PatientID: 1

KindredID: 1

Case: M, 36Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: CohortInfo: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Patient 1 presented with one peripheral tumor in the left eye and one peripheral tumor in the right eye with great exudation. Ophthalmologist wrote in his clinical history “no new lesions/no active lesions” during the visits he attended from January 2015 until December 2015. Moreover, his retinal exudation decreased during the months of treatment with the administration of propranolol.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Information obtained from Table 2.

Variant: c.463+2A>C

LegacyVariant: N/A

CaseProblemVariantFreeText: Amino acid does not coincide with position, declared by the authors. Variant c.463+2A>C could be translated to c.463+2T>C or c.463+3A>C. Needs to be confirmed with the authors.

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.463+2A>C

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 27 was not recorded with a documented VHL mutation. In the paper it is recorded as “?”. The proband is a Chinese male with multiple CNS hemangioblastomas and pancreatic cysts. His mother had multiple retinal angiomas, but also no recorded VHL mutation. No further information was given.

At age 9, a male caucasian patient was admitted with hypertension and tachicardia. His history included café-au-lait spots since birth, four months of night sweats and three weeks of fevers, bifrontal headaches and fatigue. An MRI scan showed a 3cm left adrenal mass and an MIBG showed increased activity in the left adrenal gland. One month later the patient underwent a successfull adrenalectomy. Four years post-surgery, the patient presented with bitemporal headaches, fatigue and low-grade fevers but both MRI and MIGB are inconclusive. One year later, symptoms worsened, MRI results were negative. At 18Y he later relapsed with another adrenal pheochromocytoma which was resected. DNA analysis showed a germline mutation Val84Leu in VHL. This mutation could correspond to either c.250G>C or c.250G>T. Neither of the parents carried mutations of the VHL gene. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 4

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009713; HP:0009711; HP:0006880; HP:0005584 (Spinal hemangioblastoma; Retinal capillary hemangioma; Cerebellar hemangioblastoma; Renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: c.463+2A>C

LegacyVariant: N/A

CaseProblemVariantFreeText: This splice mutation (reported as c.463+2A>C) is not possible as a T is located at c.463+2, not an A. No confirmation from authors was provided for this error.

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: WM03

KindredID: 9

Case: Sex Unknown, 3Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: Unspecified Exon 1 mutation

LegacyVariant: Unspecified Exon 1 mutation - no other information given

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: WM06

KindredID: 12

Case: Sex Unknown, 10Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: N/A - Unspecified

LegacyVariant: Given as an unspecified germline mutation

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: M, 26Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: N/A; Null (large rearrangement)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 32Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No family history: Father and brother were tested and no VHL mutation was found; Her mother died at the age of 51 years of a lung carcinoma, prior to any genetic testing. Therefore impossible to confirm de novo.

CasePresentingHPOs: HP:0002666; HP:0008256 (pheochromocytoma; adrenocortical adenoma)

CaseHPOFreeText: presented a right adrenal mass at sonography performed for gallbladder’s stones. An abdominal computed tomography (CT) confirmed the presence of a solid hypodense lesion of the right adrenal gland, 3 × 2·5 cm in size

CaseNotHPOs: N/A

CaseNotHPOFreeText: Ophthalmoscopy as well as brain, thoracic and abdominal Nuclear Magnetic Resonance (NMR) did not show any of the typically VHL associated lesions (retinal or CNS angiomas; endolymphatic sac tumours; pancreatic or renal cysts; renal carcinoma; cystoadenoma of the broad ligament).

CasePreviousTesting: RET/ SDHB/ SDHC/ SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: unknown - see CaseProblemVariantFreeText

LegacyVariant: N/A

CaseProblemVariantFreeText: Paper states: p.L198V (c.594C>G). The base at cDNA position 561 is actually a ‘G’. Could be c.592C>G as this gives a p.L198V change, however cannot justify this assumption with the evidence given, and authors were not able to confirm.

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant

CivicName: None

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 20 was found with an intron mutation in the VHL gene (paper reported as IVS1-38C>T which was converted to recommended HGVS notation): both members had CNS hemangioblastomas and retinal capillary hemangioblastomas.

This intron variant (IVS1-38 C>T) is unknown. The entered coordinates do not agree with the intron/exon boundaries for the selected transcript; The base at c.340 not "C". Authors were contacted and could not confirm.

An international consortium of registered patients with head and neck paragangliomas with VHL or RET gene mutations were analyzed. Eleven of the 12 patients were found to carry germline mutations in theVHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The 26 year old female proband was found to harbour the p.Ser139fs mutation of the VHL gene. She had a family history of VHL and presented with lumbar pain. CT showed a right adrenal pheochromocytoma that was removed. Two years later, she had left nephrectomy for multiple renal cell carcinoma. At age 33, she presented with a lateral cervical mass associated with Horner’s syndrome and pain in the right ear. CT showed a 6cm carotid paraganglioma that was removed and histologically confirmed. At age 42, a cerebellar hemangioblastoma was removed. As the publication only provides the p., the mutation p.Ser139fs was not able to be matched to the exact mutation.

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This mutation was found in 2 Croatian, VHL type 1 family members (family VHL 26). Both have hemangioblastomas of the central nervous system, one has renal cysts, and one with pancreatic cysts.

The authors report this as an AF010238.1:c.443insTCT mutation at codon 77 (insertion Ser). This does not match the associating c. and p. - NM_000551.3:c.230_231insTCT matches Cys77_Asn78insLeu., while c.231_232insTCT (p.Cys77_Asn78insSer) would give the ins Ser the authors write, however this doesn’t match the p.. Without confirmation from authors no assumption could be made.