PatientID: N/A

KindredID: 13

Case: F, Age Unknown, Indian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had Unilateral PH (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 45Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient had VHL disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 28388566

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 13

Case: F, Age Unknown, Indian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had Unilateral PH (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 45Y female.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: Variant reported as c.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient had VHL disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 28388566

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

KindredID: 17

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 17. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.76delF (c.227_229delTTC)

LegacyVariant: p.147delF (c.437_439del3)

CaseProblemVariantFreeText: c.224_226 automaps to NM_000551.3:c.227_229delTCT (updated; verified)

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

gnomAD: N/A

VariantEvidence:N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

KindredID: 17

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 17. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.76delF (c.227_229delTTC)

LegacyVariant: p.147delF (c.437_439del3)

CaseProblemVariantFreeText: c.224_226 automaps to NM_000551.3:c.227_229delTCT (updated; verified)

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del

gnomAD: N/A

VariantEvidence:N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTCT)

MultipleGeneVariants: N/A

VHL germline mutation carriers who had an ophthalmologic examination at the Erasmus Medical Centre or the Rotterdam Eye Hospital between 1984 and 2017, and were diagnosed with retinal hemangioblastoma (RH) were included in this study. A diagnosis of RH was based on the clinical appearance of a vasoproliferative retinal tumour. Peripheral blood samples from every member that had clinically suspected VHL disease of each family were collected for VHL mutation analysis. A total of 21 patients from 10 families were included on the basis of both a VHL germline mutation and ocular manifestations. Copy number analyses were carried out by multiplex ligation dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Mutations were described as one of the following two groups: truncating (complete deletion, partial deletion, nonsense mutation, splice site mutation, duplication and insertion) or missense. Ocular manifestations were not reported on an individual level, but rather were broken down based on the two groups. From Pedigree (family) 3, one individual was suspected of VHL disease and mutational analysis revealed an in-frame germline P76del(c.227_229del) deletion. This individual had RH development.

VHL germline mutation carriers who had an ophthalmologic examination at the Erasmus Medical Centre or the Rotterdam Eye Hospital between 1984 and 2017, and were diagnosed with retinal hemangioblastoma (RH) were included in this study. A diagnosis of RH was based on the clinical appearance of a vasoproliferative retinal tumour. Peripheral blood samples from every member that had clinically suspected VHL disease of each family were collected for VHL mutation analysis. A total of 21 patients from 10 families were included on the basis of both a VHL germline mutation and ocular manifestations. Copy number analyses were carried out by multiplex ligation dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH). Mutations were described as one of the following two groups: truncating (complete deletion, partial deletion, nonsense mutation, splice site mutation, duplication and insertion) or missense. Ocular manifestations were not reported on an individual level, but rather were broken down based on the two groups. From Pedigree (family) 3, one individual was suspected of VHL disease and mutational analysis revealed an in-frame germline P76del(c.227_229del) deletion. This individual had RH development.

PatientID: None

KindredID: 134

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 134

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488, 17024664

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F76del (c.440delTCT)

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTTC)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 134

Case: Age, sex ethnicity unknown

DiseaseAssertion: unknown; paper focused only on pheochromocytoma

FamilyInfo: No specific family info was present; although this was recorded as a family germline mutation belonging to Family ID 134

CasePresentingHPOs: N/A

CaseHPOFreeText: Unknown

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 32179488, 17024664

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F76del (c.440delTCT)

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229delTTC)

MultipleGeneVariants: N/A

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family were found to have the germline c.226_228del variant of the VHL gene. Member 4975 presented with moderate renal disease (RCC), members 4978, 4977 and 4976 presented with mild renal disease and member 5283 had unknown renal involvement. 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.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

Variant: p.F76del (c.226_228del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: F76del (c.226_228del)

MultipleGeneVariants: N/A

GroupID: 44

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family were found to have the germline c.226_228del variant of the VHL gene. Member 4975 presented with moderate renal disease (RCC), members 4978, 4977 and 4976 presented with mild renal disease and member 5283 had unknown renal involvement. 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.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

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

Variant: p.F76del (c.226_228del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: F76del (c.226_228del)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 2 VHL type 1 family of 8 and of 7 individuals (family ID 2956; 2693), using PCR and SSCP sequencing. The mutation of c.226_228delTTC was referred to in the paper by c.439delTTC due to a difference in transcript sequence. In the first, Family 2956, 2/8 members had a retinal angioma (hemangioma), 4 had RCC, and 5 members had CNS hemangioblastoma. In Family 2693 3/7 members had a retinal angioma (hemangioma), 3 had RCC, and 3 members had CNS hemangioblastoma. This is possibly previously published in PMID 9829911, as well as one member in a future publication: PMID: 32179488

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 2 VHL type 1 family of 8 and of 7 individuals (family ID 2956; 2693), using PCR and SSCP sequencing. The mutation of c.226_228delTTC was referred to in the paper by c.439delTTC due to a difference in transcript sequence. In the first, Family 2956, 2/8 members had a retinal angioma (hemangioma), 4 had RCC, and 5 members had CNS hemangioblastoma. In Family 2693 3/7 members had a retinal angioma (hemangioma), 3 had RCC, and 3 members had CNS hemangioblastoma. This is possibly previously published in PMID 9829911, as well as one member in a future publication: PMID: 32179488

Germline mutations were found in 20 Brazilian VHL probands and their families. The F76del (c.226_228del) germline mutation was found in a VHL type 1 family of 5 affected individuals (VHL family 1). Of the 5 affected family members four patients had hemangioblastomas of the central nervous system and 2 had renal carcinoma. In family 1 genetic testing was performed in a non-symptomatic boy, since no relatives were alive for testing. Although many members of this family had already presented with HB, the diagnosis of VHL was confirmed after necropsy of the proband’s father, who died at 37 years from complications following emergency surgery for cerebellar HB. The necropsy showed many occult lesions related to VHL, including RC, multiple pancreatic and renal cysts, and cystadenoma of the epididymis. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

Germline mutations were found in 20 Brazilian VHL probands and their families. The F76del (c.226_228del) germline mutation was found in a VHL type 1 family of 5 affected individuals (VHL family 1). Of the 5 affected family members four patients had hemangioblastomas of the central nervous system and 2 had renal carcinoma. In family 1 genetic testing was performed in a non-symptomatic boy, since no relatives were alive for testing. Although many members of this family had already presented with HB, the diagnosis of VHL was confirmed after necropsy of the proband’s father, who died at 37 years from complications following emergency surgery for cerebellar HB. The necropsy showed many occult lesions related to VHL, including RC, multiple pancreatic and renal cysts, and cystadenoma of the epididymis. This variant was not found in 120 alleles from normal subjects in the Brazilian population.