PatientID: C (Tumor 5)

KindredID: 1

Case: F, 57Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: This kindred with a VHL germline deletion was studied. Apparently inherited from her father and paternal grandmother as they were affected, and passed to son. Her sister and son also presented with hemangioblastomas and this germline deletion, and further somatic details were studied.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: a brainstem HB surgically resected at 57Y and found with a somatic mutation

CaseNotHPOs: N/A

CaseNotHPOFreeText: no VHL-associated visceral malignancies in the patient

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E16D (c.48G>T)

LegacyVariant: c.762G>T (p.Glu16Asp)

CaseProblemVariantFreeText: A somatic mutation in exon 1 (nt: c.762G>T via Latif et al.’s (1993) old transcript) was used.

ClinVarID: N/A

CAID: CA351747228 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.48G%3ET

gnomAD: N/A

VariantEvidence: unspecified germline deletion as demonstrated by FISH analysis. “Second-hit” tumorigenesis displayed due to a somatic mutation found, which was not predicted by the specific germline deletion nor by the overall genetic composition of the patient.

MutationType: missense_variant; transversion

CivicName: Deletion

MultipleGeneVariants: Germline, VHL, deletion

PatientID: 3

KindredID: 3

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Strong family history. His grandfather died of a brain tumor at the age of 45, his cousin brother was operated for a bilateral PCC and his paternal uncle was diagnosed with hemangioblastoma.

CasePresentingHPOs: HP:0006748, HP:0000107, HP:0001737, HP:0010797 (Adrenal pheochromocytoma, renal cyst, pancreatic cysts, hemangioblastoma)

CaseHPOFreeText: Subsequent CECT revealed a posterior fossa fourth ventricle tumor with hydrocephalus. He underwent a suboccupalcraniatectomy with CI laminectomy with biopsy of the tumor along with VP shunt and then was referred to SGPGIMS. He underwent DSA embolization in view of hypervascular tumor and in preparation of excision. He had a hemangioblastoma of the brainstem.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174 https://www.ncbi.nlm.nih.gov/clinvar/variation/223174/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient was heterozygous for the mutation.

MutationType: missense_variant;transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 139 (Second cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with retinal angioma (16Y). Age of diagnosis of pheochromocytoma and renal cell carcinoma is unknown.

CaseNotHPOs: HP:0000077; HP:0001732; HP:0010797 (Abnormality of the kidney, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

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: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 18

KindredID: A

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0009711; HP:0002668 (Retinal capillary hemangioma, Paraganglioma)

CaseHPOFreeText: Retinal angiomas aged 16Y. 30Y at VHL diagnosis. Abdominal paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233, https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: N/A

PatientID: II

KindredID: 5

Case: Sex Unknown, 20Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 family members with the same VHL variant. Patient 5-I presented with retinal hemangioblastoma (17Y). Patient 5-III presented with retinal hemangioblastoma (12Y), pancreatic cysts (12Y), CNS hemangioblastoma (15Y) and kidney disease (12Y).

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0001737 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 3Y. Presented with 13 CNS hemangioblastomas (11Y, 13Y, 15Y and 17Y), retinal hemangioblastoma (13Y) and 2 pancreatic cysts (16Y). Age at the end of study: 20Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: I

KindredID: 13

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797, HP:0001737, HP:0009711 (hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseHPOFreeText: The patient was diagnosed with VHL at age 13. The patient had 8 retinal hemangioblastomas at ages 13, 16,17,18. The patient had 1 pancreatic cyst at age 17 and one CNS hemangioblastoma at age 17. The patient died at age 48.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: III

KindredID: 9

Case: Sex Unknown, 24Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: Two other family members (9-I and 9-II) carried the same mutation but were asymptotic.

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

CaseHPOFreeText: The patient had two CNS hemangioblastomas and two pancreatic cysts at age 16. The patient was diagnosed with VHL at age 16.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19863552, 25834951, 27966541, 27539272

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied at have the L198P mutation, however the asymptomatic father of patient C II-1 was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.593T>C (p.Leu198Pro)

PatientID: 1

KindredID: 1

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A - no family history of VHL disease. Authors indicate probably a de novo mutation, however no testing on family members was completed.

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0100615 (pheochromocytoma, pancreatic endocrine tumor, ovarian neoplasm)

CaseHPOFreeText: hospitalized in 2011 (11Y old) due to a hypertensive crisis with end-organ damage (bilateral papilledema and left ventricular hypertrophy). MRI showed 2 heterogenous nodular lesions where the largest was in the right adrenal gland (65x51x39mm) and the other in the left adrenal gland (36x28x25mm). A bilateral adrenalectomy diagnosed both tumors as pheochromocytomas of the adrenal gland. Lymph node metastasis was detected in the adipose tissue surrounding the left adrenal gland. 2 years later (at age 13Y) a PET/CT scan showed a nodular lesion in the tail of the pancreas (11mm) and a nodule in between the inferior vena cava and the portal vein (13mm) and both were later diagnosed as neuroendocrine tumors the former in the pancreas and the latter in the perihaptic ectopic pancreatic tissue. At 14Y, more pancreatic lesions were found. At 16Y, an MRI found a nodule int he right ovary (33mm) which was later diagnosed as a benign ovarian steroid cell tumor

CaseNotHPOs: HP:0010797; HP:0006770 (hemangioblastoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: Table 1 indicates this was did not have the above manifestations

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 1

Case: M, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0000107; HP:0006748; HP:0009713; HP:0009711; HP:0006880; HP:0030405; HP:0001737 (renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, retinal hemangioblastoma, cerebellar hemangioblastoma, pancreatic endocrine tumor, pancreatic cysts)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. He was found to have renal and pancreatic cysts, adrenal pheochromocytoma, spinal hemangioblastoma, retinal hemangioblastoma, cerebellar hemangioblastoma, and pancreatic endocrine tumor (see table 1). Patient also had bone metastasis. He was diagnosed with VHL subtype 2A at age 49Y0M and passed away at age 57Y0M.

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 13

KindredID: 6

Case: M, 22Y11M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 6, patient 12 was reported as having PPGL and PNETs at 36Y, along with renal and pancreatic cysts, and retinal HB. Their relation is not clear.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient developed PPGL at 16Y of age. It was a right side Pheo measuring 1.7cm with no recurrence at follow up 83 Months after.

CaseNotHPOs: HP:0030405; HP:0010797; HP:0005584; HP:0001737; HP:0009711; HP:0000107 (pancreatic endocrine tumor, hemangioblastoma, renal cell carcinoma, pancreatic cyst, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III:6

KindredID: 1

Case: M, 18Y, Spanish

DiseaseAssertion: VHL

FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s sister had passed at 18Y with pheochromocytoma, his other sister presented with the same mutation. His father, aunt and two cousins all showed positive for the familial mutation.

CasePresentingHPOs: HP:0006748; HP:0009711; HP:0006880 (adrenal pheochromocytoma; retinal capillary hemangioma, cerebellar hemangioblastoma)

CaseHPOFreeText: at 16Y, he presented and had removed with bilateral adrenal pheochromocytoma (right: 2.7cm; left 4.7cm) with signs and symptoms of intracranial hypertension. At 17Y, brain CT and MRI were abnormal, showing cerebellar tumors (hemangioblastoma). Retinal angiomas were also displayed in this patient.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R238T, C>T

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: III-2

KindredID: 1

Case: M, 16Y0M, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo:  2 young male twins were examined with the VHL gene mutation with simultaneously manifesting hemangioblastomas of the right cerebellar hemisphere. Both parents were examined with no VHL mutation, detecting a de novo mutation in the twins. A third sibling, two years older, presented with a cafè au lait skin spot. Grand mother had bilateral high myopia and glaucoma. The medical history of the pedigree shows that member (I-1) had severe hypertension and died at 60 from a stroke, member (I-2) died at 40 from ovarian carcinoma, and member (I-3) died at 54 from clinically diagnosed intracerebral haemorrhage.

CasePresentingHPOs: HP:0006880; HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

CaseHPOFreeText: in 1994 patient came complaining of blurred vision thought to be due to his myopia. MRI showed a large cyst and a 4.3 cm mural ovoid nodule in the right cerebellar hemisphere. Another small mural nodule was present in the infero-posterolateral portion of the right cerebellar hemisphere. CT disclosed a round homogeneous, hyperintense nodule at T1 in the spinal cord. Raised intracranial pressure due to the compression of aqueduct from the tumour accounted for hydrocephalus and enlarged lateral and 3rd ventricles.

CaseNotHPOs: HP:0001901 (polycythemia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: Proband

KindredID: 1

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother was found with the same VHL germline variant. His mother presented with bilateral pheochromocytoma.

CasePresentingHPOs: HP:0002315; HP:0000651; HP:0002666; HP:0009711; HP:0000822 (Headache, Diplopia, Pheochromocytoma, Retinal capillary hemangioma, Hypertension)

CaseHPOFreeText: Admitted with complaints of headache and diplopia. MRI indicated the presence of multiple lesions in perivascular areas neighboring both adrenal glands. An iodine 123 metaiodobenzylguanidine (MIBG) scan revealed multiple focal areas of increased uptake near the adrenal glands. The diagnosis of bilateral pheochromocytoma was confirmed histologically and immunohistochemically. The patient remained asymptomatic with no laboratory or radiologic abnormalities for six years of follow-up. At the age of 16, the patient was referred to our clinic with a visual defect in the left eye. Ophthalmologic examination led to the diagnosis of bilateral retinal hemangiomas, and he underwent laser photocoagulation.

CaseNotHPOs: HP:0009713; HP:0006880 (Spinal hemangioblastoma, Cerebellar hemangioblastoma)

CaseNotHPOFreeText: Cerebral, spinal MRI and abdominal computed tomography (CT) were normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: c.695G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant was reported as “c.695G>A” which was mapped to p.Arg161Gln (c.482G>A) in accordance with reference sequence NM_000551.3.

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: II-a

KindredID: 1

Case: F, 16Y0M, Greek

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s 50-year-old father has VHL consisting of retinal HBs diagnosed at the age of 20 years. He also has spinal cord HBs located in the neck. He was also found to carry the mutation NM_000551.3:c.433C>T that the patient carried. The patient’s 18-year-old brother and her 20-year-old sister are phenotypically healthy and repeated biochemical evaluation and imaging studies are negative. Her paternal uncle, aunt and cousins are also phenotypically healthy with no indications from either biochemical or imaging studies as they denied further evaluation. In addition, her paternal grandfather of unknown genotype died at the age of 85 years while her paternal grandmother is alive and has no problems, being 86 years old at time of writing.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0001737 (Spinal hemangioblastoma, cerebellar hemangioblastoma, retinal hemangioblastoma, pancreatic cyst)

CaseHPOFreeText: The 16Y female patient first presented with back pain, headaches, numbness, dizziness, weakness and pain in the arms and the legs at 12Y. A hemangioblastoma in the thoracic spine and a hemangioblastoma in the neck were found. A year later, at the age of 13, multiple HBs in the right and smaller lesions in the left eye were found. Two asymptomatic cysts (2 cm and 0.8 cm) in the body of the pancreas were also found. During her recent evaluation, at the age of 16 years, MRI imaging revealed a large HB extending from the cerebellum to the Th8 vertebrae, with extensive solid and cystic nodules inside the mass and increased dimensions of the spinal cord.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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

gnomAD: N/A

VariantEvidence: It has been documented that dynamic organisation of pVHL–HIF1α recognition is focally centred on Gln145 within the L7 loop, and its tumourigenic mutant Q145H abolishes almost all of the correlated dynamic motions. In this report, Q145 is substituted by a stop codon, p.Q145X. This is a nonsense mutation resulting to a truncated VHL protein that lacks the last 68 amino acids and thus its function is abolished.

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Eight patients whose pheochromocytomas were suggestive of VHL but were negative for a VHL abnormality both by PCR-Sanger sequencing and by quantitative multiplex PCR of short fluorescent fragments (QMPSF).

CasePresentingHPOs: HP:0010797, HP:0002666, HP:0030405, HP:0006748 (Hemangioblastoma, Pheochromocytoma, Pancreatic endocrine tumor, adrenal pheochromocytoma)

CaseHPOFreeText: Patient developed hemangioblastoma at age 16. At age 17 he developed right pheochromocytoma, pancreatic endocrine tumour, and a small left adrenal nodule later stated to be an adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.

SupplementalData: N/A

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: The patient had a mosaic mutation with a mutated allele frequency of 5.7%.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 5069

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 41) has the same VHL mutation and presents with five pathologic pancreatic endocrine tumours.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with three pathologic pancreatic endocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

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

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 50

Case: F, 16Y0M, 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: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied. This mutation was said to be a de novo, although no more inforation provided. However the asymptomatic father of patient was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

CaseNotHPOs: HP:0005584; HP:0010797 (renal cell carcinoma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198P (c.593T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223235 https://www.ncbi.nlm.nih.gov/clinvar/variation/223235/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: Proband 5

KindredID: 1

Case: M, 16Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The family with PCCs includes 56 members of 4 generations, and is from Gansu Province. Among them, 7 extended over 3 generations were diagnosed as PCCs. One died before admission and another died due to a cardiovascular incident. Five were initially evaluated; evaluation included medical history, physical examination, abdominal ultrasonography, CT or MRI and laboratory tests. All 5 probands of this family underwent surgical resection. The tumors were benign under pathological examinations. There were no recurrence and malignant transformation over the period of up to 23-year follow-up. Twenty members, including 5 live patients and 15 direct relatives, accepted genetic examination.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral PCC diagnosed at 16Y and did not have any other clinical presentations. Stated as having VHL type IIC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H125P (c.374A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223201, https://www.ncbi.nlm.nih.gov/clinvar/variation/223201/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: H125P (c.374A>C)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 18

Case: Sex Unknown, 48Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737; HP:0000112 (Pancreatic cysts, Nephropathy)

CaseHPOFreeText: Diagnosed with VHL at age 14Y. Presented with 3 pancreatic cysts (14Y) and kidney disease (16Y). Age at the end of study: 48Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q203Tfs*53 (c.606dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 935385, https://www.ncbi.nlm.nih.gov/clinvar/variation/935385/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: Q203TfsX53 (c.606dupA)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 7

Case: Sex Unknown, 40Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: One other family member presented with this variant and was asymptomatic.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 4Y. presented with 3 retinal hemangioblastomas (8Y, 16Y). Age at the end of study: 40Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: DIII7

KindredID: D

Case: F, 16Y0M, Chinese

DiseaseAssertion: pancreatic cysts

FamilyInfo: A 3-generation family is given with 3 confirmed members with this mutation. 2 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0001737 (pancreatic cysts)

CaseHPOFreeText: initially diagnosed by genetic analysis and further verified radiologically, to be found with pancreatic cysts at 16Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: p.F76del (c.439delTCT)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_2289delTCT)

MultipleGeneVariants: N/A

PatientID: 83 (Cousin)

KindredID: 18

Case: F, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (25Y), retinal angioma (16Y) and pancreatic tumors or cysts (undefined) (22Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

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: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5 (Aunt)

KindredID: 17

Case: F, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family tested positive for the c.496_506del germline variant of the VHL gene. ID 4 presented with CNS hemangioblastoma, retinal angioma and renal and pancreatic abnormalities. ID 1, 25 and 8 were asymptomatic.ID 22 presented with CNS hemangioblastoma. 2 members were assumed to have the variant but were not genetically confirmed (ID 20 and ID 11). ID 11 and 20 presented with CNS hemangioblastoma.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: This patient presented with retinal angioma (16Y).

CaseNotHPOs: HP:0005584; HP:0002666; HP:0010797; HP:0000077; HP:0001732 (Renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Abnormality of the kidney, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.V166Sfs*4 (c.496_506del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223229, https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

CAID: N/A

gnomAD: N/A

VariantEvidence: It is unclear from the publication if this variant is reported according to legacy (AF010238.1) or NM_000551.3 reference sequence. Clinical notes from the case confirm the reference sequence to be NM_000551.3.

MutationType: deletion; minus_2_frameshift_variant

CivicName: V166SFS*4 (c.496_506del)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: F, 28Y0M, German

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748, HP:0006880, HP:0009713, HP:0030405, HP:0010302 (Adrenal pheochromocytoma, cerebellar hemangioblastoma, spinal hemangioblastoma, pancreatic endocrine tumour, spinal cord tumor)

CaseHPOFreeText: At age 16 she presented with a left adrenal pheochromocytoma which was removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized. Three of eleven lymph nodes showed metastases.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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.500G>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 29Y0M, Brazilian

DiseaseAssertion: VHL

FamilyInfo: VHL type 1. Genetic testing has been performed in her parents and brother with negative results. Her only child has not undergone predictive testing yet.

CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0000107; HP:0001737; HP:0001407 (endolymphatic sac tumor; retinal capillary hemangioma; hemangioblastoma; renal cysts; pancreatic cysts; hepatic cysts)

CaseHPOFreeText: endolymphatic sac tumor diagnosed at 11Y, retinal angiomas at 16Y; hemangioblastoma, renal, pancreatic, and hepatic cysts at 29Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 1

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 16Y0M. She had adrenal pheochromocytoma and diagnosed with VHL subtype 2A (see table 1).

CaseNotHPOs: HP:0002668 (paraganglioma)

CaseNotHPOFreeText: Patient does not have paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: 8550742

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A