DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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DOI: 10.1016/j.celrep.2026.118212

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Resource: RRID:BDSC_6972

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Resource: RRID:Addgene_52961

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Resource: RRID:AB_1925501

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Resource: RRID:SCR_014431

Curator: @beydel

SciCrunch record: RRID:SCR_014431

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DOI: 10.1038/s41418-026-01873-9

Resource: RRID:CVCL_0291

Curator: @beydel

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Resource: RRID:CVCL_0063

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DOI: 10.1038/s41418-026-01873-9

Resource: RRID:CVCL_0042

Curator: @beydel

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Resource: RRID:IMSR_JAX:026622

Curator: @beydel

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Resource: RRID:AB_2829545

Curator: @beydel

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Resource: RRID:AB_2891925

Curator: @beydel

SciCrunch record: RRID:AB_2891925

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DOI: 10.1016/j.cell.2026.08.045

Resource: RRID:IMSR_JAX:006772

Curator: @beydel

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DOI: 10.1007/s10456-026-10096-y

Resource: RRID:SCR_024227

Curator: @beydel

SciCrunch record: RRID:SCR_024227

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DOI: 10.1002/advs.77536

Resource: RRID:MGI:2159769

Curator: @beydel

SciCrunch record: RRID:MGI:2159769

What is this?

Case#: A 36-year-old Italian female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with a homozygous TPM1 p.Asn279His variant.

FamilyInfo: The patient’s parents are first cousins and confirmed heterozygotes for p.Asn279His (Fig 2).The patient’s 75-year-old father was diagnosed with HCM at 42 years of age. He reportedly has a history of heart failure but is currently asymptomatic. The patient’s 67-year-old mother had her first echocardiogram after the patient’s diagnosis.(Table I).

ParentalTesting: Father and mother

CasePresentingHPOs: HP:0100749, HP:0002875, HP:0002094, HP:0012764, HP:0003270, HP:0000131, HP:0001635

CaseHPOFreeText: She was diagnosed with RCM and is being evaluated for heart transplantation. was referred for chest pain, lightheadedness, shortness of breath, significant fatigue, dyspnea on exertion, three-pillow orthopnea and abdominal bloating. Eighteen months previously, she had been diagnosed with an unspecified form of cardiomyopathy after developing volume overload while hospitalized for a right oophorectomy and uterine fibroid removal. Her symptoms were consistent with NYHA III–IV heart failure. She has continued to have significant heart failure symptoms that have been difficult to control with medical therapy. Freedom from arrhythmias, however, has been notable. She is currently being considered for orthotopic heart transplantation but her evaluation has been complicated by psychiatric issues.

CaseNotHPOs: HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied syncope and lower extremity edema

CasePreviousTesting: The patients father and mother were tested.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: used computational analysis and evolutionary conservation to assess the variant of TPM1 p.Asn279His.

Variant: NM_001018005.2:c.835A>C

ClinVar: 43446

CAID: CA018397

gnomAD: NR

Case#: An El-Salvadoran 22-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM), associated with sarcomeric gene variants in MYL3 and MYL2

FamilyInfo: The patient’s mother was the only family member available for evaluation (Fig 2). On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age

ParentalTesting: Patients mother

CasePresentingHPOs: HP:0002099, HP:0012378, HP:0012764, HP:0001962, HP:0034807, HP:0001541, HP:0001410, HP:0031667, HP:0004749,

CaseHPOFreeText: diagnosed with RCM and advanced heart failure requiring heart transplantation. A prior diagnosis of childhood asthma presented with worsening fatigue and dyspnea on exertion over the course of 12 months. She reported having frequent episodes of shortness of breath as a child, also reported orthopnea, paroxysmal nocturnal dyspnea, and palpitations; her heart failure symptoms were classified as NYHA Class III–IV. did have ascites suggestive of congestive hepatopathy. Her cardiovascular examination revealed a nondisplaced, nonsustained point of maximal impulse, with a mild parasternal lift without a pulmonary artery tap.She had a normal S1, but P2>A2. She had an S3, but no S4. She had a soft I/IV holosystolic murmur over the apex; no knock or rub. Her electrocardiogram demonstrated atrial flutter with an atrial rate of 250–300 and a ventricular rate of 85.

CaseNotHPOs: HP:0002321, HP:0001279, HP:0010741

CaseNotHPOFreeText: She denied dizziness, syncope, and lower extremity edema.

CasePreviousTesting: The patient's mother was also tested to assess inheritance.

Genotyping Method: Sarcomere gene sequencing

FunctionalAnalysis: MYL2 p.Gly57Glu variant using sequence conservation and computational splice-site prediction

Variant: NM_000432.4:c.170G>A

ClinVar:43458

CAID: CA009910

gnomAD: gnomAD v2 12:111352094 C / T https://gnomad.broadinstitute.org/variant/12-111352094-C-T?dataset=gnomad_r2_1 gnomAD v3 12:110914290 C / T https://gnomad.broadinstitute.org/variant/12-110914290-C-T?dataset=gnomad_r3 , gnomAD v4 chr12-110914290-C-T https://gnomad.broadinstitute.org/variant/chr12-110914290-C-T?dataset=gnomad_r4

Case#: Five-year-old Iranian boy

DiseaseAssertion: asymmetric septal hypertrophy and mild LV hypertrophy

FamilyInfo: History HCM and SCD in the family

ParentalTesting: both parents and two siblings had the same test done

CasePresentingHPOs: HP:0003690 limb weakness

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: echocardiography or cardiac magnetic resonance (CMR) imaging, electrocardiography (ECG), and thorough physical examination

Genotyping Method: Whole‐exome sequencing (WES)

FunctionalAnalysis:

Variant: c.761A>G:p.D254G (NM_001018005.2)

ClinVar:not found

CAID:CA392724249

gnomAD:not found

AdditionalInfo:

PMID: 38874371

Gene: TPM1

HGNC ID: 12010

Case#: A 29 years old male DCM patient

DiseaseAssertion:Familial dilated cardiomyopathy (FDCM), associated with the TNNT2 gene missense variant p.Arg144Trp (R144W)

FamilyInfo: Family members had revealed its presence in three other individuals with DCM. A history of sudden cardiac deaths (SCD) in the family. Two individuals in the family, who were diagnosed with DCM, had died due to severe congestive heart failure at the age of 45 and 25 years. However, a 66-year-old individual in the same family with DCM having mild symptoms.

ParentalTesting:NR

CasePresentingHPOs: HP:0001644, HP:4000141, HP:0012664, HP:0004308, HP:0012828, HP:0001653

CaseHPOFreeText: Dilated cardiomyopathy with left ventricular dilation, Age of onset, 25, left ventricular internal diastolic dimension of 72mm, reduced ejection fraction of 26%, has Ventricular arrhythmia, severe mitral regurgitation.

CaseNotHPOs:NR

CaseNotHPOFreeText: NR

CasePreviousTesting:NR

Genotyping Method: Used PCR with GenBank No. NM_000364, then followed by mutation subsequent screening analysis

FunctionalAnalysis:The R144W mutation was found to be within the tropomyosin-binding domain of cTnT and alters the charge of the residue, so it is expected to have a significant impact on the structure and function of the protein. The novel unique/private R144W mutation identified in our present study is associated with FDCM

Variant:NM_001276345.2:c.430C>T

ClinVar:127070

CAID:CA004485

gnomAD: gnomAD v2: 1:201333485 G / A gnomAD v3: 1:201364357 G / A gnomAD v4: chr1-201364357-G-A AdditionalInfo:25 bp deletion was found to be associated with both HCM and DCM in India and south Asia

PatientID: 15

KindredID: 15

Case: M, 52Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Multiple involvements of CNS HB (See table 1)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9829912

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA020108 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.208G%3EA

gnomAD: 0.000004365 https://gnomad.broadinstitute.org/variant/3-10183739-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

Germline VHL mutations were found in all Korean patients who fulfilled clinical criteria for VHL disease. PCR and MLPA was done to detect each VHL mutation. No mutation of VHL was detected in other patients who did not meet clinical criteria. In all cases, samples from both parents were not available and evidence of de novo mutations could not further be evaluated. Nonsense mutation (p.R161*) identified in 22 year old Korean male with retinal hemangioblastomas (patient no. 2). Patient had confirmed family history of VHL disease and VHL type 1 phenotype. Supporting evidence of pathogenicity because of the introduction of an early stop codon in a gene where loss of function is an established mechanism of disease (ACMG code: PVS1).

PatientID: 2

KindredID: 2

Case: M, 30Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0005584 (hemangioblastoma, pancreatic cyst, renal cell carcinoma)

CaseHPOFreeText: Patient had an age of diagnosis of VHL at 30

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: p.I151T (c.452T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428803 https://www.ncbi.nlm.nih.gov/clinvar/variation/428803/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant; transition

CivicName: I151T (c.452T>C)

MultipleGeneVariants: N/A

PatientID: 29

GroupID/ KindredID: 29

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+2T>C

LegacyVariant: c.676+2C>T

CaseProblemVariantFreeText: AF010238.1: c.676+2C>T translates to NM_000551.3:c.463+2C>T, however no C exists at c.463. As no Cytosine is found around the area of c.463, will assume the authors wrote this backwards and correct variant is c.463+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

PatientID: 25

GroupID/ KindredID: 25

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F136C (c.407T>G)

LegacyVariant: p.F136C (c.620T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 496065 https://www.ncbi.nlm.nih.gov/clinvar/variation/496065/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F136C (c.407T>G)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.486C>G) was recorded in the paper as c.699C>G due to a difference in transcript sequence.It was found in one patient with a hemangioblastoma of the central nervous system. Any family information is unknown. No other phenotypes described.

PatientID: None

KindredID: 5

Case: M, 39Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No familial antecedents and no known familial tumors.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0010797; HP:0000107; HP:0002666 (Cerebellar hemangioblastoma, Pancreatic cysts, Hemangioblastoma, Renal cyst, Pheochromocytoma)

CaseHPOFreeText: Deceased at age 39.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 14722919

SupplementalData: N/A

Variant: Exon 2 Deletion (c.340-?_464+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300 retention. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: Sequencing analysis of VHL coding regions

SamplingMethod: N/A - Not specified

This abstract presented a case of a 37Y F with pheochromocytoma in her right adrenal. Family history was significant for 1 sister who died just after delivery from severe hypertensive crisis, and a 26Y niece with left adrenal tumor and pancreatic tumor. Genetic sequencing analysis of VHL coding regions revealed Q164R (c.491A<G) mutation in the patient and her still asymptomatic 5Y daughter.

PatientID: None

KindredID: None

Case: F, 17Y0M, Ethnicity unknown

DiseaseAssertion: dilatation of the cerebral artery

FamilyInfo: None

CasePresentingHPOs: HP:0004944; HP:0010797 (dilatation of the cerebral artery, hemangioblastoma)

CaseHPOFreeText: Patient had an intracranial aneurysm - SAH of a right posterior communicating artery aneurysm. She later developed hemangioblastomas

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16506495

SupplementalData: N/A

Variant: p.P86S (c.256C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 178692 https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 5

Case: Sex Unknown, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: At first presentation (age 34) the patient had a visual acuity of 20/30. The angioma showed an endophytic growth pattern and was located in the temporal and inferior disc margin.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Medical screening for other VHL lesions comprised magnetic resonance imaging (MRI) of the brain and spinal cord (gadolinium-enhanced), urine catecholamines, and abdominal sonography or computed tomography (CT). No VHL lesions present other than the retinal angioma reported.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 26

PatientID: II

Case: 40Y0M, Sex unknown, Polish

DiseaseAssertion: VHL

FamilyInfo: Family 26 consisted of 2 members; One other member (37Y) was diagnosed with a single cerebellar HAB at 32Y

CasePresentingHPOs: HP:0009713; HP:0006880 (spinal hemangioblastoma, cerebellar hemangioblastoma)

CaseHPOFreeText: Patient was diagnosed with a single spinal HAB, and a single cerebellar HAB at 38Y

CaseNotHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: complete deletion of VHL gene

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Haplotype analysis information in Table 3

MutationType: deletion

CivicName: deletion

MultipleGeneVariants: N/A

GroupID/ KindredID: 25

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Polish

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this deletion.

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

GroupHPOFreeText: Both (2) patients had hemangioblastomas and RCC, and 1 had retinal capillary hemangioma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2, 3 deletion

CaseProblemVariantFreeText: Patients were both found with an Exon 2, 3 deletion (and 11.5 kb abnormal band on QSA)

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: EXON 2-3 DELETION

MultipleGeneVariants: N/A

An 11-year-old boy with a 2-week history of nausea and vomiting was found with bilateral adrenal pheochromocytoma. Two years later he also developed a right paraspinal paraganglioma. Each were resected. The patient is now 17Y old and had no other VHL disease manifestations. Genetic testing found a c.250G>A mutation in the VHL gene. His father and paternal aunt had histories of pheochromocytoma but genetic testing for family members was not described. ACMG PP4

PMID: 19784914

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 2

DiseaseAssertion: VHL

GroupSize: 4 GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: unknown GroupAgeRange: 38-48

GroupInfo: 4 out of 82 individuals were grouped together based on all having the c.-213-?_463+?del mutation of the VHL gene. This group was classified as VHL Type 1.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0009713; HP:0005584; HP:0030405; HP:0000107; HP:0001737 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Renal cyst, Pancreatic cysts)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: N/A

Variant: c.-213-?_463+?del

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion; splice_site_variant

CivicName: c.-213-?_463+?del

MultipleGeneVariants: N/A

PatientID: None

KindredID: 11

Case: Sex Unknown, 71Y0M, 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:0006880; HP:0000107; HP:0002666 (Cerebellar hemangioblastoma, Renal cyst, Pheochromocytoma)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.P154= (c.462A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA16621934, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA16621934

gnomAD: N/A

VariantEvidence: N/A

MutationType: synonymous_variant

CivicName: P154= (c.462A>C)

MultipleGeneVariants: N/A

A 12Y old boy presented with symptomatic hemangioblastoma in the medulla. After surgical removal of the hemangioblastoma, he was also found with retinal capillary hemangioma of the right eye. PCR and MLPA genetic studies identified a germline VHL mutation c.208G>A in the patient. His mother and maternal aunt had a history of retinal capillary hemangioma but were not available for genetic testing. The patient was followed-up for 1 year 7 months with no complications. ACMG PP4

PatientID: 4

KindredID: 4

Case: M, 50Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0001737 (pancreatic cysts)

CaseHPOFreeText: At age 45, the patient presented with a cystadenoma. It was radiologically diagnosed as a mucinous cystadenoma but pathology revealed serous cystadenoma. The patient was followed up 59.5 months later.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111R (c.331A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351751320 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.331A%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:S111R (c.331A>C)

MultipleGeneVariants: N/A

A study investigated paraganglioma/pheochromocytoma tumors in a retrospective cohort and a prospective cohort. Some of these tumors were found with germline VHL mutations. Tumour ID 54 was PCC and a germline duplication mutation at base 444 of the VHL gene leading to a frameshift. Other phenotypic and demographic information was not available.

PatientID: 33

KindredID: F01

Case: F, Age Unknown, Unknown Ethnicity

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17537157

SupplementalData: Figure 2.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

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

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: II5(Cc01)

KindredID: C

Case: F?, 34Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient is the index case, reported as female but shown as male in pedigree. Patient’s father (I-2) presented with hemangioblastoma and possessed the same exon 2 deletion. The patient’s two siblings also possessed the deletion. One sister (II-1) had hemangioblastoma, while the other sister (II-3) had retinoblastoma, pancreatic cyst and pheochromocytoma. The patient and their two siblings each had one child and all possessed the same deletion, but did not exhibit phenotypes (Please see Figure 1. Family C matches with Pedigree B).

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0006770 (Hemangioblastoma; Pancreatic cysts; Clear cell renal cell carcinoma)

CaseHPOFreeText: Patient presented with hemangioblastoma, pancreatic cyst, and clear cell renal carcinoma. Patient had surgery twice.

CaseNotHPOs: HP:0009919; HP:0002666 (retinoblastoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2 Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: large fragment deletion in exon 2

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as GRCh37 chr3:10188300ATATCACACTGCCA>T in paper

MutationType: minus_2_frameshift_variant; deletion

CivicName: Exon 2 (deletion)

MultipleGeneVariants: N/A

PatientID: 4 (Proband)

KindredID: 18

Case: F, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (38 and 43Y) and pheochromocytoma (20 and 43Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0009711 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 2 (Brother)

KindredID: 3

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 3 members of this family were genetically confirmed to be carriers of a germline partial deletion of exon 2 of the VHL gene. ID 8 presented with CNS hemangioblastoma. ID 1 was asymptomatic. ID 16 presented with a retinal angioma (33Y), CNS hemangioblastoma at (32Y) and died at age 42. ID 16 was stated as having the germline variant but this was inferred from family/personal history and was not genetically confirmed.

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

CaseHPOFreeText: The patient presented with a retinal angioma (18Y) and pancreatic cyst or tumor (unspecified) (18Y).

CaseNotHPOs: HP:0005584; HP:0000077; HP:0010797; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: Exon 2 Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial deletion of Exon 2)

MultipleGeneVariants: N/A

PatientID: 1658

KindredID: 1658

Case: Sex Unknown, 60Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 44 patients with renal cell carcinoma who had known industrial exposure to trichloroethylene (TRI).

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient had TRI exposure at age 22 and was diagnosed with renal cell carcinoma at age 66.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S(c.241C>T)

LegacyVariant: p.P81S(c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: The patient had LOH. Assumed germline based on Figure 2.

MutationType: missense_variant;transition

CivicName: P81S(c.241C>T)

MultipleGeneVariants: Somatic, VHL, c.500G>A (p.Arg167Gln)

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

GenotypingMethod: N/A - not specified

SamplingMethod: N/A - not specified

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

GenotypingMethod: Mutations in a number of different genes, including VHL, were screened for in patients using Target Capture-Based Deep Sequencing (BGI Health, Shenzhen, Guangdong, China). After a mutation was discovered in the proband, the proband's family members were screened by Sanger sequencing. See Figure 2 for chromatogram of sequenced mutations.

SamplingMethod: peripheral blood

KindredID: 1

Case: F, 40Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0006880, HP:0006770, HP:0006748, HP:0001737, HP:0000107, HP:0009713 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Adrenal pheochromocytoma, Pancreatic cysts, Renal cyst, Spinal hemangioblastoma)

CaseHPOFreeText: The patient was found to have two extraneuraxial hemangioblastomas, the locations of these tumors included intra/paraspinal (extradural) and the nerve roots. Her past medical history included  cerebellar hemangioblastomas, clear cell renal cell carcinoma, an adrenal pheochromocytoma, and cysts in both the   kidney and  pancreas. Clinical symptoms and imaging features include Radicular lumbarpain, lowerlimb paresthesia &weakness/CT, MRI: contrastenhancing masses &erosion of lumbarspine & sacrum. There was no known family history.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I151N (c.452T>A)

LegacyVariant: N/A

CaseProblemVariant Free Text: N/A

ClinVarID: N/A

CAID: CA351754356

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R167Q (c.500G>A) and I151N (c.452T>A)

MultipleGeneVariants: Somatic, VHL, c.500G>A (p.R167Q)

PatientID: II

KindredID: 5

Case: Sex Unknown, 20Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 2 family members with the same VHL variant. Patient 5-I presented with retinal hemangioblastoma (17Y). Patient 5-III presented with retinal hemangioblastoma (12Y), pancreatic cysts (12Y), CNS hemangioblastoma (15Y) and kidney disease (12Y).

CasePresentingHPOs: HP:0009711; HP:0010797; HP:0001737 (Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: Diagnosed with VHL at age 3Y. Presented with 13 CNS hemangioblastomas (11Y, 13Y, 15Y and 17Y), retinal hemangioblastoma (13Y) and 2 pancreatic cysts (16Y). Age at the end of study: 20Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q145* (c.433C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625249, https://www.ncbi.nlm.nih.gov/clinvar/variation/625249/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

CivicName: Q145* (c.433C>T)

MultipleGeneVariants: N/A

PatientID: V-5

KindredID: 2

Case: F, Age Unknown, Mexican

DiseaseAssertion: Asymptomatic

FamilyInfo: This family included three affected individuals and two of them were studied. The proband (IV-6) was a 23-year-old woman who was previously diagnosed with VHL disease and had a tumor in the cerebellum; VA and IOP were normal and no ocular manifestations of the disorder were recorded at examination. Her 36-year-old sister (IV-7) had a spinal cord HB. None of them presented ocular symptoms. Remarkably, her 55-year-old mother (III-8) did not exhibit any clinical manifestation of the disease. Three of her maternal uncles (III-1, III-2 and III-3) presented with cerebellar HB and one of them also had a renal cell carcinoma; In addition, her maternal grandmother (II-2) and her maternal grandmother's sister (II-3) had unspecified CNS tumors.

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (b))

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 3

Case: F, 20Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: She was adopted and no information about her biological family was available.

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

CasePresentingHPOs: HP:0009711; HP:0001147; HP:0007917 (Retinal capillary hemangioblastoma, Retinal exudate, Tractional retinal detachment)

CaseHPOFreeText: Progressive VA loss in her left eye. VA was of 6/15 in her right eye and of light perception in the left eye. Funduscopic evaluation of the left eye revealed two temporal inferior retinal HBs accompanied by retinal hard exudate and fibrous vascular tissue that led to tractional retinal detachment.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Abdominal ultrasonography as well as abdominal and CNS computed tomography (CT) and MR imaging did not show tumoural lesions.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573129737, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573129737

gnomAD: N/A

VariantEvidence: Direct sequencing of coding region of the VHL gene exon 1 showed a pattern of peak overlap characteristic of super imposed sequences due to heterozigosity for an insertion/deletion event. Variant reported as: p.N99fs131 (c.298_299insA), cDNA change was found to be equivalent to c.198dup and this was mapped to p.T100Nfs32.

MutationType: duplication; plus_1_frameshift_variant

CivicName: T100Nfs*32 (c.298dupA)

MultipleGeneVariants: N/A

PMID: 23558940 Gene: VHL StandardizedReferenceSequence: NM_000551.3

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.486C>G), which was found in 2 individuals from France.

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (p.F76del), which was found in 4 individuals from Germany and France.


Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.470C>T), which was found in 1 individual from Italy.

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.461C>T), which was found in 2 individuals from Germany.

Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation (Y175C) was found in a 32 year old patient with unilateral pheochromocytoma (patient no. F15). The patient also had a family history of pheochromocytoma.

A 32-year old man was consulted at the Polish VHL Registry as a member of a family with suspected von Hippel-Lindau disease (VHL). He presented with endolymphatic sac tumour (19Y; 21Y); cerebral hemangioblastoma (24Y; 26Y); and retinal capillary hemangioblastoma. He had a germline missense VHL mutation NM_000551.3:c.194C>T(S65L) which was also found in two of his children. Note that the paper describes this variant as c.407C>T since it uses an older reference sequence (Latif et al.). His family members had lesions consistent with VHL disease including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and loss of sight because of retinal detachment (probably in the case of retinal hemangiomas).

PMID: 22145147

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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 Q132* (c.394C>T) germline nonsense mutation was found in a VHL type 2 patient with hemangioblastomas of the central nervous system, retinal angiomas, and pheochromocytoma (family ID 108).

PatientID: None

KindredID: 81

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

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

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90I (c.269A>T)

LegacyVariant: c.482A>T

CaseProblemVariantFreeText: 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: 32

DiseaseAssertion: VHL

GroupSize: 9

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 9 individuals from a single family (ID 32).

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

GroupHPOFreeText: CNS hemangioblastoma (5/9), retinal angioma (1/9), renal cell carcinoma (9/9) and pancreatic tumor or cyst (unspecified) (2/9).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.V155M (c.463G>A)

LegacyVariant: c.676G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 223219, https://www.ncbi.nlm.nih.gov/clinvar/variation/223219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V155M (c.463G>A)

MultipleGeneVariants: N/A

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families, using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. This splice site mutation, c.463+1G>A (reported as c.676+1G>A in the paper which used the Latif sequence as reference). This splice mutation was found in a VHL type 1 patient with hemangioblastomas of the central nervous system, retinal angiomas, pancreatic cysts, and renal cell carcinoma (family ID 107). This study contains very strong evidence for pathogenicity in the form of a canonical +1 splice-site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

PatientID: VI-7

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 7

Case: age, sex, ethnicity unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164H (c.492G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 618485 https://www.ncbi.nlm.nih.gov/clinvar/variation/618485/

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191499-G-C

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Q164H (c.492G>C)

MultipleGeneVariants: N/A

PatientID: III:1

KindredID: 6002

Case: M, 28Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Maternal uncle (II:1) had a history of testicular cancer but no genetic data was available.

CohortInfo: Patients met at least one of the criteria: RCC < forty years of age or bilateral or multifocal RCC < sixty years of age or family history of RCC or three relatives with RCC, melanoma or mesothelioma (at least one case of RCC) or patients diagnosed with RCC and melanoma. Family history of RCC is defined as two or more first-degree relatives with RCC. Patients with a previously identified pathogenic variant in a renal cancer predisposition gene were not included. Patient inclusion took place from February 2014 to January 2015. This patient was grouped in “Group 1” where only one family member was affected by renal cell carcinoma (n=20).

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient has been through the national screening program for putative VHL, which includes MRI of the cerebrum, spinal medulla and abdomen, neurological examination, auditory tests, ocular examination and blood work for chromogranin A and metanephrines, with normal results.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 3

Variant: p.M1I (c.3G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 135406, https://www.ncbi.nlm.nih.gov/clinvar/variation/135406/

CAID: N/A

gnomAD: 0.00007043, https://gnomad.broadinstitute.org/variant/3-10183534-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: M1I (c.3G>A)

MultipleGeneVariants: Germline, VHL, c.631A>C (p.Met211Leu)

MultipleGeneVariants: Germline, BAP1, c.1729+8T>C

3 unrelated patients with unexpected or non-syndromic phenotypes, accompanied by a VHL component tumor received germline gene panel testing as part of the PROACTIVE study at the Dana-Farber Cancer Institute, each detected with a low penetrant variant. At age 52, patient 1 (male) presented with worsening lower abdominal discomfort. A CT scan and histopatholoy revealed a right renal solid mass consistent with renal cell carcinoma, which required a right radical nephrectomy. A year later, CT imaging, MRI and pathological examination revealed metastatic clear cell renal cell carcinoma (ccRCC) and spindle cell lipoma. 3 years later, progression in the liver and pancreas was noted. Somatic next generation sequencing testing revealed mutations in VHL and several copy number losses. As part of the PROACTIVE study, peripheral blood was collected. Sequencing and deletion/duplication analysis of 133 genes (including MAX/NF1/RET/SDHA SHDB/SHDC/SDHD/SDHAF2/TMEM127) revealed a heterozygous germline VHL L188V(c.562C>G) variant. A somatic VHL, c.445G>A (p.Ala149Thr) was also found. The patient's two sons have not been tested for the variant, however both have skin cancer. After genetic counselling, patient reported that his sister tested positive for the same mutation. She was diagnosed with metastatic lobular breast carcinoma at age 52 following pathological examination of the tumor specimen. Previous germline genetic testing using an 88-gene cancer panel revealed the heterozygous germline VHL L188V(c.562C>G) variant, further confirmed by testing a second blood sample. Both of her children had no VHL variants, but daughter has papillary thyroid cancer. She had no features of VHL until her death at age 61 from breast cancer. Similarly, other than ccRCC, patient 1 had no other features of VHL. Finally, their parents each had cancer: father with lung cancer, mother with skin cancer, as well as 8 other family members. No genetic make up was discussed in these members. ACMG: PP4

PatientID: 2

KindredID: B

Case: F, 82Y0M (deceased), Ethnicity Unknown

DiseaseAssertion: papillary urothelial carcinoma

FamilyInfo: Positive: The patient’s mother had colon cancer at 66Y and passed away at 67Y. The maternal uncle, cousin, and grandfather all had cancers: prostate, prostate and lung, and colon cancer, respectively. No genetic testing was done for these members, however, no known VHL-related tumors reported in the family. See Fig. 3.

CasePresentingHPOs: HP:0003319; HP:0030409 (abnormality of the cervical spine; renal transitional cell carcinoma)

CaseHPOFreeText: She presented originally in 2009 at 72Y to genetics due to personal and family history of cancer: cervical cancer at age 41 (treated surgically). At age 79, presented with pelvic pain (as invasive high-grade papillary urothelial carcinoma). She died in 2019 (age 82Y) due to her cancer.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Imaging of her brain, spine, and abdomen via MRI and PET CT in 2019 found no brain, spine, kidney or adrenal gland lesions consistent with VHL-related neoplasms.

CasePreviousTesting: MAX/NF1/RET/SDHA/SHDB/SHDC/SDHD/SDHAF2/TMEM127 [133 genes evaluated by germline testing - Invitae]

PreviouslyPublished: N/A

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: 9970

KindredID: 420

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: Rearrangement

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

GroupID: 26

DiseaseAssertion: VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 6 members of this family are reported as carrying the c.163dupG germline variant of the VHL gene. Members 1418, 1261 and 1409 had unknown renal involvement. Members 1412, 558 and 1442 had mild renal disease. Member 558 also had RCC. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 3 patients with this mutation are reported but relation between patients is unknown.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: E55Gfs*77 (c.163dup)

MultipleGeneVariants: N/A

GroupID: 43

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to harbor the c.475_476insTTT germline variant of the VHL gene. Member 3207 had no renal involvement. Members 3206 and 3203 presented with mild renal disease. Member 3189 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, but no patients with this variant were found in these manuscripts.

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

Variant: p.K159delinsI* (c.475_476insTTT)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2573130359, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573130359

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion; insertion

CivicName: K159delinsI* (c.475_476insTTT)

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.R205Hfs*50 (c.614_615del) germline variant of the VHL gene was detected in a family (ID 400). Member 9698 had no renal involvement. Member 1420 presented with severe renal disease (RCC). The variant is reported in the current manuscript as “c.612_613delGC” and mapped to c.614_615del. The paper states that this family is previously reported in PMID 9829912.

PatientID: N/A

KindredID: 5

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Nonsyndromic pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93C (c.277G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.G93C (c.490G>T)

ClinVarID: 223175 https://www.ncbi.nlm.nih.gov/clinvar/variation/223175/

CAID: N/A

gnomAD: 0.0000004476 https://gnomad.broadinstitute.org/variant/3-10183808-G-T

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G93C (c.277G>T)

MultipleGeneVariants: N/A

PatientID: Son

KindredID: 13

Case: M, Age Unknown, Korean

DiseaseAssertion: Asymptomatic

FamilyInfo: Father (Proband) and Uncle presented with the same VHL variant. Father presented with CNS hemangioblastoma at 32Y, retinal hemangioblastoma at 44Y, bilateral RCC at 44Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 41Y. Uncle presented with CNS hemangioblastoma at 29Y, retinal hemangioblastoma at 52Y, bilateral RCC at 43Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 43Y and bilateral renal cysts at 43Y. Cousin presented with CNS hemangioblastoma at 22Y, retinal hemangioblastoma at 18Y, bilateral RCC at 29Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 18Y but was not genetically confirmed.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000107; HP:0002666; HP:0001732; HP:0010797; HP:0005584; HP:0009711 (Renal cyst, Pheochromocytoma, Abnormality of the pancreas, Hemangioblastoma, Renal cell carcinoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 12

Case: Sex Unknown, 53Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0001737; HP:0010797; HP:0000107; HP:0005584 (pancreatic cyst, hemangioblastoma, renal cyst, renal cell carcinoma)

CaseHPOFreeText: The patient at 53Y was confirmed with VHL. They developed renal cell carcinoma, renal and pancreatic cysts, and CNS HBs

CaseNotHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0009711 (paraganglioma, pheochromocytoma, pancreatic endocrine tumor, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Large deletion of exon 1

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

Of 31 Brazilian patients, one was found to harbour the c.74C>T (p.Pro25Leu) mutation of the VHL gene. Genomic DNA was extracted and all VHL coding regions were analyzed by Sanger sequencing. MLPA was performed to investigate large deletions using SALSA® MLPA® P016 VHL probe mix. Data analysis was performed with Genescan 3.7. This patient, age 17, presented with pancreatic endocrine tumor, pancreatic cyst, CNS hemangioblastoma and retinal hemangioblastoma. This patient was also found to harbour the germline c.256C>A (p.Pro86Thr). It is not clear if these mutations are familial. ACMG evidence codes: 'PP4' since the patients present phenotypes highly specific for a disease with a single genetic etiology.