A 50-yr-old male (II.1) presenting with hemangioblastomas of the central nervous system was found to have a hemizygous VHL c.241 C→T (p.Pro81Ser) variant and a concomitant large deletion encompassing all exons of the VHL gene. The screening of his relatives confirmed that the p.Pro81Ser has been inherited from his healthy father (I.1), whereas the large deletion occurred de novo. The proband’s son (III.1) inherited his father’s germline VHL large deletion, and not the VHL p. Pro81Ser variant. In addition, the son (III.1) was found to have a hemizygous VHL c.340 + 5 G→C (IVS1 + 5) polymorphic variant, present on the allele inherited from his healthy mother (II.2). The son (III.1) was, therefore, clinically screened and found to have retinal and cerebellar hemangioblastomas as well as pancreatic cysts, typical lesions of VHL demonstrating that VHL cosegregated with, and is therefore caused by, the VHL large deletion and not the p.Pro81Ser variant.These case reports were, therefore, instrumental in raising two issues. First, could the long-presumed pathogenic RET and VHL mutations actually be harmless polymorphisms? Second, if the RET and VHL variants are pathogenic, then how commonly do patients with heritable PGL harbor two or more pathogenic mutations in the same or different genes?
PatientID: II.1
KindredID: 3
Case: M, 50Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: He inherited the p.Pro81Ser mutation from his healthy father (I.1) and the other mutation occured de novo. The patient had a son (III.1) who inherited his germline VHL large deletion, but not the VHL p. Pro81Ser variant. The son also had another VHL mutation which he inherited from his healthy mother (II.2). The son presented with retinal and cerebellar hemangioblastomas as well as pancreatic cysts. Refer to figure 1, pedigree C for family information.
CohortInfo: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.
CasePresentingHPOs: HP:0010797, HP:0001737 (hemangioblastoma, pancreatic cysts)
CaseHPOFreeText: Presented with hemangioblastoma at age 50.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: RET/SDHB/SDHD/SDHC
PreviouslyPublished: May have been previously published in 11106358 and/or 7563486.
SupplementalData: Yes, File 1 for methods.
Variant: p.P81S(c.241C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/
CAID: N/A
gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T
VariantEvidence: The patient was hemizygous for this mutation.
MutationType: missense_variant;transition
CivicName: Exon 1-3 Deletion and P81S (c.241C>T)
MultipleGeneVariants: Germline, VHL, Exon 1-3 deletion