During the period from 2009 to 2012, 39 families with VHL disease were diagnosed with hereditary VHL disease at Peking University First Hospital Department of Urology were described as part of a broader study examining telomere length and anticipation. In these families, 19 families had two or more than two patients in two or more than two generations, including one family with obscure onset age. Therefore, a total of 57 patients with VHL disease from 18 families were enrolled in this study. Using peripheral blood and southern blotting, DNA sequencing was completed on the following patients. Family 15 involved one individual with a c.481C>T mutation leading to a p.Arg161Stop change. This individual, a male, presented with hemangioblastoma at 29, renal cell carcinoma at 29, pancreatic cysts at 36, papillary cystadenoma of the epididymis at 29, and endolymphatic sac tumor at 33. The patient’s father had died before diagnosis therefore no DNA sample available, however he presented with CNS hemangioblastomas at the age of 42. ACMG Evidence Code: 'PP4' because the patients' phenotypes and family histories are highly specific for VHL disease. 'PM4' because of the protein length change caused by the heavily premature stop codon.

A cohort of 64 pheochromocytoma and paragangliomas were screened for a BRAF mutation using direct Sanger sequencing and QRT-PCR. Genomic DNA was extracted from fresh or frozen peripheral blood. Germline mutations of VHL, SDHB, SDHD, and RET genes were also observed. The VHL mutation c.376G>A (p.D126N) was reported in patient #10, a 7Y male with a mediastinum paraganglioma. No family history was reported here.

Patients presenting with juxtapapillary capillary retinal angioma in Germany were queried for the presence of VHL mutations. Peripheral blood samples were obtained, exons of the VHL gene were amplified with polymerase chain reaction (PCR), and products were separated by single-stranded conformation polymorphism (SSCP) for the detection of intragenic mutations. Aberrant bands were sequenced to identify mutations. Southern blotting was performed to detect large deletions if the SSCP failed to show a band shift. One patient was found to have a c.492G>T VHL mutation (stated as c.705G>T in the paper which used the Latif sequence as reference). This patient (patient ID 5) was diagnosed at age 14 with juxtapapillary capillary retinal angioma, with no other VHL symptoms or family history.

PatientID: 9

KindredID: 4

Case: Sex Unknown, 55Y7M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0009711, HP:0010797, HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

CaseHPOFreeText: At first presentation (age 54) the patient had a visual acuity of 20/100. The retinal angioma showed an exophytic growth pattern and was located in the superior disc margin. Before age 54, the patient had experienced hemangioblastoma of the central nervous system. Either at first presentation or on follow-up the patient presented with pheochromocytoma and hemangioblastoma of the CNS.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q(c.533T>A)

LegacyVariant: p.L178Q(c.746T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178Q(c.533T>A)

MultipleGeneVariants: N/A

Patients presenting with juxtapapillary capillary retinal angioma in Germany were queried for the presence of VHL mutations. Peripheral blood samples were obtained, exons of the VHL gene were amplified with polymerase chain reaction (PCR), and products were separated by single-stranded conformation polymorphism (SSCP) for the detection of intragenic mutations. Aberrant bands were sequenced to identify mutations. Southern blotting was performed to detect large deletions if the SSCP failed to show a band shift. Two out of eleven unrelated patients presented with the missense mutation in the VHL gene c.292T>C (stated as c.505T>C in the paper which used the Latif sequence as reference). Patient 10 presented with retinal capillary hemangioma at age 34 and was followed up 4 years later during which time he did not develop any new lesions. The patient was indicated to have a family history of VHL but, it was not described. Patient 11, presented with retinal capillary hemangioma at age 17 years and 7 months. This patient had no family history of VHL. The patient developed a diagnosis of pheochromocytoma within 5 years of follow-up.

A 11-year-old girl with a history of bronchial asthma presented to the hospital with a an acute onset of breathlessness, chest discomfort, pallor and sweatiness and elevated blood pressure secondary to an adrenal tumour, which is consistent with a catecholamine crisis. She was given nebulised salbutamol at the emergency department and then referred to the paediatric team for hypertension. She started prazosin for initial control of her blood pressure. She had unexpectedly normal urinary metanephrine and catecholamine results, which placed doubt in an initial suspicion of pheochromocytoma. She improved spontaneously and underwent surgery later . Post-operatively, praozin was weaned off. Histopathological examination confirmed a pheochromocytoma with large central necrosis. However, while pheochromocytoma should still be suspected, other causes of adrenal mass associated with hypertension should be considered. Genetic testing revealed a heterozygous VHL c.467A>G(p.Tyr156Cys) mutation. The sample used was not mentioned, but patient's father has the same gene mutation, suggesting a germline variant. Although, patient had no family history of malignancy. An abdominal ultrasound repeated in 6 weeks showed a reduction in the size of the lesion with no further intervention and remained asymptomatic on follow-up.

PatientID: 2

KindredID: 2

Case: 18Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: isolated bilateral pheochromocytoma first presenting at 18Y

CaseNotHPOs: HP:0009715; HP:0005584; HP:0010797 (Papillary cystadenoma of the epididymis, renal cell carcinoma, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

Nine Chinese index patients were referred for the molecular analysis of VHL based on clinical suspicion. PCR and MLPA were performed on whole blood. Proband 5 was diagnosed with VHL type 1, and was found to have a c.233A>G [p.Asn78Ser] mutation in the VHL gene. They had no family history of VHL disease. They presented with a CNS hemangioblastoma at age 28, and renal cell carcinoma at age 28.

GroupID: 136

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Likely previously published in PMID 32179488 (Kindred 14) but correspondence to a patient in this group is not confirmed.

SupplementalData: N/A

Variant: p.F76del (c.227_229del)

LegacyVariant: c.439_441delTTC

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228del

gnomAD: N/A

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

MutationType: deletion; inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y175D (c.523T>G)

LegacyVariant: c.736T>G

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756228, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.523T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y175D (c.523T>G)

MultipleGeneVariants: N/A

GroupID: 93

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.481C>T variant causing a Arg161* stop gain (noted in the paper as c.694C>T due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: It was noted that this family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

93 families examined at the Clinical Center of the National Institutes of Health (Bethesda, MD) underwent genetic testing for germline mutations of the VHL gene. Whole blood was extracted and genomic DNA was amplified by PCR and products were sequences using a cycle sequencing kit with dye-labeled terminators and automatically sequenced. This missense mutation was found in a VHL type 1 family (lineage 103). The variant was reported as c.514_515CT>GG (AF010238.1) and was mapped to L101G (c.301_302delinsGG) (NM_000551.3).

PatientID: P12

KindredID: P12

Case: M, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Pheochromocytoma

FamilyInfo: N/A

CohortInfo: Tumour samples and paired peripheral blood samples were obtained from 39 patients, consisting of 31 PCs, seven extra adrenal PGLs and one metastasis from a malignant PC previously presenting with a PC.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had an atypical pheochromocytoma measuring 10 mm at age 40.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD

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

PatientID: 11

KindredID: 63

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 63 was mentioned (Patient: 19). This patient was found to have pheochromocytoma, renal cell carcinoma and pancreatic endocrine tumour.

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.Y175* (c.525C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182974 https://www.ncbi.nlm.nih.gov/clinvar/variation/182974/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y175* (c.525C>G)

MultipleGeneVariants: N/A

PatientID: 34

KindredID: 94

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.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour(EPT) (20 women and 15 men; median age:37 [21-57 years]) were included. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal cancer in addition to pancreatic tumours. The presence of other phenotypes was not described. Patient No. 12 from family 240 was found with a germline c.470C>T (p.Thr157Ile) mutation in the VHL gene and presented with pancreatic endocrine tumour and pheochromocytoma. No additional family history information was included. For the genetic analysis direct sequencing of the 3 exons of VHL was performed for all the DNA. If no mutation was detected, Southern blot analysis was performed to detect large rearrangements. ACMG code(s): suggested PP4 since the patient's phenotypes are highly specific to VHL disease.

All patients included in the study were VHL mutation carriers of 18 years or older examined between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU). Clinical data of 75 VHL mutation carriers were retrospectively retrieved from electronic and written patient record. Of these patients, one was found to harbour the c.497T>C germline mutation of the VHL gene. They presented with a pancreatic neuroendocrine tumor and pheochromocytoma. Their age at the last follow-up was 27. Previously published in: PMID 24132471.

PatientID: None

KindredID: 18

Case: Sex Unknown, 63Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: All VHL mutation carriers of 18 years or older who underwent surveillance according to Dutch VHL guidelines between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU) were included. Patients with VHL-disease subtype 2C (pheochromocytoma only) were excluded.

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0000107 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst)

CaseHPOFreeText: VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: c.464-3C>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 644549, https://www.ncbi.nlm.nih.gov/clinvar/variation/644549/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Region (c.464-3C>T)

MultipleGeneVariants: N/A

PMID: 21463266

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 67

KindredID: 67

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0001732; HP:0009711 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete deletion)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The P59Rfs*8 (c.176del) germline mutation of the VHL gene was found in a 46 yr old VHL patient with hemangioblastomas of the central nervous system, pancreatic cyst or tumor, pheochromocytoma, and renal cyst (index case 194). No family information is provided.

PatientID: 24

KindredID: 24

Case: Sex Unknown, 57Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Proband and father were found to carry the R167L (c.500G>T) germline mutation of the VHL gene. Father, siblings and nephew were analyzed but no phenotype information was provided for these family members. Genotype information for siblings and nephew was not provided.

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

CaseHPOFreeText: Pheochromocytoma, retinal hemangioblastoma, CNS hemangioblastoma and pancreatic cyst or tumor.

CaseNotHPOs: HP:0000107; HP:0006770; HP:0001732 (Renal cyst, Clear cell renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.R167L (c.500G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526685, https://www.ncbi.nlm.nih.gov/clinvar/variation/526685/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R167L (c.500G>T)

MultipleGeneVariants: N/A

PatientID: 328

KindredID: 328

Case: Sex Unknown, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

CasePresentingHPOs: HP:0002666; HP:0000107; HP:0009711 (Pheochromocytoma, Renal cyst, Retinal capillary hemangioma)

CaseHPOFreeText: Retinal hemangioblastoma, renal cystic lesion and pheochromocytoma.

CaseNotHPOs: HP:0001732; HP:0010797; HP:0006770 (Abnormality of the pancreas, Hemangioblastoma, Clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 263

KindredID: 263

Case: Sex Unknown, 50Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Transmission of the variant could not be determined (n/d) since both parents and family history were not available.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107; HP:0001732; HP:0009711 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.E12D (c.36G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 419711, https://www.ncbi.nlm.nih.gov/clinvar/variation/419711/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: E12D (c.36G>C)

MultipleGeneVariants: N/A

PatientID: 70

KindredID: 70

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030405; HP:0030421 (Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.Q96P (c.287A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625233 https://www.ncbi.nlm.nih.gov/clinvar/variation/625233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q96P (c.287A>C)

MultipleGeneVariants: N/A

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. Two patients were found with this germline mutation (c.463+37_463+39del) were recorded in the paper as having an Intron 2 +37-39 del TGT. One patient (ID 13) had CNS hemangioblastoma and the other patient (ID: 57) was asymptomatic. Whether patients were related, age, and sex data was not reported. ACMG PP4

PatientID: 8

KindredID: 8

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0030405 (hemangioblastoma, pancreatic endocrine tumour)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma and a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CaseNotHPOs: HP:0030421; HP:0006770; HP:0100634; HP:0009711 (epididymal tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm, retinal capillary hemangioma)

CaseNotHPOFreeText: patient was recorded without CCRCC, and a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), pancreatic endocrine tumour (or pancreatic neuroendocrine neoplasm), and a retinal hemangioblastoma, or a epididymal tumor

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 40

KindredID: 40

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: patient had pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm)

CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.V84L (c.250G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

PatientID: II:1

KindredID: 1

Case: M, 73Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Look to proband (III:3) for extensive family info.

CohortInfo: Patients with the diagnosis of familial or sporadic PHEO and their relatives.

CasePresentingHPOs: HP:0002666; HP:0009713 (Pheochromocytoma, Spinal hemangioblastoma)

CaseHPOFreeText: Deceased. Multiple spinal cord hemangioblastomas diagnosed after adrenal tumor resection. Unilateral pheochromocytoma diagnosed at age 73. Diagnosed with VHL type 2A.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: p.P138= (c.414A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223206, https://www.ncbi.nlm.nih.gov/clinvar/variation/223206/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P138= (c.414A>G)

MultipleGeneVariants: N/A

PatientID: V374

KindredID: V374

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70K (c.208G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

GroupID: V27

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 3/13 members of this family that underwent genetic testing had the same mutation.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Diagnosed with VHL Type 1.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Likely 15300849

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428807, https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The c.340+1_340+5del mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V313). The variant is reported as IVS1+1del5.

PatientID: V41

KindredID: V41

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Likely 15300849

SupplementalData: N/A

Variant: p.Y156* (c.468T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756053, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.468T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y156* (c.468T>G)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The K159Efs*15 (c.473dup) mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V235). The variant was reported as c.473_474insT and mapped to c.473dup.

A retrospective analysis of 164 patients waiting for surgery for hemangioblastomas at Freiburg University Medical Center, Freiburg, Germany was conducted. Bidirectional direct sequencing by use of an ABI PRISM 3130 DNA Genetic Analyzer (Applied Biosystems) was used to identify mutations in abnormal samples. One patient (#19) was found to carry a germline point mutation in the VHL gene c.292T>C, p.Tyr98His (stated as c.505C>T in the paper which uses the Latif sequence as reference). This female 75-year-old patient presented with a brainstem hemangioblastoma and elevated Hb levels indicative of polyglobulia. After the spinal hemangioblastoma was removed, the Hb level normalized. Family history was not described.

A retrospective analysis of 164 patients waiting for surgery for hemangioblastomas at Freiburg University Medical Center, Freiburg, Germany was conducted. Bidirectional direct sequencing by use of an ABI PRISM 3130 DNA Genetic Analyzer (Applied Biosystems) was used to identify mutations in abnormal samples. Patient #2 (male, 53Y) was found with germline VHL point nonsense mutation (c.548C>A, p.Ser183*) and with cerebellar hemangioblastoma and renal cysts. Family history was not described.

GroupID: 16A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I151M (c.453C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754364 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.453C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: I151M (c.453C>G)

MultipleGeneVariants: N/A

GroupID: 25A

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 VHL patients with the given VHL mutation and manifestation 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: N/A

SupplementalData: N/A

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: 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: XV-I

KindredID: 15

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history reported.

CasePresentingHPOs: HP:0005584; HP:0000107; HP:0006880; HP:0009711; HP:0030405; HP:0001737; HP:0025247 (renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, retinal capillary hemangioma, pancreatic endocrine tumor, pancreatic cysts, dermoid cyst)

CaseHPOFreeText: Patient presented with renal cell carcinoma, renal cysts, cerebellar hemangioblastoma, retinal capillary hemangioma, pancreatic endocrine tumor, pancreatic cysts, dermoid cyst at age 24Y0M. Patient was diagnosed with VHL type 1 (see table 2).

CaseNotHPOs: HP:0006748; HP:0002668 (adrenal pheochromocytoma; paraganglioma)

CaseNotHPOFreeText: Patient negative for adrenal pheochromocytoma and paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PatientID: VI-I

KindredID: 6

Case: M, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This kindred includes 3 patients: a father and his two children. The father, 55Y, had bilateral adrenal pheochromocytoma, along with his two children (13Y, 17Y).

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient first presented with adrenal pheochromocytoma at age 13Y0M and was diagnosed with VHL type 2C (see table 2).

CaseNotHPOs: HP:0001737; HP:000107; HP:0005584; HP:0002668; HP:0030405 (pancreatic cysts; renal cyst; renal cell carcinoma; paraganglioma; pancreatic endocrine tumor)

CaseNotHPOFreeText: Patient negative for pancreatic cysts, pancreatic endocrine tumors, renal cell carcinoma, renal cysts, and paraganglioma.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188del (c.562_564del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573320489, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573320489

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: L188del (c.562_564del)

MultipleGeneVariants: N/A

GroupID: 13

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, 1 individual was suspected of VHL disease, but did not develop RH.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: This VHL patient did not presented with retinal capillary hemangioma.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.L89P (c.266T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182979, https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10183797T>C

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID: 9

DiseaseAssertion: VHL

Group size: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this family, eight individuals were suspected of VHL disease. 5/8 individuals developed RH, while 3/8 did not.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: Five patients presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.L159Es*15 (c.473dup)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA432423097, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.473dup

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10191480dup

MutationType: duplication; plus_1_frameshift_variant

CivicName: L159Es*15 (c.473dup)

MultipleGeneVariants: N/A

PatientID: 1114

KindredID: 236

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 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.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: 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). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 4 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. These previously published individuals could alternatively correspond to family 345 or 379.

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

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

PatientID: 1772

KindredID: 264

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 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.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

PatientID: 9579

KindredID: 404

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 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.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: 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]). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 12202531

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

Variant: p.N78S (c.233A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93326, https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: VHL

GroupSize: 29

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 29 members of this family were found to harbor the c.313A>C germline variant of the VHL gene. Members 572, 594, 1549, 1396, 580, 1394, 1392, 1399, 704 and 1550 had unknown renal involvement. Members 1153, 5098 and 1523 had no renal involvement. Members 1154, 6435 and 304 presented with mild renal disease. Members 574, 2419 and 1157 presented with moderate renal disease (RCC). Members 929, 654, 2993, 1398, 579, 571, 2281 and 2994 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: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). 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 and/or 9829912, where 9 and 14 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.T105P (c.313A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496055, https://www.ncbi.nlm.nih.gov/clinvar/variation/496055/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: T105P (c.313A>C)

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.T105P (c.313A>C) germline variant of the VHL gene was detected in a family (ID 8). Members 572, 594, 1549, 1396, 580, 1394, 1392, 1399, 704 and 1550 had unknown renal involvement. Members 1153, 5098 and 1523 had no renal involvement. Members 1154, 6435 and 304 presented with mild renal disease. Members 574, 2419 and 1157 presented with moderate renal disease (RCC). Members 929, 654, 2993, 1398, 579, 571, 2281 and 2994 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

PatientID: IV-7

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL (Asymptomatic)

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: N/A

CaseHPOFreeText: N/A

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

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

PatientID: V-18

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

PatientID: II-1

KindredID: 1

Case: F, 32Y0M, Mexican

DiseaseAssertion: Assumed VHL

FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0006880 (Hemangioblastoma, Retinal capillary hemangioma, Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar, medullar and bilateral retinal HBs. Died in their 30’s.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1(a))

Variant: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Likely to carry the p.R82P (c.245G>C) VHL variant but did not undergo genetic testing.

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: IV-6

KindredID: 1

Case: M, Age Unknown, Mexican

DiseaseAssertion: Asymptomatic

FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: N/A

CaseHPOFreeText: Likely to be asymptomatic due to young age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (a))

Variant: p.R82P (c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P (c.245G>C)

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 26

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0005584; HP:0010797 (Retinal capillary hemangioma, Renal cell carcinoma, Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and RCC.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 10761708 (variants differ by one base pair; unclear which is accurate)

SupplementalData: N/A

Variant: p.G144Ffs*26 (c.429_439del)

LegacyVariant: codon 214 (nucleotide 642 11 base pair deletion)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106247, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573106247

gnomAD: N/A

VariantEvidence: Given that all other variants are reported in legacy variant nomenclature (i.e. AF010238.1) this variant was mapped to c.429_439del (NM_000551.3).

MutationType: minus_2_frameshift_variant; deletion

CivicName: G144fs (c.429_439del)

MultipleGeneVariants: N/A

KindredID: 11

GroupID: 52

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 11 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in this kindred indicating VHL disease type 1.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L184R (c.551T>G)

LegacyVariant: p.L255R (c.764T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756355, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.551T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L184R (c.551T>G)

MultipleGeneVariants: N/A

KindredID: 49

GroupID: 31

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no. 49 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Pheochromocytoma was observed in this kindred indicating VHL disease type 2.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Pheochromocytoma was observed in this kindred indicating VHL disease type 2.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P154L (c.461C>T)

LegacyVariant: p.P225L (c.674C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 649525, https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

PMID: 21784903

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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

GenotypingMethod: N/A - No further detail past a comprehensive study with genotyping, phenotypic analysis, structural modeling, functional and transcriptomic studies

SamplingMethod: N/A - Not stated

GroupID: 17

DiseaseAssertion: assumed VHL

GroupSize: 16

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 16 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 single family.

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

GroupHPOFreeText: 6 patients had retinal angiomas diagnosed at a mean age of 24Y, 10 members had cerebellar hemangioblastomas diagnosed at a mean age of 41Y, and 2 had RCC diagnosed at a mean age of 34Y

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.G104Hfs*27 (c.309_310delTG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA658795178 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.309_310delTG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: G104FS (c.309_310delTG)

MultipleGeneVariants: N/A

GroupID: 44

Case: Age unknown, 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 was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0006880; HP:0002666; HP:0009711; HP:0005584 (cerebellar hemangioblastoma; pheochromocytoma; retinal capillary hemangioma; renal cell carcinoma)

CaseHPOFreeText: patient had all four of cerebellar hemangioblastoma; pheochromocytoma; retinal capillary hemangioma; renal cell carcinoma, with unknown ages

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: c.341-2A>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753579 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.341-2A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.341-2A>C) 

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (R167Q(c.500G>A)) was found in 7 families with 33 affected members: 17 had retinal angioma, 9 had cerebellar hemangioblastoma, 5 had renal cell carcinoma, 15 had pheochromocytoma. ACMG PP4

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. VHL T124fs (c.369del), written in the paper as c.367delG which automaps to c.369delG, results in a frameshift, a premature stop codon. It was found in a VHL patient with retinal hemangioblastomas diagnosed at age 19Y.

GroupID: 34

DiseaseAssertion: assumed VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family 

GroupPresentingHPOs: HP:0006880; HP:0005584 (cerebellar hemangioblastoma; renal cell carcinoma)

GroupHPOFreeText: 3 had cerebellar hemangioblastomas diagnosed at mean age of 22Y, and 3 had RCC diagnosed at mean age of 48Y

GroupNotHPOs: HP:0002666; HP:0009711 (pheochromocytoma; retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R177Dfs*25 (c.528delG) 

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.528delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R177fs (c.528del)

MultipleGeneVariants: N/A

GroupID: 1190

DiseaseAssertion: VHL

GroupSize: 19 GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: German GroupAgeRange: N/A

GroupInfo: Pennsylvanian pheochromocytoma family of German origin classified as a VHL Type 2A family according to the authors criteria (i.e. presenting with pheochromocytoma and without RCC or pancreatic cysts).

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

GroupHPOFreeText: 19 members affected with pheochromocytoma, 4 with retinal angioma, 1 with CNS hemangioblastoma.

GroupNotHPOs: HP:0005584; HP:0001737 (Renal cell carcinoma, Pancreatic cysts)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T112H (c.334T>C)

LegacyVariant: T547C (Y111H)

CaseProblemVariantFreeText: N/A

ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: N/A

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

VariantEvidence: Since this family was of German origin and was classified as a VHL Type 2A family, the authors chose to test 5 affected individuals (4612, 4613, 4796, 4799, 4801) and 7 unaffected individuals mutations at nucleotide 292. A novel migration fragment was identified in all 5 affected individuals in exon 1. None of the unaffected individuals showed this variant. DNA from patients 4612 and 4613 was amplified by PCR and subcloned resulting in the detection of the p.T112H (c.334T>C) variant. Sequencing in both directions confirmed this result. The other 3 affected individuals were not sequenced. Authors declare variant as “T547C (Y111H)” (assumed to follow legacy nomenclature) which was mapped to p.T112H (c.334T>C).

MutationType: missense_variant;transition

CivicName: T112H (c.334T>C)

MultipleGeneVariants: N/A

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The T157I (c.470C>T) germline nonsense mutation was found in a VHL type 2 family presenting with pheochromocytoma (1/2) and renal cell carcinoma (2/2) (family ID 45). This family was previously published in PMID 8634692.

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The N78H (c.232A>C) germline mutation was found in a VHL type 1 family presenting with CNS hemangioblastoma (3/3), retinal angioma (3/3) and pancreatic tumor or cyst (unspecified) (2/3) (family ID 9). This family was previously reported in PMID 8634692.

KindredID: 12

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 12. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65* (c.194C>A)

LegacyVariant: p.136fs* (c.407C>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223161 https://www.ncbi.nlm.nih.gov/clinvar/variation/223161/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

CivicName: S65* (c.194C>A)

MultipleGeneVariants: N/A

PatientID: None (Mother)

KindredID: F5

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G144R (c.430G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 576437, https://www.ncbi.nlm.nih.gov/clinvar/variation/576437/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188287-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G144R (c.430G>A) and c.340+694_340+711dup

MultipleGeneVariants: N/A

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

GenotypingMethod: Sanger sequencing, whole genome sequencing performed at the clinically accredited Molecular Diagnostics Laboratory at the John Radcliffe Hospital using the Hi-Sequation 4000 platform (Illumina Inc., San Diego, CA) in high-throughput mode. As well, paired-end sequencing was carried out in a single lane on the HiSeq 2500 system (Illumina).

SamplingMethod: Whole blood

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. A patient of family F7, was found to have a germline mutation in the VHL gene, c.340+816A>C in a homozygous state. This patient was diagnosed with erythrocytosis at 7 years old. This patient's asymptomatic parents were also genetically tested and both were found to have the same germline variant.

PatientID: 48

KindredID: 15

Case: F, 19Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (oatient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52.

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

CaseHPOFreeText: The proband's niece 2 (patient 48) had a retinal angioma at 18 and a CNS hemangioblastoma at 19.

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

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.S80Tfs*77 (c.239_245del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189246; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239_245del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239_245del)

MultipleGeneVariants: N/A

PatientID: 250

KindredID: 96

Case: M, 23Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 250) presented with a CNS hemangioblastoma at 23, retinal angioma at 17, and multiple pancreatic cysts/tumors at 19. His mother (patient 251) presented with a CNS hemangioblastoma at age 43, retinal angioma at 35, renal cell carcinoma/multiple pancreatic cysts/tumors at 44.

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

CaseHPOFreeText: The proband (patient 250) presented with a CNS hemangioblastoma at 23, retinal angioma at 17, and multiple pancreatic cysts/tumors at 19.

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 1 Deletion (c.1-?_340+?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 1 Deletion

MultipleGeneVariants: N/A

PatientID: 113

KindredID: 41

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 26, and at age 36 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as 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.H115Tfs*44 (c.343del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421784, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.343delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H115FS (c.343delC)

MultipleGeneVariants: N/A

PatientID: 57

KindredID: 20

Case: F, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had a CNS hemangioblastoma at age 18. Their father (listed in this paper as the proband) presented with a retinal angioma at 32, a CNS hemangioblastoma at 34, and renal cell carcinoma as well as multiple pancreatic cysts/tumors at 38. Their father passed away before genetic testing could be confirmed.

CasePresentingHPOs: HP:0010797 (CNS Hemangioblastoma)

CaseHPOFreeText: The proband had a CNS hemangioblastoma at age 18.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)

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: p.P86L (c.257C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 242

KindredID: 93

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 242) has a mother (patient 243) who presented with renal cell carcinoma and multiple pancreatic cysts/tumors at age 43, but passed away before diagnosis/ before she could be confirmed with the mutation.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and retinal capillary hemangioma at age 18, and multiple pancreatic cysts/tumors at age 16.

CaseNotHPOs: HP:0002666; HP:0010797 (Pheochromocytoma, Hemangioblastoma)

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: Exon 1 Deletion (c.1-?_340+?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 1 Deletion

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A male patient (family #22, patient #59) was diagnosed with this mutation in the VHL gene and was diagnosed with pheochromocytoma at 11Y and multiple pancreatic cysts or pancreatic tumours at 14Y. This patient was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: M

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient's mutation was absent in the parents. Therefore the mutation is de-novo.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0002894, HP:0002666, HP:0005584 (retinal capillary hemangioma, neoplasm of the pancreas, pheochromocytoma, renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162R (c.484T>C)

LegacyVariant:p.C162R (c.697T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 496067 https://www.ncbi.nlm.nih.gov/clinvar/variation/496067/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:C162R (c.484T>C)

MultipleGeneVariants: N/A

Genetic and clinical data from 63 patients with hereditary Pancreatic neuroendocrine tumors (GpNET) and 145 with sporadic PNET (SpNET) were collected from two Polish endocrine departments from January 2004 to February 2020. Genomic DNA was extracted from peripheral blood leukocytes and the VHL and MEN1 genes were analyzed. The VHL gene was analyzed by Sanger sequencing and targeted next-generation sequencing (NGS), while the MEN1 gene was analyzed by by High-Resolution Melting, Sanger sequencing, Multiplex-ligation dependent probe amplification (MLPA), and targeted NGS. Only patients with confirmed germline mutations were included in the the GpNET cohort. Out of 53 patients with VHL, only five were diagnosed with GpNET. Patient 3 had this hereditary PNET with the confirmed germline mutation: R167Q (c.500G>A). Comparison of the two cohorts revealed that patients with GpNET are diagnosed earlier, have longer overall survival, less frequent metastases, and their tumors are smaller and often multifocal compared to the SpNET group.

PMID: 15730575

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 48

KindredID: F01

Case: F, Age Unknown, Unknown Ethnicity

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 12 members of this family (F01) had a complete deletion of the VHL gene. Five of these patients (16, 18, 21, 33, 43) presented with clinical features of VHL. This family was previously published except for patients 43 and 48 which were newly diagnosed with VHL disease in the current study.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17537157

SupplementalData: Figure 2.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of ~250.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.W88* (c.263G>A) mutation, 4 members belonging to 1 or 2 families [unclear] were described, and phenotypic information was given for this group. With ages ranging from 33.8Y +/- 17.6Y, hemangioblastoma was observed in 3/4 members, renal cell carcinoma in 2, pancreatic cysts in 2, pheochromocytoma in 1 member, and a genital system tumor (epididymis or broad ligament) in 2 members. See more information as this cohort has been previously published in PMID 29330336 and 28388566.

PatientID: 2

KindredID: 1 (group ID 5)

Case: M, 58Y0M (deceased), Chinese

DiseaseAssertion: asymptomatic

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 2 had a daughter and son with this mutation. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: N/A

CaseHPOFreeText: Phenotypes for this patient were not described

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

A 41-year-old asymptomatic caucasian male presented to his family doctor for VHL genetic testing due to family history of pheochromocytoma (PHEO). His sister was diagnosed with VHL disease after experiencing multiple tumors including paraganglioma of left carotid, spinal neuroma, bilateral adrenal PHEO and a skull based tumor with intracranial extension. His father, paternal grandmother and paternal great grandfather all had clinical history of PHEO. Genetic testing revealed a heterozygous synonymous mutation P138P(c.414A>G) in the VHL gene, the same one as his sister. 6 years later, he remained asymptomatic but decided to take an MRI, revealing a PHEO in the left adrenal gland and hemangioblastomas in the spine and brain. An adrenalectomy was performed, as well as radiotherapy with a craniotomy and resection. The family received VHL testing, where the wife was found to have wildtype VHL. Out of their 3 children, the 2 fraternal twin daughters inherited the mutation and were diagnosed at age 4. They both presented with retinal hemangioblastomas without PHEO at age 7, where one twin needed four laser treatments. To examine the mechanism of how the synonymous mutation causes VHL, primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from skin biopsies of the 5 individuals of the proband's family. To examine whether this mutation affects splicing and gene expression, RT-PCR was performed with Sanger sequencing. Mutant fibroblasts downregulated full length VHL mRNA and protein, and upregulated the short VHL mRNA isoform at the mRNA level, but not at the protein level. Despite being synonymous, the mutation is not functionally silent because it causes aberrant splicing by skipping exon 2. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts.

PatientID: 18

KindredID: A

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0009711; HP:0002668 (Retinal capillary hemangioma, Paraganglioma)

CaseHPOFreeText: Retinal angiomas aged 16Y. 30Y at VHL diagnosis. Abdominal paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y185* (c.555C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223233, https://www.ncbi.nlm.nih.gov/clinvar/variation/223233/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y185* (c.555C>G)

MultipleGeneVariants: 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 c.464-1G>T (Splice) VHL gene mutation, documented in the paper as 677-1G>T due to an older transcript used. They presented with 7 instances of renal cell carcinoma. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 7

KindredID: A (III-4)

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's father (II:3) died of cerebellar hemangioblastoma at age 39 and did not undergo genetic testing. The patient had two siblings who were healthy and did not undergo genetic testing. There was a strong VHL family history on the father's side of the family. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0009711, HP:0002666 (hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma, pheochromocytoma)

CaseHPOFreeText: Diagnosed with renal cell carcinoma and retinal angioma at age 24. He did not undergo surgery.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 33Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: N/A

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: The patient presented with a retinal tumor in October 2012 (age: 30) as well as July 2013 (age: 31). At the time of the trial she presented with a single juxtapapillary tumor in her left eye. She exited the trial 12 months later with no changes to the tumor size after 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: N/A

MultipleGeneVariants: N/A

GroupID: 1

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 5 VHL Type 1 affected individuals. Necropsy of the proband’s father, who died at 37 years from complications following emergency surgery for cerebellar HB. The necropsy showed many occult lesions related to VHL, including RC, multiple pancreatic and renal cysts, and cystadenoma of the epididymis. One non-symptomatic carrier in this family.

GroupPresentingHPOs: HP:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

GroupHPOFreeText: CNS hemangioblastoma (4/5 affected members) and renal carcinoma (2/5 affected members).

GroupNotHPOs: HP:0009711; HP:0002894; HP:0002666 (Retinal capillary hemangioma, Neoplasm of the pancreas, Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 32179488

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.226_228del

gnomAD: N/A

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

MutationType: inframe_deletion; deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

Germline mutations were found in twenty VHL probands and their families, of whom 17 presented with a family history (15 from Brazil, one from Portugal, and one from Ecuador). The germline P146Lfs*13 (c.436del) variant of the VHL gene was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, retinal angiomas, renal carcinoma and a renal tumor <3cm in size (VHL family 13). The patient's mother was originally thought to be an asymptomatic carrier but was later discovered to have two occult hemangioblastomas (spinal and cerebellar) as well as multiple pancreatic cysts. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

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

GenotypingMethod: Direct sequencing

SamplingMethod: Peripheral venous blood

PatientID: 1 (case)

KindredID: 1

Case: M, 10Y4M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No specific presentations were given for family history, however it was stated that the mutation was not found in the mother, yet the father’s DNA was not available for testing. The patient has 10 siblings, but all from a different father, none of which presented with a tumor or other severe disease known, and none was willing to be analyzed for the given mutation. It therefore cannot definitely differentiate between an inherited or a de novo mutation in this patient.

CasePresentingHPOs: HP:0003712; HP:0006737; HP:0010302; HP:0002668 (Skeletal muscle hypertrophy, extraadrenal pheochromocytoma, spinal cord tumor, paraganglioma)

CaseHPOFreeText: admitted to the hospital at 9Y with generalized seizures and marked hypertension; echocardiography showed muscular hypertrophy of the left ventricle; radiograph of the thorax revealed a round paramediastinal mass at the left side at the level of the fourth thoracic vertebra; MRI confirmed a thoracic structure (2 × 2 × 3 cm) and a tumor in the abdomen (2 × 3 × 5 cm) in the right suprarenal region; two separate tumors apart from the adrenal gland and the thoracic tumor were removed and found to be consistent with pigmented paragangliomas showing positivity for neuron-specific enolase, chromogranin A, and synaptophysin. 7 months after surgery he returned with tachycardia, vomiting, and hypertension and was found to have a new tumor in the 2 × 2 × 2 cm in the left periadrenal region; surgery found these to be three tumors in the proximity of the adrenal gland. 16 months after his first admission, the patient is in good health.

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

CaseNotHPOFreeText: Physical examination revealed no other internal and no focal neurologic abnormalities. No café-au-lait-spots were present. No angiomatosis of the retina was present

CasePreviousTesting: MEN2

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65A (c.193T>G)

LegacyVariant: p.S65A (c.406T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223160 https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: VHL-18

KindredID: 18

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

CasePresentingHPOs: HP:0010797, HP:0001737 (hemangioblastoma, pancreatic cysts)

CaseHPOFreeText: The patient had multiple hemangioblastomas.

CaseNotHPOs: HP:0005584, HP:0002666, HP:0009711 (renal cell carcinoma, pheochromocytoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S(c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

43 Italian patients were molecularly analyzed for Von Hippel-Lindau disease based on clinical suspicion. Peripheral blood samples were directly sequenced on an automatic sequencer (ABI 3100, Applied Biosystems, Foster City, CA) and real-time quantitative PCR (RQ-PCR) was used to detect partial or complete VHL gene deletions. One of the 43 patients (patient ID 8) was found to have a splice site mutation c.464-1G>A. This patient presented with CNS hemangioblastoma, renal cell carcinoma, and epididymal cysts. The patient had no family history and were classified as A2 (sporadic patients with involvement of at least two distinct organs).

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. The N78S (c.233A>G) mutation was detected in the patient, referred to in the paper by N78S (c.446A>G) due to a difference in transcript sequence. This missense mutation was found in a German, VHL type 1 family of 6. Each patient had hemangioblastomas of the central nervous system and 4 had cystadenomas of the epididymis (family VHL 51). This study contains supporting evidence of pathogenicity due to cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

Of 65 VHL families from central Europe, 53 were identified with germline mutations. The mutation of p.Q195* (c.583C>T) was referred to in the paper by c.796C>T due to a difference in transcript sequence. This nonsense mutation was found in 1 German family with 2 VHL type 1 family members both with retinal angiomas and hemangioblastomas of the central nervous system (family VHL 56). This study contains very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

GroupID/ KindredID: VHL *

DiseaseAssertion: assumed VHL

GroupSize: 52

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: family 'VHL*' represents 14 VHL families for which a common founder has been identified in 16/52 (30%) of patients. 52 patients total with the given mutation belong to this cohort.

GroupPresentingHPOs: HP:0009711; HP:0002666; HP:0010797 (retinal capillary hemangioma, pheochromocytoma, hemangioblastoma)

GroupHPOFreeText: 26 patients recorded with retinal angiomas, 6 with hemangioblastomas of the central nervous system, and 41 pheochromocytomas. The authors state that this VHL 2A mutation confers a high risk of developing pheochromocytoma (with a 63% risk).

GroupNotHPOs: N/A

GroupNotHPOFreeText:  the authors state that this VHL 2A mutation confers a high risk of developing pheochromocytoma but a low risk of developing RCC (63% risk of pheochromocytoma but only a 4% risk of RCC).

GroupPreviousTesting: N/A

PreviouslyPublished: 1673491; 7759077

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.Y98H (c.505T>C)

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

CAID: CA020246 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EC

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