PatientID: None

KindredID: 2

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666, HP:0030405, HP:0011732 (pheochromocytoma, pancreatic endocrine tumour, Abnormality of adrenal morphology)

CaseHPOFreeText: The patient had three tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: The patient had a mosaic mutation with a mutated allele frequency of 5.7%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >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: VCB.14T

KindredID: 6

Case: Sex Unknown, 34Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma, pheochromocytoma)

CaseHPOFreeText: Presented with bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: 25545346 (see table S1 and S10)

SupplementalData: Yes

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: SDHA, Germline, c.619A>C (p.Arg207=); SDHA, Germline, c.1969G>A (p.Val657Ile); KIF1B, Germline, c.2192A>G (p.Asn777Ser); MDH2, Somatic, c.26C>T (p.Ala9Val)

PatientID: N/A

KindredID: 21

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Q195* (c.796C>T)

ClinVarID: 428794 https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: CA70052558 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.583C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

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 summariezed the phenotypes of the families together. Family 7 was found with p.Asn78Thr mutation in the VHL gene: 1/2 members had CNS hemangioblastoma and 2/2 has renal cell carcinoma. ACMG PP4

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.

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 23 was found with an exon 3 deletion of the VHL gene: 4/4 members had CNS hemangioblastoma and 1/4 had retinal capillary hemangioma. ACMG PVS1 PP4

PMID:29752349 Gene:VHL StandardizedReferenceSequence:NM_000551.3

PatientID: None

KindredID: 1

Case: F, 9Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: This patient had an older brother who at 7-years-old, presented with multiple retinal haemangiomas. At the age of 9, he underwent a left adrenalectomy for a phaeochromocytoma. At the age of 13, a 9 mm solid lesion consistent with a pNET. This patient also had a renal cell carcinoma. They also had a 12-year old younger brother who had a retinal hemangioma. The patients father was diagnosed with VHL at 31 years-old and had multiple cerebellar haemangioblastomas, retinal angiomas, a phaeochromocytoma, a ccRCC and a small pNET. Pedigree: See Figure 1.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0005584, HP:0009711, HP:0030405 (pheochromocytoma, renal cell carcinoma, Retinal capillary hemangioma, Pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Arg120* (c.358A>T)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351753732 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351753732

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R120*(c.358A>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 51Y0M, Arab

DiseaseAssertion: VHL

FamilyInfo: Patient 2 (the patient’s brother) presented with the same mutation and was diagnosed with VHL at age 45. The two brothers had very similar VHL clinical manifestations including cerebellar hemangioblastomas, renal cell carcinoma, and cysts in the pancreas. However, patient 1 had testicular and epididymal cysts, as well as lesions in the spine, which were absent in Patient 2. No other family history was noted. Immediate family members were recommended to genetically test for the relevant variant or monitor for VHL-related symptoms.

CasePresentingHPOs: HP:0005584; HP:0009713; HP:0006880; HP:0000107; HP:0001737; HP:0030424; HP:0033608; HP:0000541; HP:0012215 (renal cell carcinoma; spinal hemangioblastoma; cerebellar hemangioblastoma; renal cyst; pancreatic cysts; epididymal cyst; pulmonary nodule; retinal detachment; testicular microlithiasis)

CaseHPOFreeText: At 44Y, Patient 1 exhibited cerebellar and spinal hemangioblastomas, as well as retinal detachment. He also had renal cell carcinoma in both kidneys and multiple cysts in one kidney, testis, and pancreas. He also reported a history of headaches and vertigo, leading to a diagnosis of VHL disease type 1. At 49Y, multiple nodules were found in his lungs and a year later, a nodule in the testis and scrotal lithiasis were detected. At 51Y, renal cell carcinoma was identified in the left kidney and his left epididymis was enlarged. Patient continued to present with left testicular and scrotal lithiasis, right retinal detachment, and multiple nodules in both lungs. However, tMutation:Germlinehe lung phenotype was asymptomatic (see table 1).

CaseNotHPOs: HP:0001392; HP:0005264; HP:0001743 (abnormality of the liver; abnormality of the gallbladder; abnormality of the spleen)

CaseNotHPOFreeText: No lesions were observed in the liver, gallbladder, and spleen.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/Av

PatientID: 8

KindredID: 8

Case: M, 66Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 55 patients treated at Asan Medical Center in Korea treated between January 1995 and February 2013 clinically diagnosed with VHL disease and presenting with pancreatic lesions.

CasePresentingHPOs: HP:0001737, HP:0030405 (Pancreatic cysts, Pancreatic endocrine tumor)

CaseHPOFreeText: At age 56, the patient had a serous cystadenoma of the pancreas and a pancreatic endocrine tumour. A Pylorus-preserving pancreaticoduodenectomy was performed and the largest tumour resected was 40 mm. On follow up 170 months later the patient had no evidence of disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

Recently, Lenglet et al., 2018 identified a new VHL cryptic exon termed E1' deep in intron 1 that is naturally expressed in many tissues, and found E1' mutations in eight families with either erythrocytosis or VHL disease. The goal of this study was to determine the prevalence of E1' germline mutations from two cohorts, 221 patients with a single or multiple tumours, suggestive of VHL disease, and 946 patients with a Pheochromocytoma/paraganglioma (PPGL) but without an identified mutation in the three VHL exons or in the main PPGL susceptibility genes. They identified a rare germline genetic variant (maf <1%) in the E1’ VHL cryptic exon in 1% of patients (12/1167). Patient 1 was diagnosed at the age of 47 with follow up of a 5 year duration due to a Carotid body paraganglioma (PGL) and was found to have a germline c.340+563C>T E1' variant. Tumor analysis was performed for patient 1 since there was a paraffin embedded sample. Patient 1 did not have loss of heterozygosity, but the mutated allele was lost in the tumor. Immunostaining was negative for detection of CA9 expression. CA9 is a protein reported to influence regulation cell proliferation and tumor progression and is known to be expressed at the membrane of tumour cells in the case of VHL inactivation.

GroupID: 1

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.E46* (c.136G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351748085 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.136G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E46* (c.136G>T)

MultipleGeneVariants: N/A

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 synonymous mutation (p.P154= (c.462A>C)) was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided.

PatientID: II-2

KindredID: 1

Case: F, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromoyctoma

FamilyInfo: The patient’s brother (II-1) was found to harbor the same germline mutation the patient harbored and had bilateral adrenal pheochromocytoma at 14Y. The same germline missense mutation was detected in another sister (II-4) with right adrenal pheochromocytoma and her asymptomatic daughter (III-1). The father was not available for genetic testing because he had died, apparently secondary to a hypertensive crisis. The five other family members which underwent genetic testing did not have the mutation.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: At 10Y, the patient reported palpitations, weight loss, diaphoresis, and shooting pain attacks. Her urinary metanephrines were elevated to 12.2 mg/g creatinine. A CT of the abdomen revealed a mass in the left adrenal gland. Histology and immunohistochemistry confirmed diagnosis of left adrenal pheochromocytoma. Additional screening revealed no other tumours, so this fit the criteria of VHL type 2C.

CaseNotHPOs: HP:0002668; HP:0012090; HP:0012210 (Paraganglioma, abnormal pancreas morphology, abnormal renal morphology)

CaseNotHPOFreeText: There were no lesions in the pancreas or the kidney, there was also no suggestion that the paraganglia would also be involved. Her MRI of the brain, and her echocardiogram were both normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F(c.496G>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: PCR amplified VHL gene was analyzed by Sanger sequencing.

SamplingMethod: peripheral blood

KindredID: 1112

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0009711 (Pheochromocytoma, Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030405; HP:0005584 (Pancreatic endocrine tumor, Renal cell carcinoma)

CaseNotHPOFreeText: The patient had no cysts (type or location was not specified).

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161* (c.694C>T)

ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).

MutationType: stop_gained; missense_variant;transition

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: Analysis of the RET and VHL genes in patients was done using direct bidirectional DNA sequencing

SamplingMethod: peripheral blood

PatientID: 20

KindredID: 900

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0005584 (pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P95Rfs*64 (c.284delC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497030172 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497030172

gnomAD: N/A

VariantEvidence:N/A

MutationType: minus_1_frameshift_variant

CivicName: P95Rfs*64 (c.284del)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 31

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0005584; HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177_L178ins6 (c.531_532ins18)

LegacyVariant: N/A

CaseProblemVariantFreeText: Stated in the paper as: p.R177_L178ins6 (c.531_532ins18) - NM_000551.3:c.531_532ins18: char 24: Syntax error - due to it's non specific nomenclature. (Can't verify coordinates of specific insertion).

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: R177_L178ins6 (c.531_532ins18) 

MultipleGeneVariants: N/A

PatientID: 30

KindredID: 64

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584; HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: 276

KindredID: 107

Case: M, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 276, presented with a retinal angioma at age 31, and a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 37. The proband has a father who presented with a CNS hemangioblastoma at age 50.

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

CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at age 50.

CaseNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)

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 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 208

KindredID: 79

Case: M, 49Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister had a CNS hemangioblastoma at ages 40 and 50, respectively. His nephew presented with a CNS hemangioblastoma (age 15), a retinal angioma (age 27), and renal cell carcinoma (age 25). His daughter had a retinal angioma at age 14, and a CNS hemangioblastoma at age 24. No genetic testing information was available for family members.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0002666; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 29. At age 46, they presented with renal cell carcinoma and a pheochromocytoma. At age 49 they presented with multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0009711; (Retinal Capillary Hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Kindred #79 was published in Wang et al., 2014 (PMID: 24581539). 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: p.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 186

KindredID: 72

Case: F, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001732; HP:0001737; HP:0002666 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 37, and a pheochromocytoma at 39.

CaseNotHPOs: HP:0009711 (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.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: F, 20Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother had died of pulmonary edema during pregnancy at the age of 40.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with decreased vision in the right eye with a 4-month evolution. The patient’s vital signs were within normal limits, and no abnormalities were noticed upon physical and neurological examination. Similarly, her past medical history was unremarkable. Upon ophthalmoscopic examination, a red-colored globular lesion of 3 disk diameters with prominent feeder vessels was noticed in the superior temporal region of the retina. A structural OCT B-scan showed a diffuse cystoid macular edema, which involved the posterior pole and expanded outside the vascular arcades. The other eye was normal.

CaseNotHPOs: HP:0012443; HP:0011732 (Abnormality of brain morphology, abnormality of renal morphology)

CaseNotHPOFreeText: Results of renal ultrasonography and magnetic resonance imaging of the brain were both negative for visceral lesions.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112C (c.335A>G)

LegacyVariant: N/A

ClinVarID: 223189, https://www.ncbi.nlm.nih.gov/clinvar/variation/223189/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112C(c.335A>G)

MultipleGeneVariants: N/A

PatientID: 194

KindredID: 194

Case: Sex Unknown, 46Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0002666; HP:0000107 (Hemangioblastoma, Abnormality of the pancreas, Pheochromocytoma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor, pheochromocytoma and renal cystic lesion.

CaseNotHPOs: HP:0009711; HP:0006770 (Retinal capillary hemangioma, Clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.P59Rfs*8 (c.176del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432536374, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.176del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: P59fs (c.176delC)

MultipleGeneVariants: N/A

PatientID: 259

KindredID: 259

Case: Sex Unknown, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0001737, HP:0009711 (pancreatic cysts, retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs:HP:0002666, HP:0006770, HP:0000107, HP:0010797 (pheochromocytoma, clear cell renal cell carcinoma, renal cyst, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: p.R167Q(c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q(c.500G>A)

MultipleGeneVariants: N/A

PatientID: 80

KindredID: 80

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Parents were negative for the mutation. No phenotype details are noted for these family members.

CasePresentingHPOs: HP:0010797; HP:0000107 (Hemangioblastoma, Renal cyst)

CaseHPOFreeText: CNS hemangioblastoma and renal cystic lesion.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0001732; HP:0009711 (Pheochromocytoma, Clear cell renal cell carcinoma, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.N141Ifs*12 (c.422_440del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621933, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.422_440del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: N141fs (c.422_440del)

MultipleGeneVariants: N/A

PatientID: 78

KindredID: 78

Case: Sex Unknown, 29Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0001732 (Abnormality of the pancreas)

CaseHPOFreeText: Pancreatic cysts or tumors.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0010797; HP:0009711; HP:0000107 (Clear cell renal cell carcinoma, Pheochromocytoma, Hemangioblastoma, Retinal capillary hemangioma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.C162W (c.486C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

This paper presented a pheochromocytoma detected by autopsy. The index case was a 26-year-old male who presented to the emergency department complaining of obstipation, severe headache and abdominal pain. The family background of the parents and siblings history is unavailable since the patient was an orphan. An autopsy revealed bilateral pheochromocytoma and acute myocardial infarction. Molecular genetic analyses for germline mutations of the VHL gene were performed after DNA extraction from normal liver tissue using standard methods. A mutation in VHL gene R167W (c.499C>T) was detected.

PatientID: cousin 1

KindredID: B

Case: M, 35Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: Family history is positive. A total of 7 members were genetically tested for this mutation. 5 were asymptomatic and non-VHL (no mutation was found). This patient's cousin also had HB and the mutation was found in them.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 35Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145Tfs*29(c.431dup)

LegacyVariant: p.Q145Tfs*29 (c.645insG)

CaseProblemVariantFreeText: AF010238.1:c.645insG translates to an updates NM_000551.3:c.432_433insG; or c.431dupG

ClinVarID: N/A

CAID: CA2573106040 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573106040

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: Q145fs (c.431dup)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: N/A

SamplingMethod: N/A

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline frameshift deletion (c.210delG) mutation in the VHL gene. This variant was reported as c.423delG (AF010238.1) and mapped to p.E70Dfs*89 (c.210del) (NM_000551.3). It's unclear which other VHL-related lesions were identified in this patient.

GroupID: None (9)

DiseaseAssertion: VHL

GroupSize: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This family group of 1 individual has clinically confirmed VHL disease presenting with retinal angiomatosis. This individual was found to harbor a c.210del variant causing a Glu70Asp frameshift mutation (noted in the paper as c.423delG due to Latif reference transcript being used).

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal angiomatosis.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70Dfs*89 (c.210del)

LegacyVariant: c.423del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320434, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320434

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: E70Dfs*89 (c.210del)

MultipleGeneVariants: N/A

GroupID: 85

Case: 27Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.538A>G) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCCs diagnosed at 27Y

CaseNotHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma; cerebellar hemangioblastoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.I180V (c.538A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 161401 https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/

CAID: N/A

gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10191545-A-G

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation (c.562delC) was found in 2 family members with renal cell carcinomas, one with retinal angiomas (diagnosed at 25Y), and one with cerebellar hemangioblastoma (diagnosed at 24Y).

GroupID: 50

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family

GroupPresentingHPOs: HP:0005584; HP:0006880; HP:0009711 (renal cell carcinoma; cerebellar hemangioblastoma; retinal capillary hemangioma)

GroupHPOFreeText: 4 patients had retinal angiomas diagnosed at a mean age of 27Y, and 3 had cerebellar hemangioblastomas diagnosed at a mean age of 32Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R82_V84del (c.243_251delGCGCGTCGT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658820713 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.243_251del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: R82_V84del (c.243_251del)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation. c.182_185del was found in a VHL patient with retinal angiomas diagnosed at 31Y, and hemangioblastomas of the cerebellum at 30Y.

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A - Not specified

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: VHL syndromic HB

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: A VHL subject in our patient population had a full length deletion (FLD) in the germline VHL gene, but a VHL gene tumor second hit mutation (c.360-362 del AGA) causing an amino acid change of p.RD120-121S detected in the HB tumor

MutationType: deletion

CivicName: Deletion AND R120_121S (c.360_362delAGA)

MultipleGeneVariants: Somatic, VHL, c.360_362delAGA, p.Arg120_121Ser

ArticleReferenceSequence: Not specified - Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3.

GenotypingMethod: The three exons of the VHL gene (coding region of 852 nucleotides) were sequenced. PCR products were purified with the QiA quick PCR purification kit (Qiagen, Hilden, Germany), and the sequencing reactions were done using the ABI PRISM DYE Terminator sequencing kit (Perkin-Elmer Applied Biosystems Division, Foster City, CA), and were analysed on the ABI 373 A sequencer.

SamplingMethod: Peripheral blood

PMID: 23203444

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: III-1

KindredID: 1

Case: F, 26Y0M, Chinese

DiseaseAssertion: assumed VHL

FamilyInfo: 10 members of this Chinese family were tested, and 3 were found with the same genetic mutation (c.464T>A). The proband’s grandmother (I-1, 79Y), and father (II-1, 53Y) had hemangioblastomas, and tested positive for the mutation. This mutation was not found in the other unaffected members in the family.

CasePresentingHPOs: HP:0006880; HP:0030405; HP:0002666 (cerebellar hemangioblastoma, endolyphmatic sac tumor, pheochromocytoma)

CaseHPOFreeText: patient suffered with dizziness and headache and frequent vomiting since 25Y (CT and MRI identified occupying lesions and obstructive hydrocephalus in the cerebellar vermis). The cerebellar tumor nodes were removed surgically. Abdominal CT showed multiple lesions in the liver, pancreas and posterior peritoneum. The tumors in the proband’s pancreatic tail and retroperitoneal space also were removed subsequently. Histological analysis indicated the tumors to be pancreatic isletcell tumor and phaeochromocytoma, respectively.

CaseNotHPOs: N/A

CaseNotHPOFreeText: patient was negative in the bilateral Babinski’s sign test

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V155E (c.464T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756032 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V155E (c.464T>A)

MultipleGeneVariants: N/A

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

GroupID: 394

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor a germline large rearrangement of the VHL gene. Member 9248 presented with moderate renal disease (RCC). Member 9313 and 2222 presented with severe 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:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 12 individuals with this mutation are reported. It is unclear which of the previously reported individuals correspond to which of the currently reported families/individuals (i.e. families 40, 90, 174, 237, 264, 284, 307 or 394).

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: Rearrangement

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.K159delinsI* (c.475_476insTTT) germline variant of the VHL gene was detected in a family (ID 43). Member 3207 had no renal involvement. Members 3206 and 3203 presented with mild renal disease. Member 3189 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.N67_V74del (c.197_221del) germline variant of the VHL gene was detected in a family (ID 287). Member 6396 presented with mild renal disease. Member 6611 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 9829912, where 1 patient with this mutation is reported but relation to this patient is unclear. The variant is reported as c.197_220del which was mapped to c.198_221del.

Four patients from the same family carrying missense VHL mutation c.509 T>G were screened for VHL related lesions. Patient 1, 30Y F, had undergone treatment for pancreatic endocrine tumors and pheochromocytoma. Patient 2, 30Y M, was affected by retinal angioma, bilateral adrenal pheochromocytoma and sacral, intercarotid paraganglioma. Patient 3 underwent treatment for pheochromocytoma. Investigations revealed additional pancreatic endocrine tumor and a pheochromocytoma. Patient 4 had an endocrine pancreatic tumor and a pheochromocytoma. ACMG: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology.

PatientID: 1

KindredID: 1

Case: Sex Unknown, 40Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0006770, HP:0001732, HP:0010797 (clear cell renal cell carcinoma, abnormality of the pancreas, hemangioblastoma)

CaseHPOFreeText: The patient presented with a hemangioblastoma at age 34, clear cell renal cell carcinoma at age 37, and abnormality of the pancreas at age 37.

CaseNotHPOs: HP:0009711, HP:0002666, HP:0030424, HP:0030393 (retinal capillary hemangioma, pheochromocytoma, epididymal cyst, endolymphatic sac tumor)

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

Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 43-year-old VHL type 1 patient with renal cell carcinoma, pancreatic cysts, an endolymphatic sac tumor, and an epididymal /ovarian cystadenoma (proband no. 5) and no family history. HPO terms: renal cell carcinoma, multiple pancreatic cysts, epididymal cysts, endolymphatic sac tumors.

GroupID/ KindredID: 40CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 40CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114C (c.340G>T)

LegacyVariant: p.G114C (c.553G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751376 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G>T

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114C (c.340G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 146CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to family ID Family 146CA. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A56Sfs*76 (c.165_166insA)

LegacyVariant: FS (c.378insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645524648 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.165_166insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: A56fs (c.165_166insA)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (c.468T>G) was taken from the Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 41F. It was reported in the paper as c.681T>G due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (L188fs (c.563delT)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 141CA. It was reported in the paper as c.776delT due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

PatientID: 18

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S5 describes 8 patients with frameshift or in-frame deletions, including this patient.

Variant: p.F76del(c.224_226del)

LegacyVariant: c.437_439delTCT

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: F76del(c.224_226delTCT)

MultipleGeneVariants: N/A

PMID: 22156657

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID/ KindredID: F41

Case: Sex unknown, 22Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found; unknown of any additional features to index case relatives

CasePresentingHPOs: HP:0009711; HP:0006770; HP:0006880; HP:0000107; HP:0001737 (retinal capillary hemangioma, clear cell renal cell carcinoma, cerebellar hemangioblastoma, renal cysts, pancreatic cysts)

CaseHPOFreeText: Multiple lesions were found with the patient’s cerebellar hemangioma. Unilateral ccRCC. Age of onset is 22Y0M.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128R (c.383T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753891 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.383T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L128R (c.383T>G)

MultipleGeneVariants: N/A

Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense mutation was found in a patient with retinal hemangioblastoma, cerebellar hemangioblastoma, and pancreatic cysts (patient no. F3). Patient has family history of paragangliomas, epididymial cysts, and clear cell renal carcinoma. Paper gives variant by protein sequence: L135*. NM_000551.3:c.404T>A and NM_000551.3:c.404T>G both could result in this protein change. Unclear which is correct to the given patient.

GroupID: 27B

DiseaseAssertion: Unknown. Patients were pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 patients with the given mutation were grouped as group 27(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183* (c.548C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

GroupID: 7A

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 VHL patients with the given VHL mutation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7987306

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

A cohort of 314 patients with pheochromocytoma and functional paraganglioma had blood samples collected and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened for mutations. 25 patients had germline VHL mutations, 16 of which had a family history and 9 patients had an apparently sporadic presentation, 11 were male and 14 were female, the median age of diagnosis is 23.9 and range of diagnosis was 4-49. Out of the 25 patients 23 had adrenal tumours, 4 had para-adrenal tumours, and 9 had other VHL lesions (renal tumours and hemangioblastomas). 1 patient with positive family history and/or a syndromic presentation was found with pheochromocytoma or functional paraganglioma and a germline missense VHL mutation (p.L184H (c.551T>A), referred to in the paper by c.608T>A due to a difference in transcript sequence). Other phenotypes unique to the patient are unknown. ACMG: PP4

GroupID: None

DiseaseAssertion: VHL

GroupSize: 9

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: Nine individuals from 2 different families initially diagnosed with MEN-IIA were investigated. All were found to have the same (c.562C>G) missense mutation in the VHL gene.

GroupPresentingHPOs: HP:0002666; HP:0006737; HP:0002865; HP:0011781 (pheochromocytoma, extra adrenal pheochromocytoma, medullary thyroid carcinoma, thyroid C cell hyperplasia)

GroupHPOFreeText: All 9 patients had pheochromocytoma, 2 of the 9 patients (unspecified) also had thyroid C-cell tumors, 1 (unspecified) had medullary thyroid carcinoma, and 1 (unspecified) had C-cell hyperplasia. 3 of the 9 patients (unspecified) also developed extra-adrenal pheochromocytoma.

GroupNotHPOs: HP:0000843; HP:0009711; HP:0010797; HP:0000107; HP:0001737 (Hyperparathyroidism, retinal capillary hemangioma, hemangioblastoma, renal cysts, pancreatic cysts.

GroupNotHPOFreeText: None of the patients had any clinical signs of renal cancer. Two patients (unspecified) were screened for retinal, CNS, and abdominal lesions; neither had occult VHL lesions.

GroupPreviousTesting: RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188V (c.562C>G)

LegacyVariant: c.775C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 2225, https://www.ncbi.nlm.nih.gov/clinvar/variation/2225/

CAID: CA020488

gnomAD: 0.00002121, https://gnomad.broadinstitute.org/variant/3-10191569-C-G?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

PatientID: None

KindredID: B

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PMID: 25563310

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: I

KindredID: 15

Case: Sex Unknown, 23Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: 2 other family members presented with the same VHL variant. Patient 15-II presented with 2 pheochromocytoma (8Y) 2 CNS hb (12Y and 13Y) and 2 retinal hemangioblastomas (8Y, 12Y). Patient 15-III presented with 2 pheochromocytoma (15Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 6Y. Age at the end of study: 23Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

All patients that were operated on between 1995 and 2010 in the University Medical Center Groningen from who frozen hemangioblastoma tissue was available in the tissue bank of the Department of Pathology were eligible. Through PCR (MSP) and MLPA, one patient sample was confirmed with a germline mutation (c.462A>C) in the VHL gene. The patients' manifestations was thus only stated as hemangioblastoma; No other phenotypic or demographic information was available. Note: This sample was likely duplicated in 24132471

All patients that were operated on between 1995 and 2010 in the University Medical Center Groningen from who frozen hemangioblastoma tissue was available in the tissue bank of the Department of Pathology were eligible. Through PCR (MSP) and MLPA, one patient sample was confirmed with a germline mutation (c.259_260insA) in the VHL gene. The patients' manifestations was thus only stated as hemangioblastoma; No other phenotypic or demographic information was available. Note: This sample was likely duplicated in 24132471

PatientID: V-20

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2223, https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343, https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

GroupID: III (from Hemangioma VHL Associated Group)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Studied 36 VHL-related pheochromocytoma by comparative genomic hybridization. In addition, we compared their genetic profiles with those of (1) multiple endocrine neoplasia type 2 (MEN 2)-related pheochromocytomas; (2) previously reported sporadic pheochromocytomas; and (3) VHL-related CNS hemangioblastomas.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: The patient had VHL associated hemangioblastoma (table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1 and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C77_N78insL (c.230_231insTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C77_N78insL (c.443_444insTCT)

ClinVarID: N/A

CAID: CA2499214029, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.230_231insTCT

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C77_N78insL (c.230_231insTCT)

MultipleGeneVariants: N/A

36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. Patient I with VHL-Associated hemangioblastoma was found with a germline insertion mutation (c.316insGCC) in the VHL gene. (stated as c.529insGCC in the paper which used the Latif sequence as reference) in the VHL gene. All patients have familial VHL.

PatientID: None

KindredID: 3

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

CohortInfo: The National Cancer Institute has a frozen tumour bank of ccRCC tumours that have been removed from VHL patients. We selected six patients, three males and three females, with at least five tumours from a single surgery from one kidney.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: One of the samples from this patient had few variants and clustered with the normal samples. Further inspection showed these samples were cyst-like rather than tumours, so they were excluded from further analysis. This suggests that the patient had renal cysts alongside ccRCC at age 22.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86R(c.257C>G)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223170 https://www.ncbi.nlm.nih.gov/clinvar/variation/223170/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P86R(c.257C>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 1

Case: Age, Sex, Swedish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584; HP:0002666 (renal cell carcinoma; pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma; hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S38P (c.112T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351747824 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.112T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S38P (c.112T>C)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: Direct sequencing was performed using the BigDye Terminator Cycle Sequencing Ready Reaction kit on an ABI Prism 3130 genetic analyzer (Applied Biosystems).

SamplingMethod: peripheral blood leukocytes

PMID: 22683710

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: P5

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988, https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: R79G (c.235C>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Hereditary PNET with a confirmed germline mutation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E55Gfs*77 (c.163_164insG)

LegacyVariant: N/A

CaseProblemVariantFreeText: c.163_164insG automapped to NM_000551.3:c.163dupG

ClinVarID: 223159 https://www.ncbi.nlm.nih.gov/clinvar/variation/223159/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: E55fs (c.163dupG)

MultipleGeneVariants: N/A

The patient presented at age 43 with a new left varicocele having already suffered one episode of gross hematuria. An abdominal ultrasonography revealed the presence of a left renal mass and a 2-cm renal mass in his right kidney. CT scan demonstrated two small 4-mm lung lesions. This was followed by a left radical nephrectomy. Pathological examination of the mass demonstrated a clear-cell RCC. A 1-cm isolated metastatic nodule was also found in the adrenal gland. Two years later, the lung lesions had increased to 5 mm, a further three 2-mm nodular lesions had appeared in the lungs and no growth in the small right renal lesion was found. Following this, MR imaging demonstrated an intradural intramedullary lesion (later confirmed to be consistent with a hemangioblastoma from the inferior portion of the T-5 to T-6) with a prominent feeding vessel. The patient underwent a T5–8 laminectomy. Clinical diagnosis of VHL was reached at this point. Genetic analysis found a deleting mutation in the first exon (nt. 394-406) of the VHL locus, truncating 16 amino acids (N61-77) from the first beta sheet in the VHL protein. This mutation was translated to the updated reference sequence (NM_000551.3) as p.P61_C77del (c.181_231del). This mutation was not present in any of the family members tested including the patient’s two children. At this point, MRI showed no masses, ophthalmological examination showed normal results and a congenital malformation with C-1 occipitalization and C2–3 fusion were identified. The patient underwent resection of the right renal mass, which was consistent with a clear-cell carcinoma. One year later, two cerebral lesions were diagnosed and were consistent with RCC metastases in the right occipital lobe for which he received radiation therapy. No new lesions had appeared in the spinal cord and his chest disease was found to be stable. ACMG evidence codes: 'PM6' since this mutation was declared to be non-familial but kindred testing was not specified (assumed de novo), 'PP4' since the patients phenotypes are highly specific for a disease with a single genetic etiology.

PatientID: 2

KindredID: 2

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: None - The family history was negative for PHEO or other neuroendocrine tumours. Their parents however, decided not to be tested neither to extend the test to other family members

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Apparently sporadic pheo. She had a history of primitive headache, intense nocturnal sweating and 2-month-long amenorrhoea and elevated blood pressure presented a 7-cm-diameter right adrenal mass at abdominal sonography, confirmed by MRI.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D197N (c.589G>A)

LegacyVariant: p.D197N (g.13,278)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756524 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.589G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D197N (c.589G>A)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 442

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states: Germline, de novo (no clear confirmation)

CasePresentingHPOs: HP:0005584; HP:0010797 (renal cell carcinoma, hemangioblastoma)

CaseHPOFreeText: Bilateral RCC and a hemangioblastoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.G144* (c.430G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223208 https://www.ncbi.nlm.nih.gov/clinvar/variation/223208/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: G144* (c.430G>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: N/A

SamplingMethod: N/A

33 patients diagnosed with VHL disease, according to (Maher et al. 1990), were tested for germline VHL mutations. Genetic testing was performed on high-molecular-weight DNA from peripheral blood using Southern analysis and PCR. One patient was found to harbour the 508G>T (Val170Phe) VHL gene mutation, documented in the paper as 721G>T due to a difference in transcript sequence. This patient presented with a cerebellar hemangioblastoma. As well, a somatic mutation presenting in their tumor as p.N193M*9 (c.576del13). ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PMID: 27539324 Gene: VHL StandardizedReferenceSequence: NM_000551.3