In family 4, the proband was a female who had a bilateral pheochromocytoma at the age of 46 years that recurred locally with liver metastases a few years later. Her brother had a monolateral benign pheochromocytoma. The proband also had a melanoma and bilateral renal cysts. A VHL sequence variant IVS2 +43 A>G was found in this case and also in one other unrelated sporadic pheochromocytoma. Their VHL mRNA integrity is currently being assessed. The proband had no cerebellar or spinal NMR finding or retinal alterations. Molecular analysis showed the following sequence variants: VHL IVS2 +43 A>G, RET c.2071 G>A p.G691S, SDHD c.34 G>A p.G12S, IVS2-29 A>G, c.204 C>T p.S68S, and IVS3-32 T>C.
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)