PatientID: 138 (Second cousin)

KindredID: 18

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis of retinal angioma is unknown.

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0010797 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: p.R167W (c.499C>T)

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 386

Case: M, 11Y0M, Polish

DiseaseAssertion: Pheochromocytoma

FamilyInfo: One of the patient’s brothers carried the mutation and presented with unilateral pheochromocytoma at 15Y. The patient’s mother also carried the mutation and presented with bilateral pheochromocytoma at 41Y.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W(c.499C>T)

LegacyVariant: p.R238W(c.712C>T)

ClinVarID: 2218, http://www.ncbi.nlm.nih.gov/clinvar/variation/2218

gnomAD: 3:10191506 C / T, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W(c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 2

Case: M, 11Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0030405 (Pheochromocytoma; pancreatic neuroendocrine tumor)

CaseHPOFreeText: Benign bilateral pheochromocytoma and PNET at age 11

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: A

Case: M, 11Y0M, Welsh

DiseaseAssertion: Pheochromocytoma

FamilyInfo: The patient had a sister that presented with bilateral pheochromocytoma at 17Y. The patient also had an asymptomatic parent.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with bilateral pheochromocytoma at 11Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L(c.250G>T)

LegacyVariant: p.V155L(c.463G>T)

CaseProblemVariantFreeText: bandshift in exon 1 and genomic sequencing indicated a G>T transversion at nucleotide 463, substituting a valine for leucine at codon 155 (V155L). Leading to NM_000551.3:p.V84L(c.250G>T)

ClinVarID: 2236, http://www.ncbi.nlm.nih.gov/clinvar/variation/2236

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V84L(c.250G>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: Sex Unknown, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: HP:0002666; HP:0009711 (pheochromocytoma; retinal capillary hemangioma)

CaseHPOFreeText: 11Y at first pheochromocytoma and ocular angioma (retinal capillary hemangioma). Total of 4 ocular angiomas.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: 15Y0M, F, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: The patient has no family history of VHL disease. Genetic testing reveals no mutation in patient's parents indicating that the mutation in patient is sporadic. This was further said to have occurred de novo.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: bilateral pheochromocytoma diagnosed at age 11 years. She was said to have single-organ involvement and did not fulfill diagnostic criteria of VHL. 

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

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.V166A (c.497T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43605 https://www.ncbi.nlm.nih.gov/clinvar/variation/43605/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V166A (c.497T>C)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A - not stated

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: A pheochromocytoma (PCC) diagnosed first at 11Y was found, with follow up of a 15 year duration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.340+682T>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 964770 https://www.ncbi.nlm.nih.gov/clinvar/variation/964770

CAID: N/A

gnomAD: N/A

VariantEvidence: Tumor analysis was performed since there was a paraffin embedded sample. Patient 10 did not have loss of heterozygosity, but was found to have a somatic variant in the exon 3 of VHL (c.482G>A; p.Arg161Gln). This was the only patient observed to have a cluster of tumor cells with a positive membranous CA9 immunostaining, this can be seen in VHL-related PPGL. CA9 is a protein reported to influence regulation cell proliferation and tumor progression and is known to be expressed at the membrane of tumour cells in the case of VHL inactivation can be seen in VHL-related PPGL. Subsequently as expected, the PPGL of patient 10 had a significantly low expression of VHL E1-E1' mRNA VHL and PNMT mRNA compared to VHL-tumours used as controls. This suggests that the two VHL variants change the VHL mRNA splicing.

MutationType: splice_site_variant

CivicName: Splice Site (c.340+682T>C); intron_variant

MultipleGeneVariants: Somatic, VHL, c.482G>A (p.Arg161Gln)

PatientID: 28

KindredID: 18

Case: M, 11Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Relevant family history but details are not made available.

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

CasePresentingHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma)

CaseHPOFreeText: Bilateral pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 128 (Second cousin)

KindredID: 18

Case: M, 52Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis for retinal angioma is unknown.

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0010797 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 11Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs:HP:0002666; HP:0009711 (Pheochromocytoma; retinal capillary hemangioma)

CaseHPOFreeText: Benign bilateral pheochromocytoma and retinal angioma at age 11

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A