GroupID: 14

DiseaseAssertion: VHL

Group size: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, two individual was suspected of VHL disease, but neither developed RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: This VHL patients did not present with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.R64P (c.191G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2226, https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10183722G>C

MutationType: missense_variant; transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: F, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient had a family specific p.Arg64Pro mutation, and VHL disease had a heterogeneous presentation in the family. The patient’s father initially presented with bilateral pheochromocytomas and clear cell renal carcinoma, and the patient’s son underwent unilateral adrenalectomy for pheochromocytoma at the age of 7.

CasePresentingHPOs: HP:0002668 (Paraganglioma)

CaseHPOFreeText: The patient was asymptomatic and presented with a palpable mass on the left side of the neck during a routine check-up. Somatostatin receptor scintigraphy revealed a hotspot near the left carotid artery, which indicated a paraganglioma. The paraganglioma was 2.5cm in size, and histological examination of it post-resection confirmed it was a paraganglioma. The patient did not present with any later tumors, although the length of follow-up is not specified.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P (c.191G>C)

ClinVarID: 2226, https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

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.R64P (c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226, /www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL - asymptomatic

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: No tumors were reported in this patient: it was stated that they present an additional rare disease: the patient is heterozygous for CLN5protein in the neuronal ceroid lipofuscinosis rare disease. It is thus hypothesized that the CLN5 mutation in this VHL patient offers a protective effect to prevent tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: CLN5

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.R64P(c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 64Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0000504; HP:0006770; HP:0002666; HP:0001737; HP:0009711; HP:0002403; HP:0020036; HP:0000969; HP:0025163 (Hemangioblastoma, Abnormality of vision, Clear cell renal cell carcinoma, Pheochromocytoma, Pancreatic cysts, Retinal capillary hemangioma, Positive Romberg sign, Upper limb dysmetria, Edema, Abnormality of optic chiasm morphology)

CaseHPOFreeText: Presented at age 64 with a known large suprasellar hemangioblastoma, and history of right eye enucleation presented with worsening vision of her remaining left eye. The patient had a past history of severe VHL disease with bilateral clear cell renal cell carcinomas, bilateral pheochromocytomas, pancreatic cysts, retinal HBs, and multiple CNS HBs. Neurological exam was significant for Romberg sign and mild dysmetria of bilateral upper extremities. A visual field test of the left eye revealed new onset inferior temporal quadrantanopsia. Magnetic resonance imaging confirmed a slowly growing suprasellar hemangioblastoma within the circle of Willis with increased optic tract edema and compression of the optic chiasm.

CaseNotHPOs: HP:0007686; HP:0000496 (Abnormal pupillary function, Abnormality of eye movement)

CaseNotHPOFreeText: Left eye extraocular movements and pupillary reaction intact.

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

VariantEvidence: VHL-HBs demonstrated strong expression patterns for all receptor subtypes except SSTR3 (more info available in “Results”).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 552

KindredID: 1

Case: F, 7Y4M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother had pheochromocytoma, and the patient’s maternal second-degree relatives had renal cell carcinoma and systemic lupus erythematosus/rheumatoid arthritis.

CasePresentingHPOs: HP:0002666; HP:0001085 (Pheochromocytoma, papilledema)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P (c.191G>C)

ClinVarID: 2226, https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

PatientID: III-4

KindredID: 1

Case: 34Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Family suggesting incomplete penetrance of a VHL gene germline mutation. Mutation (p.R64P) was found in a family with 6 patients total with three generations. The earliest patient described (I-1) presented with renal cell carcinoma (age at diagnosis 48 years), 1 of their 6 children (II-1) at age 59 had no typical VHL manifestations after annual clinical monitoring and suggest non-penetrance in the patient; the second of 6 children (II-3), then aged 51, had bilateral pheochromocytoma diagnosed age 14. Their only child (III-5) had a paraganglioma with an age of diagnosis of 29 years, and a renal cyst. Patient II-1 had 4 children - one (III-1; aged 40) who presented as a carrier with no typical VHL manifestations after annual clinical monitoring; and another 32 years old presenting with pheochromocytoma. (See Figure 2 for pedigree)

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma diagnosed at age 34

CaseNotHPOs: N/A

CaseNotHPOFreeText: Unclear as to whether testing for other manifestations was conducted

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

Variant: p.R64P (c.191G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: CA020089 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.191G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: N/A (case)

KindredID: 1

Case: F, 18Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Not relevant - She was the first child of consanguineous parents. Her family history was notable for type 2 diabetes and dyslipidemia but no history of pheochromocytoma, paraganglioma, unexplained sudden death, or condition relevant to VHL. However, the family screening for VHL has not been performed.

CasePresentingHPOs: HP:0006748; HP:0000819; HP:0008200 (adrenal pheochromocytoma; Diabetes mellitus; hyperparathyroidism)

CaseHPOFreeText: First brought to clinic for newly diagnosed diabetes mellitus and severe arterial hypertension. As symptoms, the patient complained of headaches, palpitations, diaphoresis, and hot flashes since one month. She reported also asthenia and body weight loss of five kilograms in two weeks. Pheochromocytoma was confirmed. CT showed adrenal masses: Right measuring 35×55×70mm, and left measuring 24×27mm. She underwent a bilateral adrenalectomy in two steps. Pathological examination confirmed bilateral adrenal pheochromocytomas. 12 months post, follow up is clear.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Thyroid, abdominal, and neurological examinations were normal.

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P (c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P (c.191G>C)

MultipleGeneVariants: N/A

PatientID: 20

KindredID: 900

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P95Rfs*64 (c.284delC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030172 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030172

gnomAD: N/A

VariantEvidence:N/A

MutationType: minus_1_frameshift_variant

CivicName: P95Rfs*64 (c.284del)

MultipleGeneVariants: N/A

PatientID: 100

KindredID: 100

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: The patient had multiple paragangliomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1. There is additional tumour specific information in Supplemental Table 2.

Variant: p.R64P (c.191G>C)

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

gnomAD: N/A

VariantEvidence: Membrane CA9 immunostaining was observed (supplemental table 1).

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A

PatientID: F119

KindredID: 1

Case: F, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a pheochromocytoma in the left adrenal gland. It was measured to be 3 cm in size and 23 grams in weight.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R64P(c.191G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R64P(c.191G>C)

MultipleGeneVariants: N/A