PatientID: None

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s daughter, age 27, presented with two right renal masses and several pancreatic cysts at 22Y. The patient’s brother, age 38, presented with unilateral ccRCC. Both the patient’s daughter and brother were found to carry the mutation the patient carried.

CasePresentingHPOs: HP:0006770; HP:0001737 (Clear cell renal cell carcinoma, pancreatic cysts)

CaseHPOFreeText: The patient presented with right ccRCC and pancreatic cysts.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: None(c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

Twelve patients with hereditary non-SDHx head and neck paragangliomas were analyzed. Eleven of the twelve 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. A total of five patients in this cohort were found to harbour the p.Tyr98His germline mutation of the VHL gene. As well as one patient from literature (previously published in 9880225). In family 1, the proband (case 1) was a 7 year old male diagnosed with malignant extra-adrenal pheochromocytoma of the left retroperitoneum with regional lymph node metastases and treated with resection of the primary tumor, lymphadenectomy, and chemotherapy. At age 9, he presented with a local reocurrance which was treated with resection and external radiotherapy of 20Gy. At age 13, he presented a right adrenal pheochromocytoma which was resected. At age 15 a left carotid body tumor was clinically detected and removed, but recurred at age 16 and again was resected. At age 17, a pheochromocytoma at the renal pelvis was diagnosed by MRI and resected. At age 18, he was disease free except for a lesion in the L1 vertebral body suggestive of hemangioma or pheochromocytoma. His mother was asymptomatic but had the mutation. His cousin had the mutation and presented with a pheochromocytoma. His aunt also had the mutation and a history of retinal hemangioblastomas. The fifth patient with this mutation (case 10), an unrelated 34 year old female, presented with no personal or family history of VHL and persistent pharyngeal discomfort. MRI demonstrated a 4cm tumor in the parapharyngeal space. The tumor was removed, and histology revealed a paraganglioma. Postoperatively, she had Horner’s syndrome and a transitory hypoglossal paresis. At age 46, bilateral adrenal pheochromocytoma and a paraaortic paraganglioma were removed. Later, her niece was diagnosed with a pheochromocytoma, and her brother suffered from pheochromocytoma, renal cell carcinoma, and retinal hemangioblastomas. The proband’s mother was then found to have pheochromocytoma. Case 23 was from the literature and was a female presenting with pheochromocytoma, paraganglioma of head and neck, retinal capillary hemangioma and pancreatic cysts. The patient had a positive family history.

The authors described the growth kinetics of 96 renal tumours in 64 VHL patients (32 males, 32 females). All patients had VHL disease with renal involvement. 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 patients, at least one or more RCC was diagnosed. However, at the time of diagnosis, an indication for treatment was not yet present. For all patients, several CT/MRI scans existed for retrospective description of tumour growth kinetics. 10-ml EDTA anticoagulated blood samples were available from each patient for mutation screening of all exons of the VHL gene. Genomic DNA from blood samples was extracted using standard methods. Small deletions/insertions or point mutations were identified by DNA sequencing followed by complete mutation screening using PCR/single-strand conformation polymorphism and denaturing high-performance liquid chromatography. A germline missense variant p.P154L(c.461C>T) was identified in patient #14. This mutation was noted as c.674C>T in the paper due to a difference in reference transcript used (see Table S1). No family information is available for this patient.

Case1: 13 year old female

DiseaseAssertion: LVNC

FamilyInfo: No family history of cardiac disease

ParentalTesting:

CasePresentingHPOs: HP:0011664. HP:0002094. HP:0001279. HP:0031295

CaseHPOFreeText:Left Ventricular noncompaction, Dyspnea (shortness of breath), Fainting, Left atrial enlargement

CaseNotHPOs:HP:0000929. HP:0001712

CaseNotHPOFreeText:Abnormal skull morphology, left ventricular hypertrophy

CasePreviousTesting:

Genotyping Method:Next-Generation Sequencing (NGS)

FunctionalAnalysis:

Variant:c.575G>A

ClinVar:12424

CAID:CA021957

gnomAD:

AdditionalInfo:

PMID: 30279906

Gene: TNNI3

HGNC ID: 11947

PMID: 20641121

Gene: MYL3

HGNC ID: HGNC:7584

Case1:Female diagnosed at 28

DiseaseAssertion:HCM, ASH, LVEF

FamilyInfo:Sister with HCM, ASH, and mid-LV cavity obstruction

ParentalTesting:

CasePresentingHPOs:HP:0001639, HP:0001670, HP:0034314, HP:0001279

CaseHPOFreeText:Hypertrophic cardiomyopathy, Asymmetric Septal Hypertrophy, Abnormal Left Ventricular Ejection Fraction, Syncope

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

Genotyping Method:Not detailed

FunctionalAnalysis:MYL3 A57G

Variant:c.170C>G (p.Ala57Gly)

ClinVar:31780

CAID:CA013589

gnomAD:

AdditionalInfo:

Case#: 30 year old female athlete

DiseaseAssertion: Subclinical hypertrophic cardiomyopathy

FamilyInfo: Her mother has HCM and the same ACTC1 gene change. Her grandmother and uncle on her mothers side died suddenly.

ParentalTesting: Her mother tested positive for the ACTC1 gene change and there isn't any information about the father.

CasePresentingHPOs: NR

CaseHPOFreeText: The patient did not have dizziness, fainting, trouble breathing or chest pain. Her heart muscle was not thickened.

CaseNotHPOs: NR

CaseNotHPOFreeText: The patient sometimes felt her heart beating unusually during exercise. A heart MRI showed small changes in her heart muscle and heart valve.

CasePreviousTesting: The patient had an ECG, heart ultrasound, heart monitor and heart MRI

Genotyping Method:Sanger sequencing was used to test the ACTC1 gene.

FunctionalAnalysis: NR

Variant: ACTC1 p.Val11Leu

Clinvar: 2947021

CAID: CA391633409

gnomAD: NR

AdditionalInfo: The patient continued playing competitive sports and had regular heart checkups.

Case1:19 Year-old male

DiseaseAssertion:HCM

FamilyInfo:None documented

ParentalTesting:

CasePresentingHPOs:HP:0001639

CaseHPOFreeText:Hypertrophic Cardiomyopathy

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

Genotyping Method:Next Generation Sequencing

FunctionalAnalysis:

Variant:c.442G>A, (p.Gly148Arg)

ClinVar:42752

CAID: CA015105

gnomAD:

AdditionalInfo:

PMID: 31293105

Gene: MYBPC3

HGNC ID: HGNC:7551

Case:Male, born at 39 weeks of gestation, evaluated during infancy-age 6. DiseaseAssertion:Arthrogryposis multiplex congenita (AMC). The patient also had Shone's complex with coarctation of the aorta. Cardiomyopathy not reported. Familyinfo:The patient was the first child of unrelated parents. No family history of arthrogryposis multiplex congenita was reported. ParentalTesting:The ACTC1 c.650A>C (p.Lys217Thr) variant was identified as de novo. Neither parent was reported to carry the variant. CasePresentingHPOs:Limited range of motion in wrists, Limited range of motion in fingers, Limited range of motion in thumbs, Hip contractures, Knee contractures, Bilateral clubfeet, Clenched hands, Hypotonia, Lower extremity weakness, CaseHPOFreeText:The patient was born at 39 weeks of gestation. At birth, he had limited range of motion in the wrists, fingers, thumbs, hips, and knees, along with bilateral clubfeet. Echocardiography revealed Shone's complex, including coarctation of the aorta, which required surgical repair. At age 1, he had clenched hands with deep single palmar creases, overlapping toes, and hypoplastic fifth toenails. He also had truncal hypotonia, mild lower extremity weakness, and delayed gross motor milestones. At age 3, moderate wrist contractures, thumb-in-palm deformities, and mild bilateral hip contractures were observed. He began walking independently at age 4. At age 5, he underwent additional heart surgery and pacemaker insertion. CaseNotHPOs:Scoliosis: not identified on spine X-rays, cognitive difficulties: not reported CaseNOTHPOFreeText:The patient did not have reported cognitive difficulties. Spine X-rays did not reveal scoliosis. CasePreviousTesting:Genome sequencing was performed to identify genetic variants associated with the patient's clinical presentation. Echocardiography was used to identify Shone's complex and coarctation of the aorta. GenotypingMethod:Genome sequencing. Plasmid sequences used for the functional experiments were verified by Sanger sequencing. FunctionalAnalysis:In vitro functional studies were performed using MC3T3-E1 preosteoblastic cells. The p.Lys217Thr variant did not demonstrate a clear effect on ACTC1 protein expression or localization compared with wild-type ACTC1. The authors reported no apparent reduction in protein levels or impaired actin filament organization. Variant:NM_005159.5 (ACTC1): c.650A>C; p.Lys217Thr. ClinVar:not reported CAID:not reported gnomAD:not reported AdditionalInfo:The variant was identified as de novo and classified as likely pathogenic using ACMG criteria (PS2, PM1, PM2, PP2, PP3). Although functional testing did not demonstrate a clear effect on ACTC1 protein expression or localization, the authors considered the variant likely pathogenic based on the genetic and clinical evidence.

Case:Female, born at 34 weeks of gestation, 5 years old at the first detailed examination, 8 years old during a later clinical description. DiseaseAssertion:Arthrogryposis multiplex congenita (AMC). Cardiomyopathy not reported. Familyinfo:The patient was the first child of unrelated parents. Her mother and one maternal aunt were born with bilateral clubfeet and later developed scoliosis. The mother also had a history of cleft palate. Neither the mother nor the patient had a reported history of cardiac problems. ParentalTesting:The patient's mother carried the same heterozygous ACTC1 c.325G>A (p.Glu109Lys) variant. The variant was therefore inherited from the mother. CasePresentingHPOs:Bilateral clubfeet, scoliosis, cleft palate, neck webbing, camptodactyly, joint contractures. CaseHPOFreeText:The patient was born by cesarean section at 34 weeks of gestation. Bilateral clubfeet, cleft palate, neck webbing, and spinal deformity were noted. At age 5, she had severe scoliosis measuring 120 degrees and severe short stature. At age 8, mild camptodactyly of both hands and mild contractures of the neck, left hip, both knees, and feet were observed. She had no significant mobility or cognitive difficulties and was independent in self-care activities. CaseNotHPOs:No reported cardiac problems, no significant cognitive difficulties, no significant mobility difficulties. CaseNOTHPOFreeText:The patient had no reported cardiac phenotype despite carrying an ACTC1 variant. Her mother also had no history of cardiac problems. CasePreviousTesting:Genome sequencing was performed to identify genetic variants associated with the patient's clinical presentation. GenotypingMethod:Genome sequencing. Plasmid sequencing was also verified by Sanger sequencing for the experimental functional studies. FunctionalAnalysis:In vitro functional studies were performed using MC3T3-E1 preosteoblastic cells. The p.Glu109Lys variant caused decreased ACTC1 protein levels and impaired actin filament assembly. Immunofluorescence and Western blotting were used to evaluate protein expression and actin filament organization. Variant:NM_005159.5 (ACTC1): c.325G>A; p.Glu109Lys. ClinVar:not reported CAID:not reported gnomAD:not found AdditionalInfo:The variant was inherited from the patient's mother, who also had bilateral clubfeet, scoliosis, and a history of cleft palate. The authors classified the variant as likely pathogenic using ACMG criteria (PM1, PM2, PP1, PP2, PP3). The functional studies demonstrated reduced ACTC1 protein levels and impaired actin filament assembly.

Case5: 65 year-old male

DiseaseAssertion: carried a known TNNT2 K247R mutation as well as two novel intronic variants in MYH7 (IVS39+7C>A) and MYBPC3 (IVS25+13T>A)

FamilyInfo: None of his five siblings were affected, judged by their clinical presentation, nor was there any history of cardiac disease or sudden death in the family.

ParentalTesting:NR

CasePresentingHPOs:HP:0003677, HP:0012828, HP:0001635, HP:0005110, HP:0034307, HP:0012666,

CaseHPOFreeText: had late-onset at age 47 IDC, with a slow progression to severe heart failure and subsequently HTX. He also suffered from atrial fibrillation in the later stages of his disease. Had left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with a value of 68mm and 3.4cm/m2. As well with 30% of left ventricular ejection fraction. His ECG is normal, clinical status is heart transplantation from the age of 56. CAG is normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis: The variant could thus possibly result in the synthesis of a limited amount of the slightly modified β-myosin. The functional significance of this is not easily established, but it suggests that the variant may be a disease modifier.

Variant:NM_001276345.2:c.869A>G

ClinVar:4881578

CAID:CA344201883

gnomAD:NR

AdditionalInfo: MYH7 (IVS39+7C>A) increased the likelihood of a cryptic donor splice site to 70%, possibly resulting in the synthesis of mRNA coding for a β-myosin with a C terminus of –VGLE instead of –GLNEE. As the variant is located in the last exon, the faulty spliced mRNA is probably not degraded but results in the synthesis of a modified protein.

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

PMID: 38586174 Gene: MYBPC3 HGNC ID: 7551

Case2: 12-year-old boy (Patient 2) DiseaseAssertion: DCM FamilyInfo: Family history unremarkable. ParentalTesting: The MYBPC3 variant was inherited from his father. The father’s cardiac phenotype is not reported. CasePresentingHPOs: HP:0001644, HP:0003546 CaseHPOFreeText: Severely depressed biventricular function; heart transplantation for decompensated heart failure. CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Previous WES was negative; the variant’s intronic region was not adequately covered. Genotyping Method: Whole-genome sequencing (WGS; Illumina NovaSeq 6000; aligned to hg19/GRCh37). FunctionalAnalysis: SpliceAI predicted a potential splicing effect; no functional assay in this patient is reported. Variant: NM_000256.3:c.1224-80G>A (heterozygous intronic variant) ClinVar: 693982 CAID: CA221697326 gnomAD: 0.0000637 AdditionalInfo: The authors classified the variant as a VUS in this DCM case because evidence for a MYBPC3–DCM relationship is limited. ClinVar currently reports a pathogenic/likely pathogenic aggregate classification, primarily in relation to HCM. Reanalysis found no second MYBPC3 variant.

Case#: Family 1, individual II-5

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The proband has a family history of DCM. His father and brother also had DCM and died from heart failure at ages 69 and 63 respectively. The disease follows an autosomal dominant inheritance pattern.

ParentalTesting: Want reported, his father had DMC but this article does not confirm genetic testing of his parents.

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644) & left ventricular systolic dysfunction (HP:0005162)

CaseHPOFreeText: The proband was diagnosed with DCM at age 45 and received medication for heart failure. At the time of the study he was 66 years old. His echocardiogram showed an enlarged left ventricle and reduced heart function with an ejection fraction of 33%.

CaseNotHPOs: NR

CaseNotHPOFreeText: The researchers reported no other structural heart diseases or conditions contributing to DCM in the affected family members, including coronary heart disease, valvular heart disease, viral myocarditis and hypertension.

CasePreviousTesting: ECG, clinical examination and routine laboratory testing were part of the study assessment. The probands echocardiogram showed a left ventricular end diastolic diameter of 63 mm and an ejection fraction of 33%.

Genotyping Method: Genome wide microsatellite screening, genetic linkage analysis, whole exome sequencing and sanger sequencing.

FunctionalAnalysis: Laboratory experiments showed that the KLF13 E144X mutation reduced the proteins ability to activate the heart related genes ACTC1 and MYH7. The mutation also affected DNA binding cooperation with GATA4 and normal nuclear localization.

Variant: KLF13 c.430G >T

Clinvar: NR

CAID: CA391891162

gnomAD: The researchers reported that the variant was absent from gnomAD and other population databases at the time of their study. No numerical allele frequency was provided.

AdditionalInfo: The proband is a male from a 4th generation Chinese family. His KLF13 mutation was associated with familial DCM. the researchers found that the mutation was shared by affected family members and was absent from unaffected family members and 418 unrelated healthy controls.

Case#: Family 2, III-10 47 year old female

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Multiple family members had DCM. The disease followed an autosomal dominant inheritance pattern.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText:Female aged 47 with DCM. Her left ventricular end diastolic diameter was 57mm and her ejection fraction was 40%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation.

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The E194X mutation reduced the ability of KLF13 to activate ACTC1 and MYH7 and bind their promoters. It also disrupted cooperation with GATA4.

Variant: KLF13 c.580G>T

Clinvar: NR

CAID: NR

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The mutation was found in affected family members and was absent from 418 unrelated healthy controls.

Case#: Family 3, III-4

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The family had multiple cases of DCM consistent with autosomal dominant inheritance.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText: Female age 41 with DCM. her left ventricular end diastolic diameter was 58 mm and her ejection fraction was 43%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The C199R mutation reduced KLF13 ability to activate ATC1 and MYH7 bind DNA and work together with GATA4.

Variant: KLF13 c.595T>C

Clinvar: NR

CAID: CA391512228

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The variant was associated with familial aDCM and was not detected in the 418 healthy controls.

PMID: 22194935

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID 37498360

Gene: TPM1

HGNC ID: 12010

Case1: HCM patient-derived cell line UKEi070-A (demographics not reported in this paper) DiseaseAssertion: HCM

ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Genotyping Method: Not reported in this paper; it references a previously established patient-derived cell line. FunctionalAnalysis: The variant is reported to cause MYBPC3 protein haploinsufficiency in cardiomyocytes. In this study, TTL overexpression normalized cell hypertrophy in the HCM cell model. Variant: NM_000256.3:c.2308G>A (heterozygous; the paper reports the splice consequence as p.Asp770Serfs98X) ClinVar: 36604 CAID: gnomAD: NR AdditionalInfo: The paper uses patient-derived induced pluripotent stem cell cardiomyocytes; it does not provide the patient’s age, sex, or pedigree.

Chronic Activation of Tubulin Tyrosination Improves Heart Function

PMID: 39279670 Gene: MYBPC3 HGNC ID: 7551

Novel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes

PMID: 31361967

Gene: MYBPC3

HGNC ID: 7551

Case1: 50 year old male DiseaseAssertion: HCM; hydroxychloroquine cardiotoxicity FamilyInfo: Six children undergoing predictive testing for the familial MYBPC3 variant; family history not reported ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: Monomorphic ventricular tachycardia, dyspnea, nausea, vomiting, biventricular hypertrophy, systolic dysfunction, cardiogenic shock CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Prior CMR showed nonobstructive HCM; cardiomyopathy gene panel identified the variant Genotyping Method: Cardiomyopathy gene panel FunctionalAnalysis: Altered splicing with exon 30 skipping; authors describe a nonfunctional protein or premature stop codon Variant: c.3330+5G>C ClinVar: 42706 CAID: gnomAD: 0.03% (as reported in the article) AdditionalInfo: Long-term hydroxychloroquine exposure for malaria prophylaxis; biopsy findings were consistent with both HCM and hydroxychloroquine cardiotoxicity

Hydroxychloroquine Cardiotoxicity and Sarcomeric Hypertrophic Cardiomyopathy.”

PMID: 40514126 Gene: MYBPC3 HGNC ID: 7551

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: 13

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 1 member is said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other 2 members are specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

ClinVarID: 193118 https://www.ncbi.nlm.nih.gov/clinvar/variation/193118/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R82P (c.245G>C)

MultipleGeneVariants: N/A

GroupID: 8

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 patients are listed with this mutation; any relation is unknown.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 4 members are said to have retinal HBs. Other manifestations are not clearly stated.

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: the other member is specifically said to not have retinal HBs

GroupPreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

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

CaseProblemVariantFreeText: N.A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: 17

KindredID: C

Case: Sex Unknown, 13Y0M, Mexican (Latino/Admixed American)

DiseaseAssertion: asymptomatic

FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient was asymptomatic at the time, likely due to young age

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).

SupplementalData: N/A

Variant: p.T100Nfs*32 (c.298dupA)

LegacyVariant: c.1012_1013insA

CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).

ClinVarID: N/A

CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA

gnomAD: N/A

VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional

MutationType: plus_1_frameshift_variant; duplication

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PMID: 16572651

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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. One proband was genetically confirmed with this germline mutation: a 46 year old female from kindred #89 who presented with a renal cell carcinoma at that age. This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 259

KindredID: 100

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24. The proband's son, patient 260, was asymptomatic at the time of analysis.

CasePresentingHPOs: N/A

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

CaseHPOFreeText: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 1-2 Deletion (c.1-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-2 Deletion

MultipleGeneVariants: N/A

PatientID: 220

KindredID: 82

Case: M, 36Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister both presented with renal cell carcinoma at ages 49 and 27, respectively. Their mother also had a CNS hemangioblastoma at 45, and their sister had a retinal angioma at 30. No genotyping information was available for either family member.

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

CaseHPOFreeText: The proband presented with renal cell carcinoma at age 22, and a pheochromocytoma at age 36.

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

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.R167Q (c.500G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 23

KindredID: 23

Case: M, 48Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Multiple or bilateral renal cell carcinoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346

SupplementalData: N/A

Variant: p.R108Hfs*23 (c.323_324del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA916832609, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA916832609

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; minus_2_frameshift_variant

CivicName: R108Hfs*23 (c.323_324del)

MultipleGeneVariants: N/A

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced. Two patients had a germline missense mutation in the VHL gene (c.383T>C; Leu128Pro). Patient 30, 27Y female, and Patient 31, 42Y female, both presented with CNS hemangioblastoma, renal cell carcinoma and a negative family history of VHL disease. The phenotypes of patient 30 were revised from a previous report (PMID 19270817).

PatientID: None (Daughter)

KindredID: 25

Case: M, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: Familial VHL. Two sons and a daughter presented with the same VHL germline mutation. All of these children presented with CNS hemangioblastomas. One of these sons also had renal cell carcinoma and was noted to have further unspecified phenotypes. His sister also had co-occurring unspecified phenotypes.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: Multiple or bilateral CNS hemangioblastomas. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0009711; HP:0005584 (Pheochromocytoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/

CAID: N/A

gnomAD: 0.01119, https://gnomad.broadinstitute.org/variant/3-10183876-G-C?dataset=gnomad_r2_1

VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism).

MutationType: missense_variant;transversion; splice_site_variant

CivicName: Splice Region (c.340+5G>C)

MultipleGeneVariants: N/A

PatientID: None (Daughter)

KindredID: 12

Case: F, Age Unknown, Korean

DiseaseAssertion: VHL

FamilyInfo: Mother has the same mutation and presented with renal cell caricnoma.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: VH6

KindredID: F3

Case: M, 54Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: Family history of pheo (type 2 VHL with no other lesions). Two other family members are given: VH5, 25Y Female, and VH7, 25Y Male both with an isolated pheochromocytoma too.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24735130

SupplementalData: N/A

Variant: p.R82L (c.245G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R82L (c.245G>T)

MultipleGeneVariants: N/A

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

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 (S80N (c.239G>A)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 39CE. It was reported in the paper as c.452G>A 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: 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 (L158V (c.472C>G)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 91CA. It was reported in the paper as c.685C>G due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 3708NCI

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 3708NCI. 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: 7728151

SupplementalData: N/A

Variant: p.L184P (c.551T>C)

LegacyVariant: p.L184P (c.764T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 419447 https://www.ncbi.nlm.nih.gov/clinvar/variation/419447/

CAID: N/A

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by location between codons 157 and 189.

MutationType: missense_variant; transition

CivicName: L184P (c.551T>C)

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 (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.

PatientID: VHL-6

KindredID: 6

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

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

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

CaseHPOFreeText: Multiple CNS hemangioblastomas. Clinical classification: A2.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114R (c.340G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

All patients included in the study were VHL mutation carriers of 18 years or older examined between 1972 and 2012 in the VHL expertise centers University Medical Center Groningen (UMCG) and University Medical Center Utrecht (UMCU). Clinical data of 75 VHL mutation carriers were retrospectively retrieved from electronic and written patient record. Of these patients, one was found to harbour the c.341-59_341-14del germline mutation of the VHL gene. They presented with a retinal hemangioblastoma, cerebellar hemangioblastoma, renal cell carcinoma, renal cyst, pheochromocytoma and pancreatic cysts. Their age at the last follow-up was 67. Previously published in: PMID 24132471.

PatientID: None

KindredID: 7

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0000107; HP:0001737 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst, Pancreatic cysts)

CaseHPOFreeText: VHL Type 1.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: c.340+1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

GroupID: 36

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 this 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.P154L (c.461C>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

GroupID: 27

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 this 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.N90I (c.269A>T)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 223172 https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N90I (c.269A>T)

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 renalcell 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. There was 1 patient reported with c.499C>T (p.R167W). This member presented with retinal hemangiomas. No family information was provided.

The 32-year-old male patient was admitted to Xiangya Hospital in 2006 and was found with multiple CNS hemangioblastoma of the pons, medulla oblongata, cerebellum and spinal cord. Clinical workup also identified a solid renal tumor. He was followed-up for 5 years with no other complications. The patient and his 7 family members (his parents, sister, son, sister’s son, brother, and brother’s son) were assessed by RQ-PCR assay, and no large deletions were found. Direct sequencing identified the p.Phe76del (c.227_229delTCT) mutation in the proband and this mutation (or any other abnormality) was not found in any of the family members. All members were asymptomatic. This is supportive of a de novo mutation ACMG PM6.

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

GenotypingMethod: Direct sequencing uaing an ABI PRISM 3730xl DNA Analyzer (Applied Biosystems, Foster City, CA, USA) using the BigDye Terminator v.3.1 Cycle Sequencing Kit (Applied Biosystems). and multiplex ligation-dependent probe amplification.

SamplingMethod: peripheral blood

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. Germline mutation c.-65_-55dup11 (mapped to c.-61_-51dup) was identified in prodand 221, 230 and 231. Proband 221 (12Y) presented with retinal capillary hemangioma. Proband 230 (40Y) presented with CNS hemangioblastoma. Proband 231 (9Y) presented with CNS hemangioblastoma. All three patients were previously published in PMID 17006605.

PatientID: 254

KindredID: 254

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

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

CaseHPOFreeText: Retinal hemangioblastoma and pancreatic cyst or tumor.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant; deletion

CivicName: Exon 2-3 Deletion

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

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. This novel, missense mutation was found in a 16 yr old VHL patient with pheochromocytoma (index case 55). Variant was transmitted from a parent (both parents were analyzed) but it is unclear which parent was positive for the variant.

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. This de novo, missense mutation, c.233A>G, was found in 2 VHL patients. A 24-year-old patient had retinal capillary hemangioma, pancreatic lesions, and renal cysts (index case 152). The other patient, a 33-year-old, presented with hemangioblastomas of the central nervous system and pancreatic lesions (index case 45). This variant also potentially alters the stability of the beta domain of the VHL protein. There is strong evidence for pathogenicity because this variant is de novo in a patient with the disease and no family history.

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 R107Pfs*25 (c.314dup) germline variant of the VHL gene was found in a 16 year old patient (ID 225) presenting with CNS hemangioblastoma. The variant is noted as Familial (i.e. “transmission of the variant from a parent”). Sibling was analyzed but details are not provided. The variant was reported as c.314_315insC and was mapped to c.314dup. There is co-segregation of disease with mutation.

PatientID: None

KindredID: 2

Case: M, Age Unknown, Chinese

DiseaseAssertion: N/A

FamilyInfo: (See figure 3 for pedigree). Nephew to proband. In family 2, the proband (Patient 2 in the paper) was a 50 year old female who presented with bilateral renal cell carcinoma, pancreatic neuroendocrine tumor, and a renal cyst. The proband's sister was diagnosed with a pancreatic NET and died of a hemorrhagic stroke at 40 years of age. Their mother also died of a stroke at 50 years of age. Genetic analysis revealed a c.232A>T (p.Asn78Tyr) mutation in the VHL gene of the proband. Based on her clinical presentation and family history, the proband was diagnosed with VHL type 1. Sanger sequencing on her family members detected the same mutation in her mother, sister, brother, and nephew.The proband's brother and nephew refused further VHL-related examination.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's brother and nephew refused further VHL-related examination.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78Y (c.232A>T)

LegacyVariant: N/A

CaseProblemVariant Free Text: N/A

ClinVar: 223167, https://www.ncbi.nlm.nih.gov/clinvar/variation/223167/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transversion

CivicName: N78Y (c.232A>T)

MultipleGeneVariants: N/A

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

GroupID/ KindredID: VHL 7

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Croatian

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation belonging to VHL family 7

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, pancreatic cysts)

GroupHPOFreeText: all 3 patients has retinal capillary hemangiomas, but only 1 tally of hemangioblastomas of the central nervous system, renal cysts, and pancreatic cysts were listed.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+2T>C

CaseProblemVariantFreeText: The mutation was referred to in the paper as c.676+2C>T - which was corrected to c.676+2T>C with a footnote indicating the correction in relation to Glavac et al Hum Mutat 1996.

LegacyVariant: c.676+2C>T (or correction of c.676+2T>C)

ClinVarID: 569414 https://www.ncbi.nlm.nih.gov/clinvar/variation/569414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.463+2T>C)

MultipleGeneVariants: N/A

42 CNS hemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre were analyzed for VHL mutations. Two patients of 17 presenting with VHL germline mutations presented with the L89P (c.266T>C) mutation (stated as c.479T>C in the paper which used the Latif sequence as reference). These patients were related but their relation is not made clear. Single strand conformation polymorphism and southern blotting for variant identification in the DNA found in blood samples. The patients were established as having VHL disease by standard of Neumann at al., 1987. Both patients presented with a single cerebellum tumors.

GroupID: 24A

DiseaseAssertion: VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 12A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.A122I (c.364_365delinsAT)

LegacyVariant: N/A

CaseProblemVariantFreeText: Authors report this as: c.364_365GC>AT; which can be translated to c.364_365delinsAT

ClinVarID: N/A

CAID: CA658820874 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.364_365delinsAT

gnomAD: N/A

VariantEvidence: N/A

MutationType: delins

CivicName: A122I (c.364_365delinsAT)

MultipleGeneVariants: N/A

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 5 patients were found to have the above mutation (c.548C>A). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other 4 patients were stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease .

GroupID: 14A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q132* (c.394C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 288749 https://www.ncbi.nlm.nih.gov/clinvar/variation/288749/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q132* (c.394C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1 (group ID 5)

Case: M, 68Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

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

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

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: He had an age of onset for RCC at 65Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: F, 33Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA020277 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.334T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients. All patients had VHL germline mutations. Age is at the time of surgery. Patients #2 (female) and #12 (male) were found with this germline VHL mutation and pancreatic endocrine tumours. The last known age of the patients was 28Y, and 43Y respectively. Other phenotypes and demographics were unknown. ACMG PP4

PatientID: 1

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: It is stated that the eight VHL patients were selected from the group of familial VHL patients. Assuming there is family history.

CohortInfo: Eight patients with VHL disease with pheochromocytoma, eight patients with MEN2 and pheochromocytoma, and 10 sporadic patients.

CasePresentingHPOs: HP:0006748, HP:0010797, HP:0005584, HP:0009715, HP:0030405 (adrenal pheochromocytoma, hemangioblastoma, renal cell carcinoma, papillary cystadenoma of the epididymis, pancreatic endocrine tumour)

CaseHPOFreeText: The patient had a left adrenal pheochromocytoma at age 42.

CaseNotHPOs: HP:0008221 (Adrenal hyperplasia)

CaseNotHPOFreeText: The patient did not have adrenomedullary hyperplasia.

CasePreviousTesting: N/A

PreviouslyPublished: Suspected to be, but not mentioned in paper. Paper says, the eight VHL patients were selected from the group of familial VHL patients withknown VHL germline mutations followed on a clinical protocol at the Urologic Oncology Branch, National Cancer Institute, National Institutes of Health (NIH).

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: I

KindredID: 19

Case: Sex Unknown, 5Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: 3 other family members presented with this VHL variant. Patients 19-II and 19-III were asymptomatic. Patient 19-IV presented with 2 retinal hemangioblastomas (10Y and 12Y) and kidney disease (17Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 0Y. Age at the end of study: 5Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Null (c.464-?_642+?del)

MultipleGeneVariants: N/A

PatientID: II

KindredID: 15

Case: Sex Unknown, 53Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 other family members presented with the same VHL variant. Patient 15-I was asymptomatic. Patient 15-III presented with 2 pheochromocytoma (15Y).

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

CaseHPOFreeText: Diagnosed with VHL at age 8Y. Presented with 2 pheochromocytoma (8Y) 2 CNS hb (12Y and 13Y) and 2 retinal hemangioblastomas (8Y, 12Y). Age at the end of study: 53Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: JK

Case: M, 40Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: One 5 year old female relative (unknown relationship) with the same heterozygous mutation was asymptomatic.

CasePresentingHPOs: HP:0001737, HP:0010797, HP:0009711, HP:0005584, HP:0030393 (pancreatic cyst, hemangioblastoma, Retinal capillary hemangioma, renal cell carcinoma, endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

GroupID: 7

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Family of 5 VHL Type 1 affected individuals.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0005584; HP:0002668 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma, Paraganglioma)

GroupHPOFreeText: CNS hemangioblastoma (4/5 affected members), renal carcinoma (2/5 affected members) and retinal angioma (3/5 affected members). The proband presented with one tumor which biopsy showed to be a non-functional paraganglioma

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R107P (c.320G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 36900, https://www.ncbi.nlm.nih.gov/clinvar/variation/36900/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R107P (c.320G>C)

MultipleGeneVariants: N/A

Germline mutations were found in 20 Brazilian, VHL probands and their families. The R107P (c.320G>C) germline missense mutation was found in a VHL type 1 family of 5 individuals, 4 with hemangioblastomas of the central nervous system, 3 with retinal angiomas, 2 with renal carcinoma, and a proband that presented with a non-functional paraganglioma (VHL family 7).

GroupID: 2

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: Unknown

CaseHPOFreeText: Other manifestations may be present although not matched with individuals so could not deduce.

CaseNotHPOs: HP:0009715 (Papillary cystadenoma of the epididymis)

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

56 male patients age 12 to 76 years, from 40 families with VHL were examined as part of a larger screening program for VHL. VHL mutations were identified in 16 families. Individual patient phenotype-genotype data was not available, but the mutations found and whether the corresponding patient had epididymal cystadenoma (EC) was reported. A p.E186* (c.556G>T) VHL mutation was found in a VHL patient without EC. This mutation was referred to in the paper as c.769G>T due to a difference in transcript sequence.

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: N/A (case)

KindredID: 1

Case: M, 18Y0M, Indian (South Asian)

DiseaseAssertion: assumed VHL

FamilyInfo: No positive family history, although his relatives have been advised to get mutation screening.

CasePresentingHPOs: HP:0006748; HP:0100653 (Adrenal pheochromocytoma; Optic neuritis)

CaseHPOFreeText: At 15Y (in 2017), male presented with history of acute bilateral vision loss, history of headaches, had bilateral disc edema - visual acuity of 6/36 both eyes (BE). A CT of his abdomen revealed bilateral pheochromocytoma, where he had an adrenalectomy.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 4

KindredID: 4

Case: M, 46Y0M, Bulgarian

DiseaseAssertion: VHL

FamilyInfo: Several family members were affected by the VHL disease: the patient's father has been operated for multiple large cHBs; the patient's brother has been operated for multiple cHBs and died from RCC; his nephew (brother's son) has been operated for large cHB. No familial genotype was confirmed.

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

CaseHPOFreeText: 2 RCC and 2 cHB were both self-reported; patient was operated and treated for RCC; follow-up for cHB.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: SNP c.870A>G in CCND1 gene (G>G)

Two groups were analyzed for germline VHL mutation where Group 1 (84 individuals) presented with only one hemangioblastoma and no other clinical VHL features and those in Group 2 (4 individuals) presented with multiple hemangioblastomas and no other VHL clinical features. Peripheral blood analysis was conducted of all exons and flanking regions (90 nucleotides upstream and 45 downstream) of the VHL gene (numbered using Genbank accession number L15409). Southern blot, PCR and SSCP were performed. Patient B1 of Group 1 presented with a singular cerebellar hemangioblastoma at age 29 and was found to be harbouring a 7bp frameshift T124del (c.369_371del), referred to in the paper as del 582 GACACAC due to a difference in transcript sequence. She developed pancreatic cysts at age 34.

PMID: 32974018

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

ArticleReferenceSequence: Specified to follow AF010238.1, although reference sequence appears to follow NM_000551.3

GenotypingMethod: Direct sequencing of the 3 exons of VHL was performed for all the DNA using PCR. If no mutation was detected, Southern blot analysis was performed to detect large rearrangements.

SamplingMethod: peripheral blood leukocytes

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. The c.500G>A mutation was found in 2 unrelated patients. Patient no 13 from family 354 presented with pancreatic endocrine tumour and pheochromocytoma. Patient no. 29 from family 372 presented with pancreatic endocrine tumour and pheochromocytoma. No family history was mentioned. The patients' phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2). Further, the mutation is occuring at a VHL hotspot (PM1).

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

PMID: 9681858

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 22

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group of 2 people has clinically confirmed VHL disease. This family were found to harbour the c.481C>T variant (noted in the paper as c.694C>T due to Latif reference transcript being used).

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

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

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: R161* (c.694C>T)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline splicing (c.463+3A>G) mutation in the VHL gene. 1 other affected relative was evaluated and found to have the variant but no phenotypes were provided. This variant was reported as c.676+3A>G (AF010238.1) and mapped to c.463+3A>G (NM_000551.3).

PMID: 25715769

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. Patient ID 12 had this germline mutation (c.463+2T>G) and clear cell renal cell carcinoma and pancreatic endocrine tumor. Whether patients were related, age, and sex data was not reported. ACMG PP4

PatientID: 62

KindredID: 62

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (Family 7 - see here for more info)

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

Variant: p.R107G (c.319C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A