PatientID: 2

KindredID: 2

Case: M, 40Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: N/A - family history was unremarkable. The paper states however that this patient inherited the duplication from a nonsymptomatic parent. Two siblings of patient 2, aged over 40 and also carriers of the same variant, underwent a thorough clinical evaluation, which was judged as negative.

CasePresentingHPOs: HP:0006880; HP:0011798 (cerebellar hemangioblastoma, renal oncocytoma)

CaseHPOFreeText: a 40-year-old male affected by cerebellar hemangioblastoma and renal oncocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 21463266

SupplementalData: N/A

Variant: c.–65_–55dup11

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 517152 https://www.ncbi.nlm.nih.gov/clinvar/variation/517152/

CAID: N/A

gnomAD: 0.00009581 https://gnomad.broadinstitute.org/variant/3-10183466-C-CTCCGCCCCGCG

VariantEvidence: Quantitative Southern blot/real-time quantitative PCR analyses was normal in this patient. The 11 bp duplication is located within the promoter region of the VHL gene, in the vicinity of the main transcription initiation site, and within the binding site of several transcription factors. There is a possibility that the variant could alter transcription of the gene from the affected allele.

MutationType: 5_prime_UTR_variant

CivicName: c.–65_–55dup11

MultipleGeneVariants: N/A

KindredID:71

GroupID: 10

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.71 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is present in this kindred.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: This study investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. No other information about disease presentation within members of a kindred could be inferred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C77Lfs*55 (c.228dup)

LegacyVariant: c.441insC (p.147fs)

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795177, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.228_229insC

gnomAD: N/A

VariantEvidence:

MutationType: plus_1_frameshift_variant; duplication

CivicName: C77Lfs*55(c.228dup)

MultipleGeneVariants: N/A

GroupID: 2

DiseaseAssertion: cerebellar hemangioblastoma

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.162_163insT) was found in 1 VHL family with 2 patients.

GroupPresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

GroupHPOFreeText: both patients had cerebellar hemangioblastomas with a mean age of diagnosis of 19Y

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.E55* (c.162_163insT)

CaseProblemVariantFreeText: The mutation was written as follows: AFO10238:375_376insT; NM_000551.2:c.162_163insT; p.54MetX. Author Maher was contacted and confirmed "A single nucleotide insertion (T) was detected at position 375 (375insT)” from 2000 lab report - June 1, 2021 - therefore assume p. was transcribed incorrectly.

LegacyVariant: p.54MetX (c.375_376insT)

ClinVarID: N/A

CAID: CA2499307063 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307063

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: E55* (c.162_163insT)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 3

Case: F, 53Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Sister was thought to be sporadic (non familial) in 2001 with a spinal T7 tumor - genetic testing in this paper describes her (the sister, case 3) without any mutations.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53. She had a germline point and 2 somatic point mutations found in the DNA of her CHB. These mutations are discussed further in PMID: 24335534

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24335534 (pt. HGB-25)

SupplementalData: Supplemental Digital Content 1. Primer Sequences for VHL gene amplification, LOH and methylation analysis.

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: P25L(c.74C>T) and D126Rfs*6(c.375_376insA) and E55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.375insA (p.Asp126Argfs), Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: HGB-25

KindredID: 6

Case: Sex Unknown, 61Y0M, Italian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CohortInfo: The patient cohort consisted of 57 patients (26 male and 31 female) from Southern Italy, most of whom (55 of 57) presented with solitary HGB of the CNS: 6 were syndromic and 51 were apparently sporadic.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: The patient had a single cerebellar hemangioblastoma that was diagnosed at age 53.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29941223

SupplementalData: N/A

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID:428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/?new_evidence=false

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:minus_1_frameshift_variant

CivicName:CivicName:P25L(c.74C>T)andD126Rfs*6(c.375_376insA)andE55Rfs(c.163delG)

MultipleGeneVariants: Somatic, VHL, c.375insA (Asn131Ter) Germline, VHL, c.74C>T (p.Pro25Leu)

GroupID/ KindredID: 3682NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3682NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma. Additionally, this family ID is stated again in Table 3 under the mutation c.226T>A. Unclear if this is a typo, or if multiple mutations belong to this one family.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151

SupplementalData: N/A

Variant: p.E55Rfs*12 (c.163delG)

LegacyVariant: (c.376delG)

CaseProblemVariantFreeText: N/A

ClinVarID: 428800 https://www.ncbi.nlm.nih.gov/clinvar/variation/428800/

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: minus_1_frameshift_variant

CivicName: E55fs (c.163delG)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1 (A)

Case: M, 15Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Both parents were healthy with no display of any mutations in the VHL gene, indicating a de novo mutation.

CasePresentingHPOs: HP:0006770; HP:0009711 (clear cell renal cell carcinoma, retinal capillary hemangioma)

CaseHPOFreeText: Patient developed bilateral retinal angioma (retinal capillary hemangioma) and had serious retinal detachment.

CaseNotHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: MRI of the craniospinal axis could not detect any alterations. No deviation from normal values was observed in the laboratory test.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E55* (c.163G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: CA351748495 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.163G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: E55* (c.163G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Hereditary PNET with a confirmed germline mutation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E55Gfs*77 (c.163_164insG)

LegacyVariant: N/A

CaseProblemVariantFreeText: c.163_164insG automapped to NM_000551.3:c.163dupG

ClinVarID: 223159 https://www.ncbi.nlm.nih.gov/clinvar/variation/223159/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: E55fs (c.163dupG)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: 55Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: Positive -- Their father and brother both had the same germline mutation. Their father was screened after genetic testing and found to have a left RCC with lung metastasis at age 80, and their brother was asymptomatic.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma first presenting at 55Y

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: II-2

KindredID: 1

Case: F, 58Y0M, Turkish

DiseaseAssertion: VHL

FamilyInfo: 17 family members from three generations were examined with the c.445G>T mutation and diagnosed with VHL type 2B. 11 individuals had clinical manifestations and 6 were asymptomatic carriers. This patient’s 3 siblings had the mutation, 2 of her sons, and 3 grandchildren, and more. See Fig. 1 for detailed family pedigree.

CasePresentingHPOs: HP: 0006748; HP:0005584; HP:0001737; HP:0030405 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic cysts, pancreatic endocrine tumor)

CaseHPOFreeText: Right adrenal nonfunctional pheochromocytoma; right renal cell carcinoma; Pancreatic serous cystadenoma (with a 7.3 cm tumor at 55Y), and this patient was reoperated 3 years later due to a pancreatic neuroendocrine tumor.

CaseNotHPOs: HP:0030393; HP:0009715 (endolymphatic sac tumor, papillary cystadenoma of the epididymis) 

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A149S (c.445G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 127829 https://www.ncbi.nlm.nih.gov/clinvar/variation/127829/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: A149S (c.445G>T)

MultipleGeneVariants: N/A