GroupID/ KindredID: F2

Case: Sex unknown, 26Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: None. Microsatellite analysis excluded nonpaternity for this patient, leading to the assumption that this variant was de novo in character. (assumed de novo without confirmation of maternity).

CasePresentingHPOs: HP:0006880; HP:0001737 (cerebellar hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: cerebellar hemangioblastoma had multiple lesions. Age of onset is 26Y0M.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 8Y0M, Ethnicity Unknown

DiseaseAssertion: endolymphatic sac tumor (ELST)

FamilyInfo: N/A

CasePresentingHPOs: HP:0030393 (endolymphatic sac tumor)

CaseHPOFreeText: ELST that occurred in the left temporal bone who presented with profound sensorineural hearing loss, intermittent vertigo. A CT demonstrated a destructive mass involving the posterior aspect of the left petrous temporal bone centered midway between the internal auditory canal and the sigmoid sinus. Bony erosion extends into the posterior semicircular canal, and there are areas of stippling and central calcification within the mass suggestive of an aggressive, erosive process

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V130L (c.388G>C)

LegacyVariant: c.601G>C mutation in the vHL gene on chromosome 3

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: None

KindredID: 7

Case: Unknown, 31Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0002666 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, pheochromocytoma)

CaseHPOFreeText:The patient presented with hemangioblastoma and pheochromocytoma at age 30. One year later he was found to have renal cell carcinoma and pancreatic cysts or tumors.

CaseNotHPOs: HP:0009711(retinal capillary hemangioma)

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229 https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. One male patient was found with this germline mutation from family #45. He was diagnosed with CNS hemangioblastoma at 30Y. One male patient was found with this germline mutation from family #46. He was diagnosed with CNS hemangioblastoma at 30Y, RCC at 31Y, pheochromocytoma at 30Y, and multiple pancreatic lesions at 30Y. No other family information was published for these two patients. Both kindreds were also likely published in a paper by Wang et al., 2018 (PMID: 29330336). Kindred #46 was also previously published in Wang et al., 2014 (PMID: 24581539). Wang et al., 2018 reported 4 patients from 2 families (corresponding with kindred #45 and #46) who were genetically confirmed with this germline mutation. Wang et al., 2014 reported one patient who was genetically confirmed with this germline mutation likely corresponding with family #46.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The V130L (c.388G>C) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V91). No unaffected family members were tested.

A case study revealed an 8Y boy, presenting with a profound sensorineural hearing loss and intermittent vertigo. He was found to have an endolymphatic sac tumor, discovered by high-resolution computed tomographic imaging. Genetic analysis revealed a missense VHL mutation c.388G>C (originally written in paper as legacy notation AF010238.1, c.601G>C). Family history was not described.

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation p.V130L (c.388G>C) was found in 3 VHL patients. 2 members were said to have retinal hemangioblastomas, while the other member was said not to have this phenotype. Other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

This paper shows the imaging result of an endolymphatic sac tumor found in the left temporal bone of an 8-year-old boy who presented with profound sensorineural hearing gloss, intermittent vertigo. VHL mutation analysis showed c.388G>C mutation (noted as G-to-C nucleotide 601 mutation in the paper).

GroupID: 91

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to harbor the c.388G>C germline variant of the VHL gene. Member 6200 had no renal involvement. Member 6410 presented with mild renal disease. Members 5838 and 5839 presented with moderate renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 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.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229, https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A