PatientID: None

KindredID: 1

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No notable family history.

CasePresentingHPOs: HP:0000541; HP:0010797; HP:0009711; HP:0030424; HP:0005562; HP:0001737 (Retinal detachment, Hemangioblastoma, Retinal capillary hemangioblastoma, Epididymal cyst, Multiple renal cysts, Pancreatic cysts)

CaseHPOFreeText: Complained of a shadow in his right eye and was diagnosed with retinal detachment secondary to a retinal hemangioblastoma. MRI of the brain revealed a hyper vascular lesion in the medulla and a smaller lesion at the medullary-spinal cord junction. Weighted abdominal MRI revealed innumerable pancreatic cysts and multiple benign-appearing renal cysts. After surgical resection of the retinal hemangioblastoma, the patient remains asymptomatic.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.K159* (c.474_475insT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423112, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.474_475insT

gnomAD: N/A

VariantEvidence: Reported as: NT474INST. Authors state that this is believed to be a novel sporadic mutation.

MutationType: insertion; plus_1_frameshift_variant; stop_gained

CivicName: K159* (c.474_475insT)

MultipleGeneVariants: N/A

PatientID: III-9

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000541; HP:0002542; HP:0001737; HP:0000107; HP:0030405; HP:0001272; HP:0007366; HP:0010873; HP:0001251; HP:0001260; HP:0001310 (hemangioblastoma, Retinal capillar hemangioma, Retinal detachment, Olivopontocerebellar atrophy, Pancreatic cysts, Renal cyst, Pancreatic endocrine tumor, Cerebellar atrophy, Atrophy/Degeneration affecting the brainstem, Cervical spinal cord atrophy, Ataxia, Dysarthria, Dysmetria)

CaseHPOFreeText: diagnosed with VHL in her early teenage years. She had retinal involvement beginning at the age of 13 treated by cryotherapy and laser therapy (presumably for retinal angiomas); and retinal detachment at the age of 23 requiring eye surgery. She had cysts of the pancreas and kidney detected at 22 years. She has also carried the diagnosis of OPCA since the age of 26-28 (new onset slurred speech and illegible handwriting). Patient had multiple renal cysts without renal tumours, however a large infiltrative enhancing mass in the tail of the pancreas was suggestive of a neuroendocrine/islet cell carcinoma, and liver metastatic foci

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: SCA2 (an abnormal increase in CAG repeats in one allele of her ataxin-2 gene. This abnormal trinucleotide expansion is consistent with the diagnosis of spinocerebellar ataxia type 2)

PatientID: IP (Proband)

KindredID: D

Case: F, 22Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Index patient was a young woman who presented with cerebellar hemangioblastoma, multiple renal cysts, retinal detachment with vitreous hemorrhage, pancreatic cyst, spinal cord hemangiomas, and recurrence of the cerebellar lesion. Family members were not available for clinical and genetic screening, but family history revealed that the patient's father died of metastatic renal cell carcinoma.

CasePresentingHPOs: HP:0006880; HP:0005562; HP:0001737; HP:0000541; HP:0007902; HP:0009713 (Cerebellar hemangioblastoma, Multiple renal cysts, Pancreatic cysts, Retinal detachment, Vitreous hemorrhage, Spinal hemangioblastoma)

CaseHPOFreeText: Patient underwent surgery for cerebellar hemangioblastoma at the age of 22 years. Multiple renal cysts and retinal detachment with vitreous hemorrhage were also observed. At the age of 26 years, pancreatic cyst, spinal cord hemangiomas, and recurrence of the cerebellar lesion were found. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: 9

KindredID: 5

Case: F, 46Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: A family pedigree is provided in figure 1. Neither parent had VHL syndrome characterized by retinal capillary hemangiomas (RCHs). They likely did not undergo molecular testing because there was no mention of de novo status.

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0009713; HP:0000541 (Cerebellar hemangioblastoma; Retinal capillary hemangioma; Spinal hemangioblastoma; Retinal detachment)

CaseHPOFreeText: A 32-year-old woman had been diagnosed in 2000 with multiple cerebellar and spinal hemangioblastomas. In 2005, she was examined at the eye clinic and were visual acuity was 20/20 and 20/25 in the right and left eye, respectively. No abnormalities were found in the right eye, but a peripheral RCH that was already partially treated with laser was observed in the left eye. Many tiny RCHs that surrounded the major lesion were also detected in this eye. Further laser treatments were scheduled, but the patient did not follow-up and instead came to the ophthalmic emergency service three years later. Visual acuity of the left eye worsened to 20/640, and she presented with retinal detachment. The partially treated RCH of the left eye worsened and and more tiny RCHs were detected. Cryotherapy was performed in the left eye but retinal detachment was still present at follow up. On follow up, no RCHs were detected in the right eye and vision loss developed in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Patient did not have other known tumours.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: First cousin (male, 33Y) presented with CNS hemangioblastoma, RCC, optic atrophy, vision loss and retinal capillary hemangioblastoma. THis cousin also had the same germline mutation as the proband.

CasePresentingHPOs: HP:0005584; HP:0011531; HP:0009711; HP:0000541 (Renal cell carcinoma, Vitritis, Retinal capillary hemangioma, Retinal detachment)

CaseHPOFreeText: About 1 month previously, percutaneous radiofrequency ablation treatment was performed on the patient due to RCC in his left kidney. Vitritis was detected in the right eye on slit-lamp biomicroscopy. The fundus examination revealed an extensive lipid exudation on the fovea and macula, and a 3-4 optic disc diameter-sized RH at the equator in the right eye; it was normal in the left eye. Optical coherence tomography (OCT) showed that there was a foveal detachment in the right eye.

CaseNotHPOs: HP:0100006 (Neoplasm of the central nervous system)

CaseNotHPOFreeText: Central nervous system involvement was not detected in the patient.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S68P (c.202T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621912, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA16621912

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S68P (c.202T>C)

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