PatientID: P34

KindredID: 1

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: diagnosed at the age of 20 years with VHL and presented with severe hypertension and a 40 mm PC of the right adrenal gland (pheochromocytoma)

CaseNotHPOs: No positive family history

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/ SDHD/ RET/ MEN2

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: also the polymorphism S69S of the SDHD gene.

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: Germline, SDHD, (p.Ser69Ser)

GroupID/ KindredID: 8CE, 59CA, 21CE

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 the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family IDs 8CE, 59CA, 21CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

LegacyVariant: p.L89P (c.479T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3708NCI

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 the National Cancer Institute database, with an unknown number of members belonging to Family ID 3708NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: p.L184P (c.764T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

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)

GroupID: 3708

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

GroupHPOFreeText: both (2) members has RCC and 1 member had hemangioblastoma

GroupNotHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L255P (c.764T>C)

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

GroupID: 4408

DiseaseAssertion: assumed VHL

GroupSize: 25

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 25 family members recorded with this mutation.

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

GroupHPOFreeText: 14 of the 25 members had an angioma (retinal hemangioma), 2 had RCC, and 16 members had CNS hemangioblastoma.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158P (c.473T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L158P (c.686T>C)

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

PatientID: 1 (proband)

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Recorded family history of VHL disease, with the patient’s mother, grandmother, two uncles and three aunts also suffering from the disease. Additionally, one uncle had succumbed to RCC and five other individuals in the family had succumbed to cerebral hemangioblastomas. No mutation was stated.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0030405 (cerebellar hemangioblastoma; renal cell carcinoma; pancreatic endocrine tumour)

CaseHPOFreeText: At 20Y was admitted to hospital with symptoms of dizziness, unsteadiness and nausea for three weeks, as well as vomiting for one week (cerebellar hemangioblastoma found in MRI); reoccured at 23Y. At 34Y patient had jaundice (multiple RCCs in the kidneys, and a nodule with a rich blood supply in the pancreatic head observed through CT). Numerous cysts were also identified throughout the pancreas (a possible PNET).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158P (c.473T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

GroupID: 81

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.506T>C) was found in 1 VHL family with 4 patients.

GroupPresentingHPOs: HP:0005584; HP:0009711 (renal cell carcinoma; retinal capillary hemangioma)

GroupHPOFreeText: 3 patients had retinal angiomas with a mean age of diagnosis of 22Y, and 2 patients had RCCs with a mean age of diagnosis of 28Y.

GroupNotHPOs: HP:0002666; HP:0006880 (pheochromocytoma, cerebellar hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.L169P (c.506T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428809 https://www.ncbi.nlm.nih.gov/clinvar/variation/428809/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L169P (c.506T>C)

MultipleGeneVariants: N/A

GroupID: 32

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.L129P (c.386T>C)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 625242 https://www.ncbi.nlm.nih.gov/clinvar/variation/625242/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L129P (c.386T>C)

MultipleGeneVariants: N/A

PatientID: 34

KindredID: 34

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0010797 (Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and RCC.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L249P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 746T>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.533T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 46

KindredID: 46

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: p.L189P (c.566T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428807, https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: Nucleotide deletion (i.e. 566T>C) coincides with legacy variant nomenclature (i.e. AF010238.1) and was mapped to c.353T>C (NM_000551.3).

MutationType: missense_variant;transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: F43

Case: Sex unknown, 27Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

CasePresentingHPOs: HP:0009711; HP:0009713; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Development of Broad ligament cysts were also observed. Age of onset is 27Y0M.

CaseNotHPOs: HP:0002666; HP:0006770 (pheochromocytoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: https://www.ncbi.nlm.nih.gov/clinvar/variation/411977/

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: N/A

PatientID: 40

GroupID/ KindredID: 40

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178P (c.533T>C)

LegacyVariant: p.L178P (c.746T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 428795 https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 8828

KindredID: 1005

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 269.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

PatientID: IV-7

KindredID: 2

Case: F, 36Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0009713 (Spinal hemangioblastoma)

CaseHPOFreeText: Spinal cord hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 3

DiseaseAssertion: assumed VHL

GroupSize: 11

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 11 patients with the given mutation belonging to VHL family 3

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts)

GroupHPOFreeText: retinal capillary hemangioma was found in 3 members, hemangioblastomas in 7 members, renal cyst in 7, renal cell carcinoma in 5, and pancreatic cysts in 6

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L89P (c.479T>C)

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: See HaeIII digestion in Fig. 3b

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: 191

KindredID: 191

Case: Sex Unknown, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107 (Hemangioblastoma, Retinal capillary hemangioma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and renal cystic lesion.

CaseNotHPOs: HP:0001732; HP:0002666; HP:0006770 (Abnormality of the pancreas, Pheochromocytoma, Clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.L153P (c.458T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621942, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.458T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L153P (c.458T>C)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: F, 41Y0M, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: Positive family history of VHL disease.

CasePresentingHPOs: HP:0006766; HP:0006770; HP:0010797 (papillary renal cell carcinoma, clear cell renal cell carcinoma, hemangioblastoma)

CaseHPOFreeText: multiple cystic, bilateral renal cysts and partial nephrectomies with tumor enucleations were performed (6 tumors total that ranged from 0.4-6.5cm); Fuhrman nuclear grade 2: identified as clear cell papillary in 2 of them, and clear cell carcinoma in 4.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1208816 https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

CAID: N/A

gnomAD: N/A

VariantEvidence: diffuse staining with cytokeratin 7 (CK7) was positive + and CD10 + (rare). P504S was negative -.

MutationType: missense_variant;transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

PatientID: V-3

KindredID: 2

Case: F, Age Unknown, Mexican

DiseaseAssertion: Asymptomatic

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: IV-6 (Proband)

KindredID: 2

Case: F, 23Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4485NCI

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 the National Cancer Institute database, with an unknown number of members belonging to Family ID 4485NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family 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.L158P (c.473T>C)

LegacyVariant: p.L158P (c.686T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

PatientID: 3087

KindredID: 1

Case: M, 68Y0M, Ethnicity Unknown

DiseaseAssertion: Clear cell renal cell carcinoma

FamilyInfo: N/A

GroupInfo: Renal cell carcinomas from 31 patients (22 of which were confirmed clear cell renal cell carcinoma) were obtained from the CentreLeon Berard (Lyon, France) and were analyzed for mutations in the VHL gene.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: Metastatic tumor at time of nephrectomy. See table 1 for more patient-specific information.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: c.764T>C

CaseProblemVariantFreeText: N/A

ClinVarID: 419447, https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: CA16617792

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L184P (c.551T>C)

MultipleGeneVariants: Germline, VHL, c.183C>G (p.P61=)

PatientID: 37

KindredID: 37

Case: M, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Patients with apparently sporadic pheochromocytomas.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L63P(c.188T>C)

LegacyVariant: p.L63P(c.401T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2227 https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L63P(c.188T>C)

MultipleGeneVariants: N/A

PatientID: None (Brother 2)

KindredID: ASP (L63P)

Case: M, Age Unknown, Hungarian

DiseaseAssertion: Asymptomatic

FamilyInfo: Family screening showed the presence of the L63P mutation in two out of the three clinically healthy brothers, whereas the mutation was absent in a clinically healthy son. Proband of this family presented with an apparently sporadic pheochromocytoma and the L63P germline mutation of the VHL gene.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L63P (c.188T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as L63P and cDNA change was mapped to c.188T>C.

MutationType: missense_variant;transition

CivicName: L63P (c.188T>C)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 6

Case: F, 49Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: CA020207 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.266T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 5

Case: Sex Unknown, 40Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 2 other members of this family presented with the same variant. Patient 13 (Gen 2) presented with bilateral pheochromocytoma. Patient 12 (Gen 2) presented with bilateral pheochromocytoma and sympathetic paraganglioma.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma.

CaseNotHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0030405; HP:0002668 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma, Pancreatic endocrine tumor, Paraganglioma)

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/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C)

MultipleGeneVariants: N/A

GroupID: 23

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant from France was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158P (c.473T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 42

Case: Sex Unknown, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Membrane CA9 immunostaining was observed.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 40/41

KindredID: 40/41

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Patient data is extracted from two rows assumed to be referring to the same patient (i.e. tumor samples 40 and 41 in Supplementary Table 1a). Carbonic anhydrase 9 (CA9) mRNA level of 795.70 (PCC) and 815.38 (PCC) were detected. Membrane CA9 immunostaining was observed in both PCC samples.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 37

Case: M, 35Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: Unilateral benign adrenal pheochromocytoma that was operated on at age 26.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488

SupplementalData: N/A

Variant: p.L63P (c.188T>C)

LegacyVariant: L63P (c.401T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2227, https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as L63P (c.401T>C), legacy nomenclature (AF010238.1), and was mapped to p.Leu63Pro (c.188T>C) in accordance with reference sequence NM_000551.3.

MutationType: missense_variant;transition

CivicName: L63P (c.188T>C)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: Bilateral involvements of RCC. 'Other' phenotypes found in patient. These are noted in the paper to include: pancreatic neuroendocrine tumors (PNETs), renal and pancreatic cysts and central nervous system tumors, although it is not clearly stated that patient 1 has all. (See Table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163P (c.488T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 2231 https://www.ncbi.nlm.nih.gov/clinvar/variation/2231/

CAID: CA020423 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.488T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L163P (c.488T>C)

MultipleGeneVariants: N/A