Case3: Male, 44,57,17, 2 Native American, European, Guaranda, Zaruma, Ibarra

DiseaseAssertion: asymmetric septal hypertrophy, dynamic left ventricular outflow tract obstruction, HCM, fatigue and presyncope

FamilyInfo: family history included parental hypertension and cancer, Relatives had cardiovascular conditions, including a paternal uncle with myocardial infarction at 58, another with a heart murmur, and a grandmother with hypertension

ParentalTesting: Family history of first degree relatives with myocardial infarction

CasePresentingHPOs: HP: 000256.3, HP: 033118.3, HP:000540.2 “Gene encodes the cardiac isoform of myosin-binding, Gene encodes an enzyme that is expressed in adult skeletal muscle, gene encodes a ryanodine receptor found in skeletal muscle”

CaseHPOFreeText: N/A

CaseNotHPOs: HP: 004168.3, HP: 000384.2, HP: 020433.4

CaseNotHPOFreeText: “Mutations in gene are linked to Leigh syndrome, mutations to gene are linked to diseases affecting plasma cholesterol, gene encodes a protein to mediate cross talk between cell surface and intracellular ion channels”

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Next-generation sequencing (NGS)

FunctionalAnalysis: N/A

Variant: NM_000256.3 c.772G>A MANE select

ClinVar: 42792

CAID: CA015823

gnomAD: 0.00003

https://www.ncbi.nlm.nih.gov/clinvar/variation/42792/?term=%22p.Glu258Lys%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

Case2: 12 year old Male, 9 month old Female

Disease Assertion:Double atrial and right ventricular hypertrophy, intermittent chest pain and left ventricular hypertrophy

FamilyInfo: No family history of sudden cardiac death, HCM, or coronary artery disease, granduncle had HCM history and died at 67

ParentalTesting: Heterozygous mutation myosin binding protein C gene(MYBPC3) is confirmed in mother

CasePresentingHPOs: “enlarged left and right atria, double ventricular hypertrophy, interventricular septal thickness”

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Sanger sequencing

FunctionalAnalysis: N/A

Variant: TNN c.50171G>T, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA012326&

Case1: 42 year old Male

DiseaseAssertion: History of acromegaly

FamilyInfo: N/A

ParentalTesting: No parental testing done

CasePresentingHPOs: “elevated levels of growth hormone, and IGF-1”

CaseHPOFreeText: Genetic analysis revealed a heterozygous nonsense variant in MYBPC3

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac MRI revealed normal dimensions of thoracic aorta, no evidence of stenosis or aneurysms

CasePreviousTesting: An oral glucose tolerance test was performed, growth hormone failed to suppress below 0.88

Genotyping Method: Echocardiography used to confirm enlarged left atrium, increased septal thickness, mild mitral and tricuspid regurgitation

Variant: NM_000256.3 c.3408C>G MANE select

ClinVar: 851340

CAID: CA380313523

gnomAD: chr11-47332896

https://www.ncbi.nlm.nih.gov/clinvar/variation/851340/?term=%22c.3408C%3EG%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

Case2: 40 year old Male, 37 year old Female

DiseaseAssertion: HCM, basal septal hypertrophy, dilated phase HCM

FamilyInfo: Family was notable for end stage HCM in father and in younger brother, family history was notable for HCM in grandmother and sudden cardiac death(SDC) due to HCM in mother

ParentalTesting: No parental testing done

CasePresentingHPOs: “Inguinal Hernia surgery, exertional dyspnea”

CaseHPOFreeText: Transthoracic echocardiography unveiled hypertrophy of the interventricular septum and left ventricular anterior wall, systolic anterior motion of the mitral valve

CaseNotHPOs: N/A

CaseNotHPOFreeText: ECG demonstrated a sinus rhythm at 58 bpm with complete right bundle branch block, heart failure progressively worsened

CasePreviousTesting: Cardiac magnetic resonance reveals ring like late gadolinium enhancement(LGE) as a imaging phenotype

Genotyping Method: Cardiac magnetic resonance

FunctionalAnalysis: N/A

Variant: NM_000257.4 c.2302G>A, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA012326

GroupID: 24a

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 2/4 patients with a P86H (c.257C>A) mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86H (c.257C>A)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750632 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C>A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86H (c.257C>A)

MultipleGeneVariants: N/A

GroupID: 24b

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: N/A

GroupHPOFreeText: These 2/4 patients with a P86H (c.257C>A) mutation did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86H (c.257C>A)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750632 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C>A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86H (c.257C>A)

MultipleGeneVariants: N/A

GroupID: 11

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with a c.493del mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.V165Lfs*5 (c.493del)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423224 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.493del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V165fs (c.493del)

MultipleGeneVariants: N/A

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. Out of the 4 patients with a p.P86H (c.257C>A) mutation, 50% (2/4) of individuals had RH while the other 50% (2/4) did not. No family information was provided.

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 L198Gfs*57 (c.592_593del) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, retinal angioma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma (family ID 67).

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 E173Rfs*29 (c.516del) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma (family ID 105).

PatientID: None

KindredID: 26

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma and renal cell carcinoma.

CaseNotHPOs: HP:0001732 (Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692 (variants differ by one base pair; unclear which is accurate)

SupplementalData: N/A

Variant: p.D143Efs*13 (c.429_438del)

LegacyVariant: c.642del10bp

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131814, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131814

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: D143Efs*13 (c.429_438del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma and renal cell carcinoma.

CaseNotHPOs: HP:0009711; HP:0001732 (Retinal capillary hemangioma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.C77Sfs*82 (c.230del)

LegacyVariant: c.443del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106239, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.230del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant; deletion

CivicName: C77Sfs*82 (c.230del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 105

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E173Rfs*29 (c.516del)

LegacyVariant: c.729del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA645525089, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.516del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: E173Rfs*29 (c.516del)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 25

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Retinal angioma, renal cell carcinoma and pancreatic cyst or tumor (unspecified).

CaseNotHPOs: HP:0010797 (Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.Q96_P97delinsH (c.288_290del)

LegacyVariant: c.501_503del

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573106244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.288_290del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: Q96_P97delinsH (c.288_290del)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: A-704 (cell line)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Renal cell carcinoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: Described as sporadic RCC from cell line A-704

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I180N (c.539T>A)

LegacyVariant: p.I251N (c.752T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756277 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.539T%3EA

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant; transversion

CivicName: I180N (c.539T>A)

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline p.T152Hfs*22 (c.452_453insA) mutation, stated in the paper as c.665insA due to an older transcript. It was seen in family [pedigree No] 11, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

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. A mutation, F76del(c.227_229del) (noted as g.941_943delTCT in the paper originally) was found in a patient with cerebellar hemangioblastomas, renal cyst, and pancreatic cyst, the pateints age on onset was 31 years old. No family history was mentioned, other than a note of no familial antecedents with the disease.

An Israeli specialized centre identified 32 VHL patients belonging to 16 different kindreds. This retrospective collection and analysis of clinical, laboratory and imaging data of VHL patients involved 3 individuals belonging to kindred V. Genetic analysis via direct VHL gene sequencing and quantitative Southern blot identified the L188del (c.562_564delCTG) mutation. 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).

PatientID: 5299

KindredID: 235

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:0009726 (Renal neoplasm)

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 negative.

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 1 individuals respectively with an equivalent mutation (i.e. 473insT) 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.K159Efs*15 (c.473dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: 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: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: K159Efs*15 (c.473dup)

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.L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA) germline variant of the VHL gene was detected in a family (ID 31). Member 2656 had unknown renal involvement. Members 2511, 4325, 2744 and 2668 presented with mild renal disease (RCC). Members 2588, 2746 and 4630 presented with moderate renal disease (RCC). Members 2060 and 2279 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 9829912.

PatientID: 6321

KindredID: 343

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: N/A

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

Variant: p.R69Afs*63 (c.204dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.204dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: R69Afs*63 (c.204dup)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This delins (c.393_394delinsA) mutation was found in two VHL type 1 family members (family no. 26). Both had retinal hemangioblastomas, one had renal cysts and one had pancreatic cysts.

GroupID/ KindredID: 25

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 registrants belonging to the same family (25) have the germline VHL mutation.

GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0005584 (retinal capillary hemangioma, hemangioblastoma, renal cell carcinoma)

GroupHPOFreeText:  2 members with retinal hemangioblastomas and renal cell carcinoma, as well as 1 member with CNS hemangioblastoma

GroupNotHPOs: HP:0001737; HP:0000107; HP:0002666 (pancreatic cysts, renal cyst, pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

Variant: p.F76del (c.227_229delTCT)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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_229delTCT)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This in-frame deletion variant (c.227_229delTCT) was detected in 2 VHL families: 24 and 25. Family no. 24 was a type 2 family with 1 patient with central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and epididymal cysts. They were identified as sporadic with their parents being excluded from having a germline mutation, although they were not available for DNA analysis. Family no.25 had 2 members with retinal hemangioblastomas and renal cell carcinoma, as well as 1 member with CNS hemangioblastoma. This was published in a future publication: PMID: 32179488.

A novel heterozygous mutation (c.349 T > A, p.W117R) was detected in affected family members of a chinese family. No mutation was detected in unaffected family members or in the 150 normal controls. The mutation segregated with the disease phenotype throughout three generations. Case II:1 (the proband) was a 32 year old female who complained of blurred vision for the past 2 years in her left eye. Fundus examinations showed several retinal hemangioblastomas in the temporal area of the left eye. The patient had previously undergone the operation for cerebellar hemangioblastoma 3 years prior. Case III:1 (the proband’s son) was an asymptomatic 6-year-old male, who was found to have a small hemangioblastoma in the distant peripheral retina of his right eye. Case III:2 (the proband’s daughter) was a 12 year old female who complained of a curtain coming across the vision in her left eye during the screening examination. Fundus examinations revealed a small hemangioblastoma in the infratemporal region of the peripheral retina in her right eye. A sizeable hemangioblastoma with 2.5 papilla diameters and prominant feeder vessels were detected in the inferior peripheral retina of her left eye. Case I:2 (the proband’s mother) had blindness in one eye and died of renal carcinoma, genetic testing was not preformed on this patient. Genomic DNA was extracted from peripheral blood using a DNA extraction kit (TIANGEN). Genomic DNA from all available family members were obtained for PCR and next-generation sequencing (NGS). Sites of variation were identified through a comparison of DNA sequences with the corresponding GenBank reference sequences.

GroupID:N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 301 were enrolled to evaluate the natural history of vHL-associated pancreatic lesions. Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study.

CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121Y(c.361G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753754 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.361G%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:D121Y(c.361G>T)

MultipleGeneVariants: N/A

Twelve patients with hereditary non-SDHx head and neck paragangliomas were analyzed. Eleven of the 12 patients were found to carry germline mutations in the VHL gene. Blood was used for molecular genetic analyses and the NM_000551.2 reference sequence was used. The paper includes 3 additional VHL patients: case 22, 23, 27. Case 24 is a 24Y female who was found to harbour the p.T152I (c.455C>T) mutation of the VHL gene. The variant was written in paper under p.Tyr152Ile. This is incorrect however is paired to a paper where this variant it described (PMID: 18031321) referenced Thr152Ile, so this mutation was deduced. She presented with a a carotid body (paraganglioma), with no other details. A negative family history was described.

PatientID: 30

KindredID: 11

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 30) has a son (patient 31) who was genetically confirmed with the mutation, who was asymptomatic at the time of analysis. She also has a father (patient 32, CNS hemangioblastoma at 42), a brother 1 (patient 33, CNS hemangioblastoma at 28), brother 2 (patient 34, CNS hemangioblastoma at 30), and uncle (patient 35, retinal angioma at 60) who passed away before they could be diagnosed/ genetically confirmed with the mutation.

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

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at 28, retinal angioma at 26, renal cell carcinoma at 37, and multiple pancreatic cysts/tumors at 28.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

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

Variant: p.F76del (c.227_229del)

LegacyVariant: F76del (c.224_226delTCT)

CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

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. This frameshift mutation was found in the VHL gene of family #15. The 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 (patient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336). It is likely that the same family was published in both papers, with two additional members added in the 2018 paper.

PatientID: 132

KindredID: 50

Case: F, 45Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 132) had multiple family members who were unconfirmed with the mutation. Her brother 1 (patient 133) had a CNS hemangioblastoma at 29, and renal cell carcinoma and multiple pancreatic cysts/tumors at 48; however no DNA sample was available for testing. Her brother 2 (patient 134) had a CNS hemangioblastoma at 27, but passed away before he could be genetically confirmed with the mutation. Similarly, her father (patient 135) had a CNS hemangioblastoma at 25, but passed away before he could be genetically confirmed.

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

CaseHPOFreeText: The proband's nephew (son of brother 2) (patient 233) had a renal cell carcinoma at age 30.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.Q145Yfs*27 (c.433_437del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573131796, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131796

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: Q145fs (c.433_437delCAGCC)

MultipleGeneVariants: N/A

PatientID: 109

KindredID: 37

Case: M, 20Y0M, 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 19, renal cell carcinoma and multiple pancreatic cysts/tumors at 20.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient 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.S111Tfs*48 (c.332delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189247; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.332delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S111fs (c.332del)

MultipleGeneVariants: N/A

PatientID: 156

KindredID: 58

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 155) has a sister (patient 156) and a nephew (son of sister, patient 157) that were both genetically confirmed with the mutation. The sister presented with a CNS hemangioblastoma at 21 and multiple pancreatic cysts/tumors at 27, and the nephew was asymptomatic at the time of analysis.

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

CaseHPOFreeText: The proband's sister presented with a CNS hemangioblastoma at 21, and multiple pancreatic cysts/tumors at 27.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711 (Pheochromocytoma, Renal cell carcinoma, 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.E160Dfs*10 (c.480del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423139; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA432423139

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.480delG)

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. This mutation was confirmed in kindred 56. A female proband, patient 153, presented with a retinal angioma at 26 and multiple pancreatic cysts/tumors at 31. No family information was given. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 97

KindredID: 33

Case: M, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 97) presented with a CNS hemangioblastoma at 37, retinal angioma at 20, and renal cell carcinoma and multiple pancreatic cysts/tumors at age 29. Their brother, patient 98, presented with a retinal angioma at age 32, and at age 43 presented with renal cell carcinoma and multiple pancreatic cysts/tumors.

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

CaseHPOFreeText: The proband, patient 291, presented with a CNS hemangioblastoma at 27, and at 31 presented with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.P97Afs*35 (c.287_288insA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420510, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.287_288insA

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: P97Afs*35 (c.287_288insA)

MultipleGeneVariants: N/A

PatientID: 29

KindredID: 10

Case: M, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 21) and his son were both confirmed with this mutation. His son was asymptomatic at the time of assessment.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's son (patient 29) was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0002666, HP:0009711; HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma, 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: p.F76del (c.227_229del)

LegacyVariant: F76del (c.224_226delTCT)

CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 41

KindredID: 14

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with renal cell carcinoma and multiple pancreatic cysts/ tumors at age 44.

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

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.S80Ifs*79 (c.239del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239del

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239del)

MultipleGeneVariants: N/A

PatientID: IV-6

KindredID: 2

Case: F, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her 48Y father (Patient III-4) presented with hematuria at age 39Y and was found to have clear-cell renal-cell carcinoma, renal cysts, pancreatic cysts, and multiple hemangioblastomas of the cerebellum and lower brainstem. Her father was found to have mosaic VHL disease and the NM_000551.3:c.227_229del mutation the patient carried in approximately one of seven peripheral blood lymphocytes. The patient’s mother was unaffected. Of the patient’s three sisters and two brothers, one underwent clinical examination and two underwent genetic testing of unclear nature, and were found to be unaffected. The remaining two siblings were not evaluated.

CasePresentingHPOs: HP:0009713; HP:0001737; HP:0000107; HP:0000077; HP:0009711 (Spinal hemangioblastoma, pancreatic cyst, renal cyst, renal lesion, retinal hemangioma)

CaseHPOFreeText: The 23Y female patient was diagnosed with VHL disease at age 15 years, when she developed symptoms caused by spinal cord hemangioblastomas. At age 20 years, she was diagnosed with multiple cystic lesions in the right kidney, a solid lesion of the left kidney, multiple pancreatic cysts, and a small peripheral retinal angioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del(c.226_228delTTC)

LegacyVariant: p.F76del(c.439_441delTTC)

ClinVarID: N/A

CAID: CA357012

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del(c.226_228delTTC)

MultipleGeneVariants: N/A

PatientID: 21 (tumour 36)

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Two other members of this patient's family (patient 19 and patient 20) were found to harbour the same VHL gene mutation.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

LegacyVariant: p.L188V (c.775C>G)

CaseProblemVariantFreeText: N/A

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

CAID: CA020488 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.562C%3EG

gnomAD: 0.00002121 https://gnomad.broadinstitute.org/variant/3-10191569-C-G

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transversion

CivicName: L188V (c.562C>G)

MultipleGeneVariants: N/A

PatientID: 13 (tumour 21)

KindredID: 14

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

ClinVar: 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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 9 (tumour 13)

KindredID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one malignant pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

ClinVar: 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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 3 (tumour 3)

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

ClinVar: 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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4

Case: Unknown, 24Y0M, Chinese

DiseaseAssertion:VHL

FamilyInfo: None.

CasePresentingHPOs: HP:0010797, HP:0001732 (hemangioblastoma, abnormality of the pancreas)

CaseHPOFreeText:The patient presented with hemangioblastoma at age 23. One year later he/she was found to have pancreatic cysts or tumors.

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

CaseNotHPOFreeText: No epididymal/ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished: 29330336

Variant: p.D92Afs*40(c.275delAinsCC)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA1139768933 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275delAinsCC

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName:D92fs(c.275delAinsCC)

MultipleGeneVariants: N/A

Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012 were examined. One proband (family 8) was found to carry the mutation c.350G>C in exon 2 of the VHL gene. The proband presented with hemangioblastoma at age 18 and renal cell carcinoma and abnormality of the pancreas at age 24. The patient had negative VHL family history. This patient was previously published in 29330336.

PatientID: 5

KindredID: 3 (C)

Case: F, 38Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Family C consists of two parents and their two daughters. Patient's 14 year old daughter (see patient 4) shares the same mutation as him. She developed a retinal angioma at 12 years of age and a spinal cord hemangioma was detected at 14 years. The mother and the other daughter were free from any manifestations of the disease and showed no mutations in the VHL gene.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0006770 (spinal hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma)

CaseHPOFreeText: Radiological investigations detected bilateral kidney tumors, a cerebellar and a spinal cord hemangioma at 34 years of age. Histological analysis of the kidney verified RCC. Four years later (38 years of age), retinal angioma developed in both of his eyes.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: CA357042 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.340+1G>A

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 4 (D)

Case: M, 25Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Patient was the only available member of the family. His father had died several years ago due to a central nervous system tumour, probably a complication of VHL disease

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0006770 (cerebellar hemangioblastoma, spinal hemangioblastoma, clear cell renal cell carcinoma)

CaseHPOFreeText: Cerebellar and spinal cord hemangioma diagnoses.

CaseNotHPOs: HP:0002666; HP:0009711 (pheochromocytoma, retinal capillary hemangioma)

CaseNotHPOFreeText: No other manifestations of VHL disease were detected. See table 1.

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: CA351756378 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.555C%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: T185* (c.555C>A)

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) . An intronic variant, c.340+7G>A, (reported as IVS1+7G>A in the paper) was found in 2 affected family members that both presented with with hemangioblastomas of the CNS. They were able to analyze the germline mutation linkage to disease in this family. The pathogenic nature of the variant was not confirmed at the mRNA level; however, the fact that this alteration was not detected in one unaffected first degree relative (after clinical and radiological screening) suggests that it may be associated with the disease. Additionally, the reported novel mutation were not represented in 120 alleles from normal subjects in the Brazilian population suggesting that these base changes are not common polymorphisms.

PatientID: None

KindredID: 13

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother of this patient was also found to harbor the c.436delC germline variant of the VHL gene and presented with spinal and cerebellar hemangioblastomas and multiple pancreatic cysts.

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584; HP:0009726 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma, Renal neoplasm)

CaseHPOFreeText: CNS hemangioblastoma, retinal angioma, renal carcinoma and a renal tumor <3cm in size.

CaseNotHPOs: HP:0002894; HP:0002666 (Neoplasm of the pancreas, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P146Lfs*13 (c.436del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421892, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.436del

gnomAD: N/A

VariantEvidence: This variant was not found in 120 alleles from normal subjects in the Brazilian population.

MutationType: deletion; minus_1_frameshift_variant

CivicName: P146fs (c.436del)

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian, VHL probands and their families. The P102Rfs*57 (c.305del) germline mutation was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, pancreatic cystadenoma, and renal carcinoma (VHL family 6). The patient had no family history. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

PatientID: 117

KindredID: 117

Case: Sex Unknown, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.Y156_T157del (c.465_470del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621939, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.465_470del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion; deletion

CivicName: Y156_T157del (c.465_470del)

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 D126Rfs*6 (c.375dup) germline variant of the VHL gene was found in a 24 year old patient (ID 107) presenting with CNS hemangioblastoma and retinal hemangioblastoma. Parents and siblings were negative for the mutation confirming it as de novo in the proband. No phenotype details are noted for these family members. The variant was reported as c.375_376insC and was mapped to c.375dup. This variant also potentially alters the beta domain of the VHL protein.

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 P138T (c.412C>A) missense mutation was found in a 21 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 115). Proband and father were found to carry the P138T (c.412C>A) germline mutation of the VHL gene. Father, siblings and cousins were analyzed but no phenotype information was provided for these family members. Genotype information for siblings and cousins was not provided.

PatientID: 89

KindredID: 89

Case: Sex Unknown, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0009711, HP:0006770 (retinal capillary hemangioma, clear cell renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0001737, HP:0002666, HP:0000107 ( hemangioblastoma, pancreatic cyst, pheochromocytoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: CA020186 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86L(c.257C>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Parents, siblings and nephew were negative for the mutation confirming that this variant was de novo in the proband. No phenotype details are noted for these family members.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000107; HP:0006770; HP:0010797; HP:0001732 (Renal cyst, Clear cell renal cell carcinoma, Hemangioblastoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.V155G (c.464T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621938, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.464T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V155G (c.464T>G)

MultipleGeneVariants: N/A

PatientID: 214

KindredID: 214

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0001737, HP:0010797, HP:0000107 (pancreatic cyst, hemangioblastoma, renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666, HP:0006770, HP:0009711 (pheochromocytoma, clear cell renal cell carcinoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

PatientID: 351

KindredID: 351

Case: Sex Unknown, 40Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but no details provided.

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

CaseHPOFreeText: CNS hemangioblastoma and renal cystic lesion.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19464396

SupplementalData: Table S1, S2 and S3

Variant: p.I109Tfs*50 (c.326del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658820709, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.326del

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_1_frameshift_variant

CivicName: I109fs (c.326delT)

MultipleGeneVariants: N/A

PatientID: 363

KindredID: 363

Case: Sex Unknown, 44Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009711 (Hemangioblastoma, Clear cell renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: Retinal hemangioblastoma, CNS hemangioblastoma and Clear cell renal cell carcinoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

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

PatientID: 77

KindredID: 77

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (hemangioblastoma )

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0001737, HP:0002666, HP:0000107, HP:0006770 (retinal capillary hemangioma, pancreatic cyst, pheochromocytoma, renal cyst, clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

Variant: p.R113*(c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: CA348491 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.337C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113*(c.337C>T)

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 (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. 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. 1 from Family 81 was found with a c.509T>G germline missense mutation and a pancreatic endocrine tumour. A second patient, was also found with this mutation: Patient No. 9 from family 81, and presented with pancreatic endocrine tumour and pheochromcytoma. Both the patient's phenotype is highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).

PatientID: 9

KindredID: 81

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 81 was mentioned (Patient: 1). This patient was found to have a pancreatic endocrine tumour without pheochromocytoma or renal cell carcinoma.

CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 81

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 81 was mentioned (Patient: 9). This patient was found to have a pancreatic endocrine tumour and pheochromocytoma, without renal cell carcinoma.

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.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts)

CaseHPOFreeText: Patient 4 was a 52-year-old female a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, retinal angioma, pancreatic cyst.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.446A>G

CaseProblemVariantFreeText: N/A

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

CAID: CA351749194

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S (c.223A>G)

MultipleGeneVariants: N/A

The data of 18 patients with solid renal tumours associated with VHL disease were analyzed. All patients except for Patient 12 came from families with a definite VHL family history (the paper does not provide further details on this.) The patients came from 12 Chinese families and 5 were from the same family. Extrarenal manifestations of VHL disease were detected in 17 patients. Of 18 patients, 15 (including 6 asymptomatic) volunteered for DNA testing as previously described. Patients 6 and 7 had genetic testing and were found to have the same germline frameshift mutation c.447del (p.Asn150Ilefs*)(noted as c.661delA in the paper due to a difference in the VHL reference sequence notation used.). It is unclear if these patients are related. Patient 7 had family study DNA test as their reason for treatment. Patient 6 was a 50-year-old female with a medical history of synchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, pancreatic cyst. Patient 7 was a 48-year-old male with a medical history of solid renal tumours some which were further characterized as clear cell RCC, multiple renal cysts, CNS hemangioblastoma , pancreatic cyts. AMCG evidence codes: ’PP4’ because the patients phenotype is highly specific for a mutation in the VHL gene.

PatientID: 16

KindredID: 16

Case: F, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0010797 (Renal neoplasm, Hemangioblastoma)

CaseHPOFreeText: Patient 16 had genetic testing and was found to have a germline mutation c.286C>T (Gln96*).

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96* (c.286C>T)

LegacyVariant: c.499C>T

CaseProblemVariantFreeText: N/A

ClinVar: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: CA351750811

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

Thirty-two surgically resected HB specimens from 28 patients treated at the University of Tokyo Hospital between 1995 and 2012 were analyzed retrospectively. Of the 32 specimens, 11 were VHL-related HBs from 7 patients. Two brothers identified as hemangioblastoma patients were confirmed with a germline c.216delC deletion in the VHL gene. Identical single base-pair deletions were found in 3 hemangioblastomas from these 2 patients with VHL disease from the same family, indicating that this small frameshift deletion was a germline mutation. One brother had hemangioblastoma in the cerebellum at 22Y and then again at 24Y, and the 30Y brother had a hemangioblastoma in the brainstem. No other phenotypic information was available.

PatientID: V1

KindredID: 1

Case: M, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient’s brother also had this germline mutation and at least one brainstem hemangioblastoma at 30 years old.

CasePresentingHPOs: HP:0006880 (Cerebellar hemangioblastoma)

CaseHPOFreeText: Study reports 2 cerebellar hemangioblastomas at the ages of 22 and 24. Other phenotype information not provided.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table 2

Variant: p.Q73Rfs*86 (c.216del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432536422, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA432536422

gnomAD: N/A

VariantEvidence: The c.216delC variant was not genetically confirmed to be germline but was found in tumor samples from both the siblings.

MutationType: minus_1_frameshift_variant

CivicName: S72fs (c.216delC)

MultipleGeneVariants: N/A

GroupID: V31

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: Patients are grouped by family.

FamilyInfo: 3/6 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: N/A

SupplementalData: N/A

Variant: p.L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130363, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.531_532insCTGAGAGTAAAGCCTGAA

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: L178_D179insRVKPEL (c.531_532insCTGAGAGTAAAGCCTGAA)

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 E46* (c.136G>T) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V65).

A case describes a 22Y male presenting with a believed novel sporadic mutation labeled as 'NT474INST' by the authors (c.474insT resulting in a frameshift mutation). He complained of a shadow in his right eye and was diagnosed with retinal detachment secondary to a retinal hemangioblastoma. MRI of the brain revealed a hyper vascular lesion in the medulla and a smaller lesion at the medullary-spinal cord junction. Weighted abdominal MRI revealed innumerable pancreatic cysts and multiple benign-appearing renal cysts. He also presented with an epididymal cyst. After surgical resection of the retinal hemangioblastoma, the patient remained asymptomatic. The patient has a no family history of VHL but family genotype is not described.

PatientID: None

KindredID: 1

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No notable family history.

CasePresentingHPOs: HP:0000541; HP:0010797; HP:0009711; HP:0030424; HP:0005562; HP:0001737 (Retinal detachment, Hemangioblastoma, Retinal capillary hemangioblastoma, Epididymal cyst, Multiple renal cysts, Pancreatic cysts)

CaseHPOFreeText: Complained of a shadow in his right eye and was diagnosed with retinal detachment secondary to a retinal hemangioblastoma. MRI of the brain revealed a hyper vascular lesion in the medulla and a smaller lesion at the medullary-spinal cord junction. Weighted abdominal MRI revealed innumerable pancreatic cysts and multiple benign-appearing renal cysts. After surgical resection of the retinal hemangioblastoma, the patient remains asymptomatic.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.K159* (c.474_475insT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423112, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.474_475insT

gnomAD: N/A

VariantEvidence: Reported as: NT474INST. Authors state that this is believed to be a novel sporadic mutation.

MutationType: insertion; plus_1_frameshift_variant; stop_gained

CivicName: K159* (c.474_475insT)

MultipleGeneVariants: N/A

Of 38 PPGL (pheochromocytoma and paraganglioma) cases studied, two were associated with an individual carrying the germline mutation c.308C>A (ENSP00000256474.2 p.Pro103His) of the VHL gene. This mutation was identified using germline clinical sequencing on fresh and formalin-fixed and paraffin-embedded (FFPE) tissue and confirmed with sanger sequencing. The authors identified the reference sequence used as NM_000551.3. The first patient (ID: WM01) presented with pheochromocytoma said to be MAX-Like (7yo), and the second (ID: WM04) with a pheochromocytoma (13yo). No family history, or relation, was presented.

PatientID: VCB.04T

KindredID: 5

Case: Sex Unknown, 24Y0M, 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.V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573119327 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573119327

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift_variant

CivicName: V166Dfs*9 (c.480_481insCGATGCCTCCAGGT)

MultipleGeneVariants: N/A

Of 38 PPGL (pheochromocytoma and paraganglioma) cases studied, one was associated with an individual carrying the germline mutation ENST00000256474.2:c.480_481insCGATGCCTCCAGGT (ENSP00000256474.2:p.Val166AspfsTer9) of the VHL gene. This mutation was identified using Sanger sequencing. The authors identified the reference sequence used as NM_000551.3. This patient presented with phechromocytoma and paraganglioma. This patient was previously published in PMID: 25545346. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: 2

KindredID: 1

Case: M, 30Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 4 patients from the same family (2 male 2 female; age range 27-35Y) carry this mutation (c.509T>G).

CasePresentingHPOs: HP:0009711; HP:0002666; HP:0002668 (retinal capillary hemangioma, pheochromocytoma, paraganglioma)

CaseHPOFreeText: scans showed he was affected by retinal angiomas, bilateral adrenal pheochromocytoma, 2 intra-foraminal masses at the S1 level (suggestive of sacral paragangliomas), and a solid hypervascular lesion in the right carotid region (indicative of intercarotid paraganglioma).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 22YO

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 Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 22YO. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80Ifs*79 (c.239delG)

LegacyVariant: FS (c.452delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239delG

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239delG)

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 (G57fs (c.167_168insA)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 110CA. It was reported in the paper as c.380insA due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 3710NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 3710NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L135* (c.404T>A)

LegacyVariant: p.L135* (c.617T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754021 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.404T>A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: stop_gained

CivicName: L135* (c.404T>A)

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 (S111fs (c.331delA)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3669NCI. It was reported in the paper as c.544delA 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.

GroupID/ KindredID: 110CA

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 110CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, ithout phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL familywith RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G57Rfs*75 (c.167_168insA)

LegacyVariant: (c.380insA)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA916084344 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.167_168insA

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: plus_1_frameshift_variant

CivicName: G57fs (c.167_168insA)

MultipleGeneVariants: N/A

GroupID/ KindredID: 85CA

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 85CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C77Lfs*55 (c.228_229insC)

LegacyVariant: FS (c.441insC)

CaseProblemVariantFreeText: NM_000551.3:c.228_229insC automaps to c.228dupC

ClinVarID: N/A

CAID: CA658795177 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.228dupC

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: plus_1_frameshift_variant; duplication

CivicName: C77fs (c.228dupC)

MultipleGeneVariants: N/A

GroupID/ KindredID: 102CA

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 102CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D126Rfs*6 (c.375_376insC)

LegacyVariant: FS (c.588insC)

CaseProblemVariantFreeText: c.375_376insC automaps to NM_000551.3:c.375dupC

ClinVarID: N/A

CAID: CA16621931 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.375dupC

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site either by truncating the protein.

MutationType: duplication; plus_1_frameshift_variant

CivicName: D126fs (c.375dupC)

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 (G104Hfs*27 (c.309_310delTG)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 53CA. It was reported in the paper as c.522delTG 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 (V170F (c.508G>T)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 26CA. It was reported in the paper as c.721G>T due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

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 (V74G (c.221T>G)) was taken from the Munich, university of Freiburg and Institude of Pathology database (reported in Table 3, found in VHL family without pheochromocytoma, and with renal cell carcinoma) with an unknown number of members belonging to Family ID 53CE, as well as Family ID 9CE (reported in Table 4, found in VHL families with pheochromocytoma). It was reported in the paper as c.434T>G due to a difference in transcript reference. Other phenotypes are likely, however not detailed here.

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. R113FS (c.337del) was found in a patient with retinal hemangioblastomas diagnosed at age 28Y.

Genotype-phenotype correlations of 573 VHL patients 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). A missense mutation (c.346C>G), affecting residue with pVHL protein core, was detected in a VHL type 1 family with 3 affected individuals. All 3 patients had retinal angioma.

GroupID: 80

DiseaseAssertion: assumed VHL

GroupSize: 33

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 33 of the 573 patients discussed in this paper were found to have identical variants. This mutation (R161Q (c.500G>A)) was found in 7 VHL families with 33 patients altogether.

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

GroupHPOFreeText: 17 had retinal hemangioblastoma, 9 had cerebellar hemangioblastomas, 5 had renal cell carcinoma, and 15 had pheochromcytoma. Mean ages for each diagnosis follows: 28 (RH), 23 (CHB), 41 (RCC), 17 (Pheo)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.R161Q (c.500G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: R161Q (c.500G>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients 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 nonsense mutation (c.375insT: p.Glu55*) in a VHL family with 2 affected members. They both had hemangioblatomas. No other info was given.

The mutation was written as follows: AFO10238:375_376insT; NM_000551.2:c.162_163insT; p.54MetX. Author Maher was contacted and confirmed "A single nucleotide insertion (T) was detected at position 375 (375insT)” from 2000 lab report - June 1, 2021 - therefore assume p. transcribed incorrectly.

GroupID: 32

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 of the 573 patients discussed in this paper were found to have the following mutation belonging to 1 family. 

GroupPresentingHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma; retinal capillary hemangioma)

GroupHPOFreeText: 1 patient had retinal hemangiomas diagnosed at an unknown age and 1 had cerebellar HB diagnosed at 31Y

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.Y175* (c.525delC) 

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913185019 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.525del

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Y175* (c.525delC) 

MultipleGeneVariants: N/A

PatientID: Proband 8

KindredID: 4

Case: M, 29Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666; HP:0005562 (Pheochromocytoma, Multiple renal cysts)

CaseHPOFreeText: Unilateral PCC diagnosed at 29Y and bilateral renal cysts. Stated as having VHL type IIB.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P138Afs*6 (c.410dup)

LegacyVariant: 623insTTTGTtG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup

gnomAD: N/A

VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.

MutationType: insertion; plus_1_frameshift_variant

CivicName: P138fs (c.410dup)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 32

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation belonging to VHL family 32

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0001737; HP:0000107; HP:0005584; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cyst, renal cell carcinoma, papillary cystadenoma of the epididymis)

GroupHPOFreeText:  1 patient has retinal angiomas (retinal capillary hemangioma), 2 have CNS hemangioblastoma, 1 has renal cysts and renal cell carcinoma (RCC), 1 has pancreatic cysts, and one has cystadenomas of the epididymis (papillary cystadenoma of the epididymis).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: 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: CA020408 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.481C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This mutation was found in 2 German, VHL type 1, family members with hemangioblastomas of the central nervous system, renal cell carcinoma, renal cysts, and pancreatic cysts. Hepatic adenomas were also listed as an additional complication (family VHL 44). The L129fs (c.384delT) mutation was detected in the patient, referred to in the paper by c.597delT due to a difference in transcript sequence. This study contains very strong evidence of pathogenicity in the form of a frameshift variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

GroupID/ KindredID: VHL 44

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation belonging to VHL family 44

GroupPresentingHPOs: HP:0010797; HP:0005584; HP:0000107; HP:0001737; HP:0009715; HP:0012028 (hemangioblastoma, renal cell carcinoma, renal cyst, pancreatic cysts, Hepatic adenoma)

GroupHPOFreeText: both patients had hemangioblastomas, renal cell carcinomas, renal cysts, and pancreatic cysts. Hepatic adenoma was also listed as an additional complication

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129fs*30 (c.384delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L129fs*30 (c.597delT)

ClinVarID: N/A

CAID: CA70049452 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.384delT

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: L129fs (c.384delT)

MultipleGeneVariants: N/A

PatientID: 42

KindredID: 5069

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 41) has the same VHL mutation and presents with five pathologic pancreatic endocrine tumours.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with three pathologic pancreatic endocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

ClinVar: 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: 7

KindredID: 2656

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of her family (patient 8) also presented with pancreatic endocrine tumour.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with one pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V62Cfs*5 (c.180delG)

LegacyVariant: p.V62Cfs*5 (c.393delG)

CaseProblemVariantFreeText: N/A

ClinVar: 182986 https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: CA020069 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.180delG

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V62Cfs*5 (c.180delG)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 2735

Case: F, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with one pathologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Q73* (c.430C>T)

CaseProblemVariantFreeText: N/A

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

CAID: CA357036 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.217C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 33

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.L140Qfs*3 (c.417_418delTC)

CaseProblemVariantFreeText: recorded in paper as c.417_418delTC, this automaps to NM_000551.3:c.419_420delTC

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA357039 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.417_418delTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift

CivicName: L140fs (c.417_418delTC)

MultipleGeneVariants: N/A

GroupID: 29

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.V130Wfs*30 (c.386_387insCT)

CaseProblemVariantFreeText: recorded in paper as c.386insCT, this automaps to NM_000551.3:c.385_386dupCT

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2573130306 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.385_386dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication

CivicName: V130fs (c.385_386dup)

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 mutation p.Y156* (c.468T>G) was found in 3 VHL patients. All 3 were said not to have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

GroupID: 39

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: all 3 members are said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 6

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N67_V74del (c.197_220del)

CaseProblemVariantFreeText: Paper describes this as a frameshift via c.197del24 (p.66)

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA645524685 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.197_220del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: N67_V74del (c.197_220del)

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 stop mutation (p.E46* (c.136G>T)) was found in a single patient with VHL retinal manifestation, which coincides with mutations confirmed to be associated with VHL type 1 in this study. No family information was provided. This is possibly previously published in PMID: 15300849

GroupID: 54

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R205Hfs*50 (c.612_613delGC)

CaseProblemVariantFreeText: c.612_613delGC automaps to NM_000551.3:c.614_615delGC

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA020525 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.612_613delGC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: R205fs (c.614_615delGC)

MultipleGeneVariants: N/A

GroupID: 20

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: N/A

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.R108L*52 (c.322_323insTG)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2501548609 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2501548609

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_2_frameshift

CivicName: R108fs (c.322_323insTG)

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 frameshift mutation (c.211insT, p.P71Lfs*61) was found in a 1 patient, without retinal hemangioblastomas, but other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849