GroupID/ KindredID: 4325NCI, 25CA

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 databas, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 4325NCI and 25CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL families 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.S65W (c.194C>G)

LegacyVariant: p.S65W (c.407C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65W (c.194C>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

GroupID/ KindredID: 28BMS

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 Bristol Myers Squibb database, with an unknown number of members belonging to family ID: Family 28BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.464-2A>G)

LegacyVariant: Splice (c.677-2A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: splice_site_variant

CivicName: Splice Site (c.464-2A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 41F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 41F. 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.Y156* (c.468T>G)

LegacyVariant: p.Y156* (c.681T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756053 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.468T>G

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: Y156* (c.468T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 9YO, 51CE, 4327NCI, 160CA

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 Department of Uroglogy, Yokohama database, the Munich, university of Freiburg and Institute of Pathology database, the National Cancer Institute database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 9YO, 51CE, 4327NCI, 160CA. 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.N78S (c.233A>G)

LegacyVariant: p.N78S (c.446A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 53CE

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 Family ID 53CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

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.V74G (c.221T>G)

LegacyVariant: p.V74G (c.434T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 53CE

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 Family ID 53CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

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.V74G (c.221T>G)

LegacyVariant: p.V74G (c.434T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>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: VHL 31

Case: Sex unknown, Age unknown, Italian

DiseaseAssertion: assumed VHL

FamilyInfo: One patient with the given mutation is stated to belong to VHL family 31 - this was said to be not inherited from either parent, indicating a de novo germline mutation.

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-2A>G

CaseProblemVariantFreeText: N/A

LegacyVariant: c.677-2A>G

ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-2A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 13

Case: Sex unknown, Age unknown, German

DiseaseAssertion: assumed VHL

FamilyInfo: One patient with the given mutation is stated to belong to VHL family 13

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0000107; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161G (c.481C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161G (c.694C>G)

ClinVarID: 618484 https://www.ncbi.nlm.nih.gov/clinvar/variation/618484

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R161G (c.481C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 51

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 6 patients with the given mutation belonging to VHL family 51

GroupPresentingHPOs: HP:0010797; HP:0009715 (hemangioblastoma, Papillary cystadenoma of the epididymis)

GroupHPOFreeText: CNS hemangioblastomas found in all 6 members of this cohort, and epididimal cystadenomas found in 4 members.

GroupNotHPOs: GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 2

DiseaseAssertion: hemangioblastoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 out of the 81 patients listed in this hemangioblastoma cohort were found with this c.194C>G mutation. Any relation is unknown.

GroupPresentingHPOs: HP:0010797 (hemangioblastoma)

GroupHPOFreeText: all patients had hemangioblastoma of the CNS; other phenotypes are unknown

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

LegacyVariant: p.S65W (c.407C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

GroupID: 4414

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 7 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma)

GroupHPOFreeText: 2/7 members had retinal angiomas (hemangiomas), 3 had CNS hemangioblastomas, 1 had RCC and 1 had pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151 (type 2 4414NCI)

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F190L (c.570C>G)

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

GroupID: 4325

DiseaseAssertion: assumed VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 4 family members recorded with this mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma, retinal capillary hemangioma)

GroupHPOFreeText: 1 of the 4 (1/4) patients were recorded with a hemangioblastoma; 3/4 with retinal angiomas

GroupNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, renal cell carcinoma)

GroupNotHPOFreeText: None of the patients were recorded to have RCC or pheos

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S65W (c.407C>G)

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s aunt died of a cerebellar tumor of unknown pathology at 30Y. The patient’s father presented with giant pheochromocytoma at age 46, meningothelial meningioma and capillary hemangioblastoma at age 66, and died from cerebral infarctions and RCC at age 69.

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L158V(c.472C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 66Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s elder sister died of a cerebellar tumor of unknown pathology at 30Y. As well, the patient’s son presented with cerebellar hemangioblastoma and was diagnosed with VHL disease.

CasePresentingHPOs: HP:0002666; HP:0006880; HP:0100009; HP:0005584 (Pheochromocytoma, cerebellar hemangioblastoma, intracranial meningioma, renal cell carcinoma)

CaseHPOFreeText: The 66Y male patient presented with mild dementia, and was found to have multiple tumours in the cerebellum; the tumours were resected, and histological examination determined that the tumours included meningothelial meningioma and a capillary hemangioblastoma. The patient was also found to have renal cell carcinoma, and underwent nephrectomy. The patient had also previously undergone resection for a giant pheochromocytoma associated with malignant hypertension 20 years prior at 46Y. The patient died of multiple cerebral infarctions and RCC three years after the surgery to remove the cerebellar tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L158V(c.472C>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: 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

GroupID: 20A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

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

GroupID: 19A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

GroupID: 10B

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

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation were grouped as group 10(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

GroupID: 10A

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

PatientID: 4 (proband)

KindredID: 4

Case: F, 46Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history with her brother having a monolateral benign pheochromocytoma

CasePresentingHPOs: HP:0002666; HP:0002861; HP:0000107 (pheochromocytoma; melaonoma; renal cyst)

CaseHPOFreeText: Bilateral pheochromocytoma at the age of 46Y with a local reccurance a few years later. She also presented with liver metastases from the pheochromocytoma, as well as melanoma and bilateral renal cysts

CaseNotHPOs: (HP:0006880; HP0009713; HP:0009711)

CaseNotHPOFreeText: She had no cerebellar or spinal hemangiostaomasm nor retinal alterations

CasePreviousTesting: RET/SDHB/SDHC/SDHD/EGLN3

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+43A>G

LegacyVariant: IVS1+43A>G

CaseProblemVariantFreeText: N/A

ClinVarID: 1244574 https://www.ncbi.nlm.nih.gov/clinvar/variation/1244574/

CAID: N/A

gnomAD: 0.01186 https://gnomad.broadinstitute.org/variant/3-10188363-A-G

VariantEvidence: this intronic sequence variant may have a role in VHLd because it was also detected in this study in a case of sporadic pheochromocytoma. However, this variant’s large allele frequency means this is likely non disease causing (not deleterious; polymorphism).

MutationType: splice_site_variant; intron_variant

CivicName: c.463+43A>G

MultipleGeneVariants: Germline, RET, c.2071G>A (p.Gly691Ser); Germline, SDHD, c.34G>A (p.Gly12Ser); SDHD, (IVS2-29A>G); SDHD c.204C>T (p.Ser68Ser); SDHD (IVS3-32T>C)

PatientID: 12

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1 describes 19 patients with missense mutations, including this patient.

Variant: p.H115R(c.344A>G)

LegacyVariant: c.557A>G

CaseProblemVariantFreeText: N/A

ClinVarID: 664415, https://www.ncbi.nlm.nih.gov/clinvar/variation/664415/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: H115R (c.344A>G)

MultipleGeneVariants: N/A

GroupID: 87

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor the c.466T>G germline variant of the VHL gene. Member 4587 presented with severe renal disease (RCC). Members 4588 and 5177 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:0005584 (Renal cell carcinoma)

GroupHPOFreeText: 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).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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.

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

Variant: p.Y156D (c.466T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756043, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.466T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y156D (c.466T>G)

MultipleGeneVariants: N/A

PatientID: IV-14

GroupID/ KindredID: 6

Case: 46Y0M, F, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0001732; HP:0005584; HP:0002666; HP:0009711 (abnormality of the pancreas, Renal cell carcinoma, pheochromocytoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: II-4

GroupID/ KindredID: 6

Case: Age unknown (deceased), M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0001732; HP:0002666 (retinal capillary hemangioma, abnormality of the pancreas, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: No VHL gene test was conducted but due to substantial family pedigree history, can assumed with confidence this mutation

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 6

DiseaseAssertion: assumed VHL; asymptomatic

GroupSize: 22

GroupNumberMales: 14

GroupNumberFemales: 8

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 22 family members were recorded in this group with the given mutation. 18 had VHL manifestations while 4 were asymptomatic carriers. See individual-case info by following GroupID/KindredID: 6

GroupPresentingHPOs: HP:0005584; HP:0010797; HP:0009711; HP:0001732; HP:0002666 (Renal cell carcinoma, hemangioblastoma, retinal capillary hemangioma, abnormality of the pancreas, pheochromocytoma)

GroupHPOFreeText: 12 family members had renal cell carcinoma, 10 had CNS hemangioblastomas, 5 had retinal hemangiomas, 7 had an abnormality of the pancreas (either cysts or a tumor), and 1 had a pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: IV-13

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, Renal cell carcinoma,abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: IV-13

GroupID/ KindredID: 6

Case: Age unknown, M, Chinese

DiseaseAssertion: asymptomatic

FamilyInfo: Positive - 22 family members were recorded with the given mutation. 18 had VHL manifestations while 4, including this patient, are asymptomatic carriers. See pedigree (Fig 3.), or follow GroupID/KindredID: 6

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0002666; HP:0009711; HP:0005584; HP:0001732 (hemangioblastoma, pheochromocytoma, retinal capillary hemangioma, Renal cell carcinoma,abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: Named a carrier as positively tested without symptoms

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 29b

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: N/A

CaseHPOFreeText: This was 1 of 4 patients discussed with this mutation. The individual did NOT have retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.R107G (c.319C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

GroupID: 8

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 a splice c.464-2A>G mutation. 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: c.464-2A>G

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: spice site (c.464-2A>G)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 10

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F119L (c.570C>G)

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: M, 48Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's son also had this mutation, and presented with a CNS hemangioblastoma at age 22. The proband's mother presented with a CNS hemangioblastoma at age 61, and his brother presented with a CNS hemangioblastoma at age 33. His mother passed away before diagnosis, and there was no DNA sample available for his brother.

CasePresentingHPOs: HP:0005584; HP:0001732; HP:0001737 (Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts)

CaseHPOFreeText: The proband presented with renal cell carcinoma and pancreatic cysts at the age of 48.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal Capillary Hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597, https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 3

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: No family information was provided for this patient. A total of 291 patients from 115 different families were included for analysis. VHL mutation confirmation was verified in at least one patient of each family.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0001732 (Hemangioblastoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 34. At age 37, they presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0009711; HP:0002666; (Retinal Capillary Hemangioma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.S65W (c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597, https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID:

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 115

KindredID: 42

Case: M, 12Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 42) had four family members confirmed with the mutation: his son (CNS hemangioblastoma at 12, retinal angioma at 11); his sister 1 (patient 116) presented with multiple pancreatic cysts/tumors at 53; his niece (daughter of sister 2) was asymptomatic at the time of assessment, and his nephew (son of brother 2) presented with a CNS hemangioblastoma at 12, and pheochromocytoma and multiple pancreatic cysts/tumors at 18. The proband also had three family members who passed away before diagnosis/ before they could be confirmed with the mutation: his sister 2 (patient 117) had multiple pancreatic cysts/tumors at 46, his brother 1 presented with a CNS hemangioblastoma at 47, renal cell carcinoma at 59, and multiple pancreatic cysts/tumors at 59; and his brother 2 presented with a retinal capillary hemangioma at 43, and CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 44.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 36, multiple pancreatic cysts and/or tumors at 40, and retinal angioma and renal cell carcinoma at 44.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732; HP:0005584 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.W117G (c.349T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346; https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W117G (c.349T>G)

MultipleGeneVariants: N/A

GroupID: 4577

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Each group represents a family.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Pheochromocytoma, Renal cell carcinoma)

GroupHPOFreeText: 2/3 members with pheochromocytoma, 1/3 members with CNS hemangioblastoma, 1/3 members with retinal angioma and 1/3 members with RCC. Diagnosed as a VHL Type 2B family.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

LegacyVariant: c.570C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 625240, https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 570, C to G (Phe to Leu), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.357C>G, p.Phe119Leu (NM_000551.3).

MutationType: missense_variant;transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 3Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother aged 38 was diagnosed with bilateral pheochromocytoma resected when she was the age of 18 years. She presented several relapses, the most recent one at the age of 32, when she was also diagnosed with cerebral angioma. Genetic testing revealed the presence of the VHL c 244 C>G (p. Arg 82 Gly) heterozygote mutation, while the tests for RET, SDHB, SDHC and SDHD were negative.

CasePresentingHPOs: HP:0001954; HP:0000980; HP:0001649; HP:0000822; HP:0002666; HP:0006748 (Recurrent fever, Pallor, Tachycardia, Hypertension, Pheochromocytoma, Adrenal pheochromocytoma)

CaseHPOFreeText: Several months history of febrile episodes, sweating and irritability. An abdominal ultrasound performed in a pediatric hospital revealed a right adrenal tumor mass. The clinical examination of our patient revealed: pallor, paroxysmal febrile episodes with irritability and sweating, tachycardia, hypertension. There was no palpable abdominal mass. Abdominal ultrasound showed a tumor of the right adrenal gland. MRI showed a right adrenal tumor confirmed by pathology to be a malignant pheochromocytoma. After 6 months from the complete resection of the tumor, the daughter is without any clinical symptoms, with normal blood pressure, normal ophthalmoscopy, no tumor markers and no evidence of tumor on cerebral or abdominal MRI.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82G (c.244C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1297059, https://www.ncbi.nlm.nih.gov/clinvar/variation/1297059/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82G (c.244C>G)

MultipleGeneVariants: N/A

GroupID: None

KindredID: 17

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: 10 members of a South American family expressed this c.183C>G mutation.

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

GroupHPOFreeText: All 10 family members had a central nervous system hemangioblastoma. One also had a retinal angioma. Five had renal carcinoma. One patient per family with renal tumour <3 cm under follow up detected by imaging.

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: P61= (183C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 135951 https://www.ncbi.nlm.nih.gov/clinvar/variation/135951/

CAID: N/A

gnomAD: 0.0009632 https://gnomad.broadinstitute.org/variant/3-10183714-C-G

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL, Partial Deletion

GroupID: None

KindredID:9

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed/Latino

GroupAgeRange: N/A

GroupInfo: Three members of a South American family expressed this c.344delA mutation.

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

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.H115Pfs*44 (c.344delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:N/A

CAID: CA70049370 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.344delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115Pfs*44(c.344delA) and P61=(c.183C>G)

MultipleGeneVariants: Germline, VHL,c.c.183C>G (p.Pro61Pro)

GroupID: None

KindredID: 17

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: 10 members of a South American family expressed this mutation.

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

GroupHPOFreeText: All 10 family members had a central nervous system hemangioblastoma. One also had a retinal angioma. Five had renal carcinoma. One patient per family with renal tumour <3 cm under follow up detected by imaging.

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: Deletion

CivicName: Partial Deletion and P61=( c.183C>G)

MultipleGeneVariants: Germline, VHL, c.183C>G (Pro61Pro)

GroupID: 5

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 2 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

GroupHPOFreeText: CNS hemangioblastoma (2/2 affected members).

GroupNotHPOs: HP:0002894; HP:0009711; HP:0002666; HP:0005584; HP:0009726 (Neoplasm of the pancreas, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, Renal neoplasm)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L101R (c.302T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751004, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.302T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L101R (c.302T>G)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: M, 10Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: (See figure 3E for pedigree). The proband (Patient 5's) mother had left adrenal pheochromocytomas, and his grandmother had bilateral adrenal pheochromocytomas.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Proband presented with bilateral adrenal pheochromocytoma

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98C (c.293A>G)

LegacyVariant: N/A

CaseProblemVariant Free Text: N/A

ClinVar: 223176, https://www.ncbi.nlm.nih.gov/clinvar/variation/223176/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: Y98C (c.293A>G)

MultipleGeneVariants: N/A

PatientID: 1 (case)

KindredID: 1

Case: F, 70Y0M, Ethnicity Unknown

DiseaseAssertion: NF1

FamilyInfo: Her son bearing the clinical characteristics of NF 1 died at the age of 17Y from an undefined malignancy. The patient has another son, 40 years old, who is clinically well.

CasePresentingHPOs: HP:0002666; HP:0000843; HP:0002865 (pheochromocytoma; hyperparathyroidism; medullary thyroid cancer)

CaseHPOFreeText: diagnosed with an isolated pheochromocytoma of the right adrenal gland underwent adrenalectomy) at 20Y. Further diagnosed with hyperparathyroidism and medullary thyroid cancer, having the full spectrum of the clinical picture of the MEN2A syndrome. Patient was diagnosed with NF1 at 20Y with multiple café–au-lait spots on her back and lower limbs were identified. She also had multiple dermal neurofibromas on the abdomen and lower limbs. Her medical history included diabetes mellitus type II, as well as hypertension.

CaseNotHPOs: N/A

CaseNotHPOFreeText: MRI of the brain was performed at 20Y, which did not reveal any brain neurofibromas.

CasePreviousTesting: NF1, RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P192R (c.575C>G)

LegacyVariant: p.P192R (c.788C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 825946 https://www.ncbi.nlm.nih.gov/clinvar/variation/825946/

CAID: N/A

gnomAD: N/A

VariantEvidence: According to in silico analysis and clinical history of the patient, VHL was more likely a rare polymorphic variant of the population of patient’s origin, rather than a disease causing mutation.

MutationType: missense_variant;transversion

CivicName: P192R (c.575C>G)

MultipleGeneVariants: Germline, NF1, c.3516_3517delTC, p.D1172Dfs*21

PatientID: 9

KindredID: 8

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.TF136C (c.407G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496065, https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

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.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988, https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: R79G (c.235C>G)

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The two patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W(c.194C>G)

GroupProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID:43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID:N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 4

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This is the proband. 3 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: hemangioblastoma, parathyroid nodule, and esophageal carcinoma but the presenting patient is unclear. Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 25 years later but it is unclear if this pertained to all affected family members. Pheochromocytoma diagnosed at age 20. VHL type 2C.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: Unknown

KindredID: 2

Case: Sex Unknown, 53Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This is the proband. 5 members of this family were found to have the mutation and pheochromocytoma. Other declared diseases in this family are: paraganglioma, hemangioblastoma, lung metastases and spinal hemangioblastoma but the presenting patient is unclear.Relationship between these family members is unclear.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Follow-up 18 years later but it is unclear if this pertained to all affected family members.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: M, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666; HP:0000107 (Pheochromocytoma, Renal cyst)

CaseHPOFreeText: Unilateral pheochromocytoma diagnosed at age 34.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: II:5

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: VH3

KindredID: F2

Case: F, 18Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history of pheo (type 2 VHL) - Her asymptomatic sibling however was tested and did not carry the mutation nor had large deletion.

CasePresentingHPOs: HP:0002666; HP:0030405 (pheochromocytoma; pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24735130

SupplementalData: N/A

Variant: c.463+3A>G

LegacyVariant: IVS2+3A>G

CaseProblemVariantFreeText: N/A

ClinVarID: 428796 https://www.ncbi.nlm.nih.gov/clinvar/variation/428796/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Region (c.463+3A>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 6Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history revealed VHL in the father and grandfather. Molecular genetic analysis confirmed familial VHL by detecting a mutation of the VHL gene in the patient, her father, and her sister. Magnetic resonance imaging revealed spinal hemangioblastomas and kidney cysts in the father, but not in the patient.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: The patient had symptomatic juxtapapillary capillary retinal angioma with associated epiretinal membrane (ERM). Pars Plana Vitrectomy and removal of ERM resulted in substantial improvement of vision.

CaseNotHPOs: HP:0009713, HP:0000107( Spinal Hemangioblastoma, Renal Cyst)

CaseNotHPOFreeText: Magnetic resonance imaging revealed spinal hemangioblastomas and kidney cysts in the father, but not in the patient.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

LegacyVariant: (407C>G)

CaseProblemVariantFreeText: N/A

ClinVar: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020099

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Familial VHL

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

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.S65W (c.194C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: 152

KindredID: 152

Case: Sex Unknown, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0009711, HP:0001737, HP:0000107 (retinal capillary hemangioma, pancreatic cyst, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0010797, HP:0006770 (pheochromocytoma, hemangioblastoma, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: p.N78S(c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

PatientID: 55

KindredID: 55

Case: Sex Unknown, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Variant was transmitted from a parent (both parents were analyzed) but it is unclear which parent was positive for the variant.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000107; HP:0006770; HP:0010797; HP:0001732; HP:0009711 (Renal cyst, Clear cell renal cell carcinoma, Hemangioblastoma, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.P103A (c.307C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219823, https://www.ncbi.nlm.nih.gov/clinvar/variation/219823/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P103A (c.307C>G)

MultipleGeneVariants: N/A

PatientID: 78

KindredID: 78

Case: Sex Unknown, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0001732 (Abnormality of the pancreas)

CaseHPOFreeText: Pancreatic cysts or tumors.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0010797; HP:0009711; HP:0000107 (Clear cell renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Retinal capillary hemangioma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.C162W (c.486C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: 45

KindredID: 45

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0001737, HP:0010797 ( pancreatic cysts, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0006770, HP:0009711, HP:0000107 (pheochromocytoma, clear cell renal cell carcinoma, retinal capillary hemangioma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: p.N78S(c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA020131 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.233A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

PatientID: 53

KindredID: 53

Case: Sex Unknown, 37Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0001732; HP:0010797; HP:0000107 (Clear cell renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: 105

KindredID: 105

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0001732 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, renal cystic lesion and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666 (Clear cell renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.P86A (c.256C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P86A (c.256C>G)

MultipleGeneVariants: N/A

PatientID: 105

KindredID: 105

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0001732 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, renal cystic lesion and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666 (Clear cell renal cell carcinoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.P86A (c.256C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93327, https://www.ncbi.nlm.nih.gov/clinvar/variation/93327/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P86A (c.256C>G)

MultipleGeneVariants: N/A

PatientID: V95

KindredID: V95

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G104= (c.312C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420538, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.312C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; synonymous_variant

CivicName: G104= (c.312C>G)

MultipleGeneVariants: N/A

PatientID: V265

KindredID: V265

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43600, https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y156C (c.467A>G)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 1

Case: F, 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 7) had both mutations and presented with pheochromocytoma, and the third (patient 6) was unaffected and carried neither mutation. 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.P81S (c.241C>T)

LegacyVariant: P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVar: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: CA020148 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.241C%3ET

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: Germline, VHL, c.562C>G (p.Leu188Val)

PatientID: 11

KindredID: 1

Case: M, Age Unknown, German

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (patient 8) was had both mutations and presented with pheochromocytoma. The patient's brother (patient 10) did not carry the mutation and was unaffected. The patient's maternal grandfather (patient 3) presented with pheochromocytoma and carried both mutations. The patient's materal grandmother (patient 4) was unaffected and did not carry either mutation. The patient's great aunt (patient 2) presented with pheochromocytoma and had both mutations. Her husband (patient 1) was unaffected and did not carry either mutation. They had four children; one died and presented with pheochromocytoma, 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. See Figure 3 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVar: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: CA020148 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.241C%3ET

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

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

MultipleGeneVariants: Germline, VHL, c.562C>G (p.Leu188Val)

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: Case

KindredID: 1

Case: M, 9Y5M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient has a large family history of VHL disease (4 generations). 12 other members are reported in Fig 1. as having VHLd although their genotyping is not availably discussed. Only the proband’s mother was said to have the disease and the Exon 3 deletion, passing away due to complications of a hemangioblastoma in the CNS.

CasePresentingHPOs: HP:0030424 (Epididymal cyst)

CaseHPOFreeText: This is a pediatric patient with both familial erythrocytosis type 2 and VHL disease. First diagnosed with polyglobulia (polycythemia) at 8Y. A physical examination showed a tumor in the right testicle (cyst in the right epididymis)

CaseNotHPOs: N/A

CaseNotHPOFreeText: Several studies were conducted, such as venous blood gas, lung VQ scan, echocardiogram, cardiac catheterization, bone marrow aspirate, bone biopsy, respiratory function analysis, and ocular fundus study, all of which were reported as normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S139C (c.416C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 135956 https://www.ncbi.nlm.nih.gov/clinvar/variation/135956/

CAID: N/A

gnomAD: 0.00008130 https://gnomad.broadinstitute.org/variant/3-10188273-C-G

VariantEvidence: This is a case of a compound heterozygote patient with von Hippel-Lindau disease and familial erythrocytosis type 2. c.416C>G (p.Ser139Cys) and deletion of exon 3 of the VHL gene coexist in the same individual. This should explain the polyglobulia found in the case.

MutationType: missense_variant; transversion

CivicName: Exon 3 deletion AND S139C (c.416C>G)

MultipleGeneVariants: Germline, VHL, exon 3 deletion

PatientID: proband (F1-II-1)

KindredID: 1

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This proband had a 5-year-old asymptomatic son who carried the same mutation. The proband's brother (F1-II-3) was a 30 year-old who presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts. Histopathological analysis revealed right renal cell carcinoma with hemorrhagic cyst

CasePresentingHPOs: HP:0002666, HP:0005584, HP:0009715 (pheochromocytoma, renal cell carcinoma, Papillary cystadenoma of the epididymis)

CaseHPOFreeText: Ultrasound (US) and magnetic resonance imaging (MRI) scans confirmed single masses, multiple tumors and multiple cysts in the right adrenal glands, bilateral kidney and pancreas, respectively. Right pheochromocytoma and multiple right renal cell carcinomas were confirmed by histopathological examination. In 2012, the patient was diagnosed with bilateral epididymal head multiple nodules. Bilateral epididymal tubercle resection was performed and epididymal papillary adenoma was confirmed by histopathological examination.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: N/A

ClinVar: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: CA020131

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>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)

Case#: Family D proband, female, 2 months and 5 days old (age of diagnosis), 14 months old (age of onset), 10 years old (age at report), Tunisia.

DiseaseAssertion: MPS1-H

FamilyInfo: No affected family members (See Fig. 1), parents were 1st degree relatives (first cousins) (See Table 1).

CasePresentingHPOs: HP:0002094, HP:0001605, HP:0001999, HP:0004322 (Dyspnea, laryngeal paralysis, abnormal facial shape, short stature)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity (0.1 nmol/h/mg) (usual values: 1-5).

CaseUrineGAGs: glycosaminoglycans (97 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1743C>G (p.Y581X)

Variant1ClinVarID: 550883

Variant1CAID: N/A

Variant2: c.1743C>G (p.Y581X)

Variant2ClinVarID: 550883

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID:

Gene: OPA1

Disease: hereditary optic neuropathy

980 patients in this study with suspected hereditary optic neuropathies were evaluated by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes. 295 had variants in OPA1; however the exact count for this variant was not provided and neither was any additional phenotypic information.

Case#: Family AU-1, 35yo, female, Austrian

DiseaseAssertion: DOA+

FamilyInfo: positive family history, 2 relatives in table 1

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0000590, HP:0001138

CaseHPOFreeText:

CaseNotHPOs: HP:0003198

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing

Variant: c.1635C>G (p.S545R) aka c.1800C>G (p.S600R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

This case has been added to the VCI and assessed already.

PreviouslyPublished: PMID: 18158317

This family has been added to the VCI and assessed separately.

PreviouslyPublished: PMID:18065439

Case#: Family FR-1, 30yo, male, French

DiseaseAssertion: DOA+

FamilyInfo: positive family history, but no information provided

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0003198, HP:0001138

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing

Variant: c.1635C>G (p.S545R) aka c.1800C>G (p.S600R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Cultured patient fibroblasts showed disappearance of filamentous mitochondria in favor of fragmented and punctuated mitochondria and a 20% decrease of mitochondrial content in fibroblasts.

PatientID: None

KindredID: 1

Case: F, 20Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother had died of pulmonary edema during pregnancy at the age of 40.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with decreased vision in the right eye with a 4-month evolution. The patient’s vital signs were within normal limits, and no abnormalities were noticed upon physical and neurological examination. Similarly, her past medical history was unremarkable. Upon ophthalmoscopic examination, a red-colored globular lesion of 3 disk diameters with prominent feeder vessels was noticed in the superior temporal region of the retina. A structural OCT B-scan showed a diffuse cystoid macular edema, which involved the posterior pole and expanded outside the vascular arcades. The other eye was normal.

CaseNotHPOs: HP:0012443; HP:0011732 (Abnormality of brain morphology, abnormality of renal morphology)

CaseNotHPOFreeText: Results of renal ultrasonography and magnetic resonance imaging of the brain were both negative for visceral lesions.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112C (c.335A>G)

LegacyVariant: N/A

ClinVarID: 223189, https://www.ncbi.nlm.nih.gov/clinvar/variation/223189/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112C(c.335A>G)

MultipleGeneVariants: N/A