PatientID: III-9

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. See family pedigree (Fig. 1).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000541; HP:0002542; HP:0001737; HP:0000107; HP:0030405; HP:0001272; HP:0007366; HP:0010873; HP:0001251; HP:0001260; HP:0001310 (hemangioblastoma, Retinal capillar hemangioma, Retinal detachment, Olivopontocerebellar atrophy, Pancreatic cysts, Renal cyst, Pancreatic endocrine tumor, Cerebellar atrophy, Atrophy/Degeneration affecting the brainstem, Cervical spinal cord atrophy, Ataxia, Dysarthria, Dysmetria)

CaseHPOFreeText: diagnosed with VHL in her early teenage years. She had retinal involvement beginning at the age of 13 treated by cryotherapy and laser therapy (presumably for retinal angiomas); and retinal detachment at the age of 23 requiring eye surgery. She had cysts of the pancreas and kidney detected at 22 years. She has also carried the diagnosis of OPCA since the age of 26-28 (new onset slurred speech and illegible handwriting). Patient had multiple renal cysts without renal tumours, however a large infiltrative enhancing mass in the tail of the pancreas was suggestive of a neuroendocrine/islet cell carcinoma, and liver metastatic foci

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: SCA2 (an abnormal increase in CAG repeats in one allele of her ataxin-2 gene. This abnormal trinucleotide expansion is consistent with the diagnosis of spinocerebellar ataxia type 2)

PatientID: 136

KindredID: 51

Case: M, 25Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 136) has a mother (patient 137) who presented with a CNS hemangioblastoma at 32, and renal cell carcinoma/ pheochromocytoma at 38. However, no DNA sample was available for his mother's genetic testing.

CasePresentingHPOs: HP:0010797, HP:0001737, HP:0001732, HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The proband (patient 136) presented with multiple pancreatic cysts/tumors at 21, renal cell carcinoma at 23, and a CNS hemangioblastoma at 25.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: p.P146Gfs*14 (c.435_436ins)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131810, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131810

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: P146Gfs*14 (c.435_436insGG)

MultipleGeneVariants: N/A

PatientID: 288

KindredID: 113

Case: M, 24Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 288) presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 23, and a retinal angioma at 24. Their sister (patient 289) presented with a CNS hemangioblastoma, retinal angioma, and renal cell carcinoma at 30.

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0009711 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband (patient 288) presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 23, and a retinal angioma at 24.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 24Y0M, Brazilian

DiseaseAssertion: VHL

FamilyInfo: VHL type 1 family. No family history of VHL disease. Parents were not available for testing. However, this paper reports that this proband belongs to a different family from that reported by Rocha et al. (PMID: 12624160) as Family 1, with 5 individuals.

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001737 (hemangioblastoma; renal cysts; pancreatic cysts)

CaseHPOFreeText: hemangioblastoma diagnosed at 23Y; and renal and pancreatic cysts at 24Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 12624160; 32179488

SupplementalData: Yes

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: N/A

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT due to redundancy

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.226_228delTTC)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: M, 33Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Genetic analysis of the patient's parents and brothers, who were unaffected, confirmed a diagnosis of de novo VHL disease.

CasePresentingHPOs: HP:0030424, HP:0009711, HP:0005584, HP:0006770, HP:0001737, HP:0000107 (epididymal cyst, retinal capillary hemangioma, renal cell carcinoma, clear cell renal cell carcinoma, pancreatic cysts, renal cyst)

CaseHPOFreeText: He was admitted to the hospital with a two-month history of progressive right flank pain, accompanied by a one-month history of recurrent painless gross hematuria. The patient's previous medical history included urological surgery at the age of 23 years due to an epididymal cyst and an ophthalmologic surgery at 26 years of age for retinal detachment resulting from bilateral retinal angiomatosis. Contrast-enhanced computed tomography (CT) scanning and angiography were used to detect the presence of quasi-circular enhancing lesions in the middle of the left kidney and large irregular enhancing lesions in the right kidney, extending into the vena cava, that formed an embolus. In addition, multiple cysts in the pancreas and kidney were detected radiologically. The patient underwent a radical nephrectomy with an embolectomy of the right kidney for treatment of T3b-stage renal cell carcinoma. After three months, he successfully underwent laparoscopic nephron-sparing surgery (NSS) of the left kidney. Histological analysis of the renal tissue revealed clear cell carcinomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W(c.194C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S65W(c.194C>G)

MultipleGeneVariants: N/A