PatientID: 21 (tumour 36)

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Two other members of this patient's family (patient 19 and patient 20) were found to harbour the same VHL gene mutation.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

GroupID/KindredID: 5959

DiseaseAssertion:VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: These two patients were from the same family (5959) and both had the same VHL gene mutations.

GroupPresentingHPOs: HP:0002666; HP:0009711; HP:0030405 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic endocrine tumor)

GroupHPOFreeText: One patient in this family had a pheochromocytoma and cysts (type of cyst was not specified). Both patients had retinal angioma. It is unclear how many of the patients had pancreatic endocrine tumors.

GroupNotHPOs: HP:0005584; HP:0010797 (Renal cell carcinoma, Hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: c.775C>G

ClinVarID: 2225, https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/3-10191569-C-G?dataset=gnomad_r2_1

VariantEvidence: Variant reported as 775, C to G (Leu to Val), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.562C>G, p.Leu188Val (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

GroupID/ KindredID: 91CA

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, with an unknown number of members belonging to Family ID 91CA. 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.L158V (c.472C>G)

LegacyVariant: p.L158V (c.685C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

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; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F35

Case: Sex unknown, 21Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found with pancreatic tumors

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

CaseHPOFreeText: Age of onset is 21Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158V (c.472C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

PatientID: II-4

KindredID: 3

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including II-4, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this assumption

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: IV-2

KindredID: 3

Case: M, Age Unknown, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: The transition mutation was found and confirmed in this patient, his great-aunt, and his first-cousin once removed. 5 additional members had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation. His mother, two uncles, and grandfather are all individuals with hemangioblastomas who have passed away.

CasePresentingHPOs: N/A

CaseHPOFreeText: Stated as carrier, however he is young (likely before the age of onset)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G)

LegacyVariant: p.L116V (c.559C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: 3

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including II-1, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 1

Case: F, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: This patient and her unaffected spouse (patient 1) had four children; one died and was affected, two (patient 5 and 7) had both mutations and presented with pheochromocytoma, and one child (patient 6) was unaffected and carried neither mutation. Patient 7 had a child (patient 9) who also carried both mutations and presented with pheochromocytoma. Furthermore, this patient's brother (patient 3) carried both mutations and presented with pheochromocytoma. He had a child with patient (4) who was unaffected. Their child (patient 8) carried both mutations and presented with pheochromocytoma. Patient 8 had two children; one that did not carry the mutation and was unaffected (patient 10) and another that carried both mutations but was disease free (patient 11). See Figure 3 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8772572, 7563486

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P81S (c.241C>T) and L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

PatientID: N/A

KindredID: 1

Case: M, 3Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Family history was remarkable for a renal tumor in the paternal grandmother at age 65, treated by nephrectomy in 1998. Furthermore, a maternal uncle had a history of thyroid cancer, and a maternal cousin had a history of breast cancer. The patient’s parents and a 13-year-old half-brother were healthy.

CasePresentingHPOs:HP:0005584, HP:0000790 ( renal cell carcinoma, hematuria)

CaseHPOFreeText: Computed tomographic scan showed a right renal mass. The tumor was impinging on the renal sinus and extended to the renal capsule. The patient underwent a right nephrectomy. In addition, one of five hilar lymph nodes was positive for metastatic disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p. L188V (c.562C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: t(X;1)(p11.2; p34.3)

GroupID: 69

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 2 individuals from a single family (ID 69).

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

GroupHPOFreeText: Pheochromocytoma (1/2), CNS hemangioblastoma (2/2), pancreatic cyst or tumor (unspecified) (2/2) and renal cell carcinoma (1/2).

GroupNotHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158V (c.472C>G)

LegacyVariant: c.685C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 567944, https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4410

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129_V130insGlu (c.386_387insAGA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.200insE (c.599insAGA)

ClinVarID: N/A

CAID: CA16602182 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.386_387insAGA

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: L129Q (c.386insAGA)

MultipleGeneVariants: N/A

GroupID: 20B

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: Unknown. Patient was pulled from either the VHL-Registry or NET- Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: HP:0030405 (pancreatic endocrine tumor)

CasePreviousTesting: Patient was negatively tested for islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158V (c.472C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

GroupID: 66

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 3 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.346C>G) was found in 1 VHL family with 3 patients.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 3 patients had retinal capillary hemangioma (RH), with a mean age of diagnosis of 43Y (RH).

GroupNotHPOs: HP:0002666; HP:0006880; HP:0005584 (pheochromocytoma; cerebellar hemangioblastoma; renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.L116V (c.346C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351753642 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: II,4

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient had significant family history. His mother refused genetic testing but presented with bilateral pohechromocytoma. His father was found to have the same VHL mutation. One of his siblings (patient II,3) was unaffected, while another (patient II,2) was found to have the mutation and presented with bilateral pheochromocytoma. His sibling (patient II,1) passed during childbirth with symptoms and signs of a hypertensive crisis with the autopsy showing a left adrenal and extraadrenal pheochromocytoma. However, cause of death was a cerebral hemorrhage. His half sister (patient II,5) also had the same VHL mutation and presented with bilateral pheochromocytoma. Refer to figure 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: bilateral pheochromocytoma

CaseNotHPOs: HP:0006737 (Extraadrenal pheochromocytoma)

CaseNotHPOFreeText: Absence of extraadrenal pheochromocytoma. Absence of thyroid disease at age 24.

CasePreviousTesting: RET

PreviouslyPublished: 7563486, 12414898

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L259V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 37CE, 38CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to two family IDs: Family 37CE and 38CE. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as multiple 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.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

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

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

PatientID: III-2

KindredID: 3

Case: F, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including III-2, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: III-3

KindredID: 3

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including III-3, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: III-1

KindredID: 3

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including III-1, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: III-7

KindredID: 3

Case: F, Age Unknown, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: The transition mutation was found and confirmed in this patient’s mother (II-3) and 2 carriers, her, and her first-cousin once removed (III-7, IV-2). 5 additional members had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: Stated as carrier, however she is young (likely before the age of onset)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G)

LegacyVariant: p.L116V (c.559C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: A

Case: M, 61Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive: the patient’s sister also presented with the germline c.562C>G mutation, and metastatic lobular breast carcinoma. In a family pedigree, 10 additional members affected with cancer were displayed. This included both of their parents: father with lung cancer, mother with skin cancer, additional sister with breast cancer, brother with melanoma. Lastly, his two sons presented with skin cancer, however no description of their genotyping. See Fig. 3.

CasePresentingHPOs: HP:0006770; HP:0001028 (Clear cell renal cell carcinoma, hemangioma)

CaseHPOFreeText: He presented in 2012 (52Y) with worsening lower abdominal discomfort (CT scan revealed a right renal solid mass of renal cell carcinoma). A right renal nephrectomy was done, confirming ccRCC. 4 years later, new lung nodules and an enhancing lesion in the L1 vertebral body was found (metastatic ccRCC). Additionally, in 2020, a pancreatic lesion present on his scans was presumed to be a metastatic RCC lesion (consistent with an atypical hemangioma).

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, retinal capillary hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX/NF1/RET/SDHA/SHDB/SHDC/SDHD/SDHAF2/TMEM127 [133 genes evaluated by germline testing - Invitae]

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.L188V (c.562C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: In 2013, somatic next generation sequencing (NGS) testing using a panel of 447 cancer genes (OncoPanel, BWH Pathology, MA, USA) was performed on the resected renal specimen. This revealed the following variants: VHL p.Leu188Val (c.562C>G), CHEK2 p.Val395Leu (c.1183G>C), VHL p.Ala149Thr (c.445G>A) variant, and several copy number losses including a large single-copy deletion in 3p. 6 years later, germline testing revealed a heterozygous germline VHL p.Leu188Val variant, a CHEK2 and ERCC4 mutation.

ClinVarID: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: N/A

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Somatic, VHL, c.445G>A (p.Ala149Thr)

GroupID: None

DiseaseAssertion: VHL

GroupSize: 9

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: Nine individuals from 2 different families initially diagnosed with MEN-IIA were investigated. All were found to have the same (c.562C>G) missense mutation in the VHL gene.

GroupPresentingHPOs: HP:0002666; HP:0006737; HP:0002865; HP:0011781 (pheochromocytoma, extra adrenal pheochromocytoma, medullary thyroid carcinoma, thyroid C cell hyperplasia)

GroupHPOFreeText: All 9 patients had pheochromocytoma, 2 of the 9 patients (unspecified) also had thyroid C-cell tumors, 1 (unspecified) had medullary thyroid carcinoma, and 1 (unspecified) had C-cell hyperplasia. 3 of the 9 patients (unspecified) also developed extra-adrenal pheochromocytoma.

GroupNotHPOs: HP:0000843; HP:0009711; HP:0010797; HP:0000107; HP:0001737 (Hyperparathyroidism, retinal capillary hemangioma, hemangioblastoma, renal cysts, pancreatic cysts.

GroupNotHPOFreeText: None of the patients had any clinical signs of renal cancer. Two patients (unspecified) were screened for retinal, CNS, and abdominal lesions; neither had occult VHL lesions.

GroupPreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: c.775C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 2225, https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/3-10191569-C-G?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 1

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: The patient's father (patient 1) was unaffected and did not carry the mutation. The patient's mother (patient 2) presented with pheochromocytoma and carried the mutation. The patient had three siblings; one died and was affected, another (patient 5) had both mutations and presented with pheochromocytoma, and the third (patient 6) was unaffected and carried neither mutation. This patient (patient 7) had a child (patient 9) who also carried both mutations and presented with pheochromocytoma. The patient's uncle (patient 3) carried the mutation and was affected. He had a child with patient (4) who was unaffected. Their child (patient 8) carried both mutations and presented with pheochromocytoma. Patient 8 had two children; one that did not carry the mutation and was unaffected (patient 10) and another that carried both mutations but was disease free (patient 11). See Figure 3 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8772572, 7563486

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P81S (c.241C>T) and L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Pro81Ser)

PatientID: 43

KindredID: 5959

Case: F, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with four pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 2225 https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.241C>T (p.Prp81Ser)