PatientID: 4

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 48Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter had bilateral adrenal pheochromocytoma at 27Y, and was found to have bilateral small lesions suspicious for inactive retinal angiomas upon further investigation. Genetic testing found that the patient’s daughter carried the same NM_000551.3:c.277G>A mutation that the patient was found to carry. The patient’s granddaughter was also found to carry the mutation. The patient's mother had also died at 42Y as a result of a stroke, and the patient’s uncle had died at 57Y as a result of a stroke. There is no genetic information available about them. The other daughter of the patient did not carry the mutation.

CasePresentingHPOs: HP:0006748; HP:0030424; HP:0000107 (Adrenal pheochromocytoma, epididymal cyst, renal cyst)

CaseHPOFreeText: The 48Y male patient presented with a right adrenal pheochromocytoma at 48Y. Further investigation revealed left epididymal cysts and bilateral renal cysts.

CaseNotHPOs: HP:0009713; HP:0009711 (Spinal hemangioblastoma, retinal hemangioblastoma)

CaseNotHPOFreeText: An MRI of the brain and spinal cord showed no signs of hemangioblastomas and examination of the eyes showed no retinal hemangioblastomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93S (c.277G>A)

LegacyVariant: N/A

ClinVarID: 2237, https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93S(c.277G>A)

MultipleGeneVariants: N/A

GroupID/ KindredID: 62CE, 4873NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from multiple databases, including: the Munich, university of Freiburg and Institute of Pathology database, and the National Cancer Institute database, with an unknown number of members belonging to two family IDs: Family ID 62CE and 4873NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as 2 VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93S (c.277G>A)

LegacyVariant: p.G93S (c.490G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 2237 https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93S (c.277G>A)

MultipleGeneVariants: N/A

PatientID: AII2

KindredID: A

Case: F, 33Y0M, Serbian

DiseaseAssertion: VHL

FamilyInfo: Families were selected based on their clinical data and family history. Patient’s mother (AI1) had CNS hemangioblastoma. The patient’s son (AIII3) had severe arterial hypertension since 12Y0M and left pheochromocytoma was found and removed at 24Y0M. The patient’s sister (AII2) has pheochromocytoma and CNS hemangioblastoma. Genetic testing was performed on nine family members and two carried the heterozygous missense variant - current patient and her son. The patient’s mother and sister with VHL were not genetically tested. See pedigree in figure 1.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient was diagnosed with pheochromocytoma at 33Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93C (c.277G>T)

LegacyVariant: p.G93C (c.490G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 223175, https://www.ncbi.nlm.nih.gov/clinvar/variation/223175/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense variant; transversion

CivicName: G93C (c.277G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 5

Case: Sex Unknown, 60Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0009713; HP:0000107; HP:0002666; HP:0001737 (Retinal capillary hemangioma, Spinal hemangioblastoma, Renal cyst, Pheochromocytoma, Pancreatic cysts)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.G93S (c.277G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2237, https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93S (c.277G>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 5

Case: M, 19Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient had 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: HP:0005584; HP:0000107; HP:0006748; HP:0009713; HP:0001737; HP:0030939; HP:0100684 (renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor, salivary gland neoplasm)

CaseHPOFreeText: Patient presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. Patient was diagnosed with VHL type 1 (see table 2).

CaseNotHPOs: HP:0002668; HP:0030405 (paraganglioma; pancreatic endocrine tumor)

CaseNotHPOFreeText: Patient negative for paraganglioma and pancreatic endocrine tumor.

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: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93_Y98del (c.277_294del)

LegacyVariant: c.488_490del18bp

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA891843321, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275_292del

gnomAD: N/A

VariantEvidence: Variant reported as c.488_90del18bp and mapped to c.275_292del (equivalent to c.277_294del).

MutationType: deletion; inframe_deletion

CivicName: G93_Y98del (c.275_292del)

MultipleGeneVariants: N/A