, and epididymal or ovarian cystadenoma.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

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