Case#: Deceased child, female; age 5.5 months

DiseaseAssertion: Hypertrophic cardiomyopathy with endomyocardial fibroelastosis

FamilyInfo: The mother carried c.2373dup, and the father carried c.592G>T.

ParentalTesting: The mother carried c.2373dup, and the father carried c.592G>T.

CasePresentingHPOs: HP:0001706 HP:0200128 HP:0012664 HP:0002094 HP:0000961

CaseHPOFreeText: Acute heart failure; massive biventricular cardiac enlargement; biventricular dysfunction; progressive dyspnea; blue lips; pale appearance; endocardial fibrosis; cardiopulmonary arrest.

CaseNotHPOs: NR

CaseNotHPOFreeText: No congenital heart disease or valve abnormalities were found at autopsy

CasePreviousTesting: NR

Genotyping Method: Postmortem molecular testing

FunctionalAnalysis: NR

Variant: MYBPC3 c.592G>T (p.Asp198Tyr); missense

MYBPC3 c.2373dup, p.Trp792Valfs*41); frameshift duplication

ClinVar: c.592G>T: NR; c.2373dup: 42619

CAID: c.592G>T: NR; c.2373dup: CA012139

gnomAD: c.592G>T was not observed in more than 123,000 individuals; c.2373dup: 0.0017% overall

AdditionalInfo: The child died from severe early-onset cardiac disease at 5.5 months. Autopsy showed endomyocardial fibroelastosis and severe biventricular involvement.

PMID: 33849460

Gene: MYBPC3

HGNC ID: HGNC:7551

Case#:24-year-old male

DiseaseAssertion:non-obstructive HCM and long QTc

FamilyInfo:family history of long QT (mother and maternal grandmother), (family pedigree in Fig. 2)

ParentalTesting:Sanger sequencing done in the father confirming the paternal origin of the variant.

CasePresentingHPOs:HP:0001712, HP:0001657, HP:0005135

CaseNotHPOs:HP:0001654, HP:0006673

CasePreviousTesting: Cardiac MRI, Electrocardiogram, echocardiogram

Genotyping Method:Next Generation Sequencing

FunctionalAnalysis:Pathogenic missense variant

Variant:NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

ClinVar:177694

CAID:CA022019

gnomAD:chr19-55151875-G-C

PMID:33777698

Gene:TNNI3

HGNC ID:11947

PMID:38548731

Gene:TNNI3

HGNC ID:11947

Case#:14 year old Female

DiseaseAssertion:nonobstructive hypertrophic cardiomyopathy

FamilyInfo:lacked any family history of cardiomyopathy, including sudden death or cardiac hypertrophy, Family Pedigree (Figure. 1a)

ParentalTesting:none, healthy parents

CasePresentingHPOs:HP:0001663

CaseHPOFreeText: cardiopulmonary arrest

CaseNotHPOs: HP:4000004

CaseNotHPOFreeText: myocardial edema, ventricular arrhythmias, obstructed outflow tract

CasePreviousTesting: echocardiogram, cardiac MRI

Genotyping Method:Whole genome sequencing

FunctionalAnalysis:heterozygous missense variant

Variant: NM_000363.5:c.583A>T (p.Ile195Phe)

CAID:CA407439576

Case#: IV-2; female; age 51; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: IV-2 is the mother of V-1

ParentalTesting: NR

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Atypical hypertrophy with a septal thickness of 23 mm; exertional angina for 10 years.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing and targeted next-generation sequencing

FunctionalAnalysis: NR

Variant: c.3624delC, frameshift

ClinVar: 42727

CAID: CA014493

gnomAD: NR

AdditionalInfo: Also carried CACNB2 p.Ser533Leu and DSP p.Arg1308Gln.

Case#: V-1; male; age 28; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: V-1 is part of a large consanguineous HCM pedigree. Family segregation information was reported for the MYBPC3 variant. V-1 died suddenly at age 29

ParentalTesting: NR

CasePresentingHPOs: HP:0001712 HP:0005144 HP:0032092

CaseHPOFreeText: Left ventricular hypertrophy; increased interventricular septal thickness; left ventricular outflow tract obstruction

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing and next-generation sequencing

FunctionalAnalysis: NR

Variant: c.3624delC, missense

ClinVar: 42727

CAID: CA014493

Case#: IV-6; female; age 64; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: IV-6 is a member of the MYBPC3-positive HCM pedigree

ParentalTesting: NR

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Moderately affected, asymmetrical hypertrophy with a maximum wall thickness of 15 mm; normal left ventricular dimensions and systolic function.

CaseNotHPOs: NR

CaseNotHPOFreeText: No cardiac symptoms or cardiac events were reported.

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing and targeted next-generation sequencing

FunctionalAnalysis: NR

Variant: c.3624delC, frameshift

ClinVar: 42727

CAID: CA014493

gnomAD: NR

AdditionalInfo: No additional CACNB2 variant was reported.

PMID: 28614222

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID:28382084

Gene:TNNI3

HGNC ID:11947

Case#: Female, 57, Korea

DiseaseAssertion:hypertrophic cardiomyopathy

FamilyInfo: Proband and 13 family members with diverse phenotypic expression of cardiomyopathies, elder sister had expired due to severe RCMP. large family, in which the p.Arg145Trp mutation of TNNI3 causes diverse phenotypes ranging from RCMP to HCMP to near-normal heart. Six relatives with RCMP or near-normal phenotypes also carried this mutation. Family pedigree (Figure 1) and Clinical data of affected individuals in a family with the c.433C>T mutation (table 1)

CasePresentingHPOs:HP:0002094, HP:0001640, HP:0001639, HP:6000313, HP:0031295, HP:0001670, HP:0004757, HP:0005135, HP:0004756, HP:0001962

CaseHPOFreeText:restrictive filling pattern, delayed hyper-enhancement, which reflects fibrotic change in the myocardium in the hypertrophied segments (Fig. 2D).

CaseNotHPOs:HP:0032092

CaseNotHPOFreeText:normal LV systolic function and normal cavity size

CasePreviousTesting:Chromatograms, Echocardiogram

Genotyping Method:Sanger Sequencing (Fig. 5)

FunctionalAnalysis:heterozygous nonsynonymous mutation

Variant:NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)

CAID:CA021667

gnomAD:chr19-55154146-G-A

Case1: Female, 53

DiseaseAssertion: Restrictive Cardiomyopathy

FamilyInfo:Pedigree in Fig 1. shows “ The proband (II.11) has five siblings and three nieces with cardiomyopathy,” “the proband’s two oldest siblings were diagnosed with idiopathic DCM”

CasePresentingHPOs: HP:0002094, HP:0001962, HP:0031329, HP:0001688, HP:0001709

CaseHPOFreeText:”Echocardiography revealed massive biatrial enlargement (Fig. 2a) and markedly abnormal diastolic function” “she had mild hypertrophy localized to the mid-septum” “progressive atrial enlargement”

CaseNotHPOs:HP:0012436,

CaseNotHPOFreeText: “with no systolic anterior motion of the anterior mitral valve leaflet or left ventricular outflow tract obstruction” “The sample was negative for eosinophilic infiltrate, myocarditis, sarcoidosis, amyloidosis and hemochromatosis.”

CasePreviousTesting: Sequenced TNNT2, TTN, MYL3, MYBPC, MYL2, MYH7, ACTC1, TPM1, and TNNI3

Genotyping Method: PCR

Variant: c.266T>A (p.Ile89Asn)

ClinVar:CA004157

gnomAD: To be found

AdditionalInfo: Autosomal Dominant trait, heterozygous missense mutation in TNNT2

PMID:30953456

Gene:TNNI3

HGNC ID:11947

Case#:52 year old female from a small mountainous village in Peloponnese, Greece

DiseaseAssertion:severely manifested phenotype of RCM leading to heart transplant at 41

FamilyInfo:Family Pedigree Figure 1.Parents were third-degree cousins from the same village and were heterozygous for the same variant but displayed no symptoms of the disease. The older sister who was also found heterozygous was asymptomatic. Twin sister and brother were homozygous for the same variant and displayed a restrictive and a hypertrophic phenotype, respectively. Their children are all carriers of the mutation and remain asymptomatic until the age of 21

ParentalTesting:Family of the proband had Electrocardiogram and Doppler Echocardiogram (shown in figure 2) as well as TNNI3 genetic testing by targeted Sanger sequencing for the detection of the variant. Her twin sister and her brother were found homozygous for the variant, while both parents and the older sister were found heterozygous.

CasePresentingHPOs:HP:0002875, HP:0004757

CaseNotHPOFreeText:normal left ventricular dimensions

CasePreviousTesting:electrocardiogram, Right heart catheterization

Genotyping Method:NGS (filtered using VariantStudio Data Analysis Software and the Sophia Genetics DDM platform)

FunctionalAnalysis: a novel homozygous TNNI3 variant

Variant:NM_000363.4:c.586G > C, p.(Asp196His)

ClinVar:2169619

CAID:CA407439559

Case3: 73 year old man

DiseaseAssertion: He carried the MYL2 p.Ala13Thr variant

FamilyInfo: Yes, his wife, son, and daughter

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0002094, HP:0003388, HP:0012828, HP:0001650, HP:0034313, HP:0030882

CaseHPOFreeText: presented with dyspnea on exertion and easy fatigability. He was found to have severe aortic stenosis with an aortic valve area of 1 cm2 and a peak gradient of 68 mmHg. He had mild LVH with a wall thickness of 13 mm on an echocardiogram and a left ventricular ejection fraction (LVEF) of > 70%. A 12-lead ECG was unremarkable without evidence of LVH. He also had an 80% luminal diameter stenosis of left anterior descending coronary artery on coronary angiography. He underwent aortic valve replacement and a single vessel coronary artery bypass surgery. He has been asymptomatic since surgery

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case4: 43 year old woman.

DiseaseAssertion: diagnosed with HCM and carried variants in TTN, ALPK3, and MYL2 (p.Ala13Thr).

FamilyInfo:Other family members, II-1 is a 72-year old woman with history of intermittent atrial flutter with a normal interventricular septal thickness (8 mm) and a normal LVEF (58%). Likewise, individual II-4 is an asymptomatic 70-year old male, who had normal ECG, echocardiogram, and myocardial stress perfusion tomography. Proband’s children (IV-1 and IV-2) were asymptomatic and had normal ECGs and echocardiograms on the last evaluation. Likewise, individual IV-3 was a 7-year old asymptomatic boy who had a normal ECG and echocardiogram.

ParentalTesting: Yes, mother, brother, and father were tested

CasePresentingHPOs:HP:0031664, HP:0012835, HP:0004972, HP:0001670, HP:0034313, HP:0031656, HP:0012825

CaseHPOFreeText: Her physical exam was notable for the presence of a II/VI mid-systolic ejection murmur at left sternal border that radiated toward base of the heart. She also had a mildly elevated arterial blood pressure. A 12-lead ECG showed evidence of LVH, interventricular conduction delay, and repolarization abnormalities. An echocardiogram showed severe asymmetric septal hypertrophy with a hyperdynamic LV systolic function, systolic anterior motion of the mitral leaflet, and a LVOT gradient of 60 to 70 mmHg at rest (Figure 3B). CMR findings were also notable for asymmetric septal hypertrophy and mild patchy hyperenhancement.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case2: 63 year old woman, diagnosed with HCM

DiseaseAssertion: Individual carried the MYL2 p.Ala13Thr, TTN, and ALPK3 variants.

FamilyInfo: Yes, son and daughter and husband was all diagnosed.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0004383, HP:0005144, HP:0001962, HP:0001279, HP:0001278, HP:0031295, HP:0040284, HP:0011703, HP:0025275

CaseHPOFreeText: Echocardiographic findings of a hyperdynamic left ventricle and an interventricular septal thickness of 19 mm. She had a history of brief episodes of palpitations and one episode of syncope a few years earlier, which was thought to be due to orthostatic hypotension. A 12-lead ECG was notable for possible left atrial enlargement. A 30-day rhythm monitoring showed rare ventricular ectopic beats and episodes of sinus tachycardia. CMR showed a normal LV wall thickness and function and minimal patchy mid myocardial hyperenhancement in the basal inferior and infero-lateral wall.

CaseNotHPOs: HP:0000822, HP:0001639, HP:0032092

CaseNotHPOFreeText: No history of systemic arterial hypertension, valvular disease, or other conditions to explain cardiac hypertrophy. No LVOT obstruction.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case#: Pedigree C, C.6, age 38, Female

FamilyInfo: C.6 is the daughter of C.4 in Pedigree C. C.6 carries the MYBPC3 P910T variant only and does not carry the TNNC1 D145E variant. Normal cardiac screening was reported at age 38.

ParentalTesting: Mother, C.4, carries MYBPC3 P910T and TNNC1 D145E

CasePresentingHPOs: NR

CaseNotHPOs: NR

CasePreviousTesting: NR

Genotyping Method: DNA was isolated from a peripheral blood sample of the patient and was screened for mutations by direct sequencing

FunctionalAnalysis: NR

Variant: NM_000256.3: c.2728C>A (p.Pro910Thr; P910T)

ClinVar: 42656

CAID: CA012881

gnomAD: NR

Case#: Pedigree C, C.4, age 60, Male

DiseaseAssertion: Dilated Cardiomyopathy

FamilyInfo: Pedigree C, Fig. 2 and Table 2. The individual carried MYBPC3 P910T and TNNC1 D145E. A brother was affected with hypertrophic cardiomyopathy. A daughter, C.6, carried MYBPC3 P910T only and had normal cardiac screening at age 38.

CasePresentingHPOs: HP:0200128 HP:0001644

“Dilated cardiomyopathy; left ventricular dilation; severely reduced ejection fraction; left bundle branch block; first-degree atrioventricular block”

Genotyping Method: DNA was isolated from a peripheral blood sample of the patient and was screened for mutations by direct sequencing

Variant: NM_000256.3: c.2728C>A (p.Pro910Thr; P910T)

ClinVar: 42656

CAID: CA012881

Case#: A94, male, age 57; Chinese family

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: positive family history of cardiomyopathy

ParentalTesting: NR

CasePresentingHPOs: HP:0001712 HP:0005144

CaseHPOFreeText: Interventricular septal thickness was 16.3 mm

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: Targeted sequencing using the Ion Torrent PGM system with Sanger sequencing confirmation.

FunctionalAnalysis: NR

Variant: MYBPC3 c.706A>G (p.Ser236Gly), missense

ClinVar: 42786

CAID: CA015725

gnomAD: 0.09513

PMID:40656892

Gene:TNNI3

HGNC ID:11947

Case#:53-year-old female

DiseaseAssertion:non-obstructive HCM with progressive deterioration of right heart function

FamilyInfo:mother has cardiac hypertrophy, the TNNI3 variant was also detected her sister and daughter

CasePresentingHPOs:HP:0005110, HP:0012398, HP:0001962, HP:0031352, HP:0033118, HP:0011675

CaseHPOFreeText:enlarged cardiac silhouette

CaseNotHPOs:HP:0030829, HP:0030148

CaseNotHPOFreeText: jugular venous distention

CasePreviousTesting:Electrocardiogram, Echocardiograms

Genotyping Method:next-generation sequencing (NGS)

FunctionalAnalysis: Hybridized pathogenic variant in exon 7 of TNNI3 (table 1)

Variant:NM_000363.4:c.470C>T(p.Ala157Val)

ClinVar:43388

CAID:CA021720

gnomAD:chr19-55154109-G-A

PMID: 35861968 Gene: TNNT2 HGNC ID: HGNC:11949

GroupID: 3682b

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation. Paper gives 2 families with the ID 3682 - the other family (given here as 3682a) was mentioned with 1 individual. Unclear if these are the same family.

GroupPresentingHPOs: HP:0010797 (hemangioblastoma)

GroupHPOFreeText: both (2/2) members had hemangioblastomas

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.F76I (c.226T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.F147I (c.439T>A)

ClinVarID: 820994 https://www.ncbi.nlm.nih.gov/clinvar/variation/820994/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F76I (c.226T>A)

MultipleGeneVariants: N/A

GroupID: 2547

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 5 family members recorded with this mutation.

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

GroupHPOFreeText: 3/5 members had a retinal angioma (hemangioma), 4 had CNS hemangioblastoma, and 2 had pheochromocytoma

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 2547NCI);

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.G164D (c.491G>A )

ClinVarID: 496054 https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

GroupID: 4405

DiseaseAssertion: assumed VHL

GroupSize: 41

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 41 family members recorded with this mutation.

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

GroupHPOFreeText: 29/41 members had retinal angioma (hemangioma), 10 had CNS hemangioblastoma, 15 had RCC and 28 had pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 2 4405NCI)

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R238W (c.712C>T)

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-

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in 3 VHL type 1 family members (family ID 3738), using PCR and SSCP sequencing. The mutation of c.334T>C was referred to in the paper by c.547T>C due to a difference in transcript sequence. All had pheochromocytomas and one with retinal hemangioblastomas.

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 the c.386T>C (p.L129P) mutation. This member presented with retinal hemangiomas. No family information was provided.

GroupID: 7b

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: N/A

CaseHPOFreeText: This individual patient was 1/9 with an exon 3 deletion that did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: Exon 3 deletion

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: exon 3 deletion

MultipleGeneVariants: N/A

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. Out of the 3 patients with a p.Q164* (c.490C>T) mutation, 67% (2/3) of individuals had RH while 33% (1/3) did not. No family information was provided.

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.562C>G (p.L188V). This member presented with retinal hemangiomas. No family information was provided.

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There were 2 patients reported with the p.C162W (c.486C>G) mutation. One member presented with retinal hemangiomas, while the other did not - however no other clinical manifestations were discussed. Additionally, no family information was provided.

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There were 2 patients reported with the p.F136S (c.407T>C) mutation. One member presented with retinal hemangiomas, while the other did not - however no other clinical manifestations were discussed. Additionally, no family information was provided.

Two VHL syndrome pedigrees were investigated in this study; family 1 was a three-generation pedigree including 6 individuals. In family 1, the proband (F1-II-1), a 31-year-old male patient, presented with headache, paroxysmal hypertension and dizzy spells in 2009 with a 4-year history. Ultrasound and MRI scans confirmed single masses, multiple tumors and multiple cysts in the right adrenal glands, bilateral kidney and pancreas, respectively. Right pheochromocytoma and multiple right renal cell carcinoma were confirmed by histopathological examination. In 2012, the patient was diagnosed with bilateral epididymal head multiple nodules. Bilateral epididymal tubercle resection was performed and epididymal papillary adenoma was confirmed by histopathological examination. Additionally, the patient's younger brother (F1-II-3, 30 years old) presented with multiple right renal masses, epididymal nodules and multiple pancreatic cysts. Radical right nephrectomy was performed and histopathological analysis revealed right RCC with hemorrhagic cyst. In family 1 they identified a heterozygous variant, c.233A>G (p.N78S), within exon 1 of the VHL gene in two affected cases and one clinically normal family member (F1-III-1, the proband's 5-year-old son). Peripheral blood samples were collected for mutation analysis of the RET proto-oncogene and VHL tumor suppressor gene. PCR amplification of all exons and the flanking splice junctions of RET and VHL was performed, followed by direct bidirectional DNA sequencing. One hundred unrelated controls with a similar ethnic background were also included in this study. ACMG evidence codes: ‘PP4’ because the family history is highly specific for a disease with a single genetic etiology, ‘PP1’ because there is co-segregation of the variant with VHL disease in the family.

PatientID: 6

KindredID: 6

Case: F, 34Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: Positive VHL family history.

CasePresentingHPOs: HP:0002011, HP:0001732, HP:0007850, HP:0012210, HP:0030424 (Morphological central nervous system abnormality, abnormality of the pancreas, retinal vascular proliferation, abnormal renal morphology, epididymal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78D (c.232A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625226 https://www.ncbi.nlm.nih.gov/clinvar/variation/625226/

CAID: CA351749284 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.232A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78D (c.232A>G)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. One female patient, patient 112, was found with this germline mutation from family #40. Shee was diagnosed with a CNS hemangioblastoma at 34Y, renal cell carcinoma at 44Y, and multiple pancreatic cysts/tumors at 44Y. This kindred was likely also published in a later paper by Wang et al., 2018 (PMID: 29330336).

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 male patient was found with this germline mutation from family #45. He was diagnosed with CNS hemangioblastoma at 30Y. One male patient was found with this germline mutation from family #46. He was diagnosed with CNS hemangioblastoma at 30Y, RCC at 31Y, pheochromocytoma at 30Y, and multiple pancreatic lesions at 30Y. No other family information was published for these two patients. Both kindreds were also likely published in a paper by Wang et al., 2018 (PMID: 29330336). Kindred #46 was also previously published in Wang et al., 2014 (PMID: 24581539). Wang et al., 2018 reported 4 patients from 2 families (corresponding with kindred #45 and #46) who were genetically confirmed with this germline mutation. Wang et al., 2014 reported one patient who was genetically confirmed with this germline mutation likely corresponding with family #46.

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. Genotyping confirmation was performed by PCR-direct sequencing on peripheral blood samples. This mutation was confirmed in families #4, #5, and #5. Only the proband of family #4 (male, patient #7) was genetically confirmed with the mutation. He was diagnosed with renal cell carcinoma and multiple pancreatic cysts/tumors at age 33. Only the proband of family #5 was genetically confirmed with the mutation. He presented with a CNS hemangioblastoma at age 21 and multiple pancreatic cysts and tumors at age 30. His grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease. Family #6 is large: the proband (F, renal cell carcinoma at age 36 and pheochromocytoma at age 37) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13 (asymptomatic,) 14 (CNS hemangioblastoma at age 59,) 15 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19 (asymptomatic), 20 (asymptomatic), 21 (CNS hemangioblastoma and retinal angioma at 53,) and 22 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16 (CNS hemangioblastoma at 22) and 17 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

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: an 18 year old male from kindred #88 who was diagnosed with CNS hemangioblastoma, retinal angioma, renal cell carcinoma, and multiple pancreatic cysts/tumors. This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 93

KindredID: 30

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; (Hemangioblastoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 51.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.E94* (c.280G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 584477; https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: E94* (c.280G>T)

MultipleGeneVariants: N/A

PatientID: 88 (Second cousin)

KindredID: 18

Case: F, 52Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed 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 (18Y) and pheochromocytoma (17Y).

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: N/A

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Authors state that the c.712C>T germline familial variant of the VHL gene in this patient is “inferred from the family”. No genetic testing was done on this patient to confirm this. Being that this familial 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: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: 21 (Aunt)

KindredID: 1

Case: F, 48Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 1 (proband), 28, 2, 6, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified).

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

CaseHPOFreeText: The patient presented with a pheochromocytoma at age 39 and retinal angioma at age 41.

CaseNotHPOs: HP:0005584; HP:0001732; HP:0000077; HP:0010797 (Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 7

Case: M, 12Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6 members of this family were found to harbor the c.319C>G germline variant of the VHL gene. ID 11 presented with renal and pancreatic abnormalities, pheochromocytoma and other undefined phenotypes. ID 24 presented with renal abnormalities, and pheochromocytoma, and died at age 62. ID 2 presented with pancreatic abnormalities. ID 10 presented with CNS hemangioblastoma, pancreatic abnormalities and pheochromocytoma. ID 4 presented with pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented pheochromocytoma (4Y).

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0010797; HP:0000077 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Abnormality of the kidney)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

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

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence AF010238.1 and NM_000551.3

GenotypingMethod:N/A

SamplingMethod: N/A

PatientID: 8

KindredID: 5

Case: M, 5Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Positive. The patient's mother (5) and aunt (4) were confirmed to have the mutation and had VHL presentations. The patient's cousin was the proband (1) and also had the mutation and presented with hemangioblastoma and abnormality of the pancreas.The grandfather (13) was inferred to have the mutation and had a hemangioblastoma. See Figure 2a for family pedigree.

CohortInfo: 20 unrelated VHL families from an ethnically diverse cohort containing both affected and unaffected individuals.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0005584, HP:0002666, HP:0001732, HP:0000077, HP:0010797 (retinal capillary hemangioma, renal cell carcinoma, pheochromocytoma, abnormality of the pancreas, abnormality of the kidney, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 31368132

SupplementalData: Supplementary file 1.

Variant: p.F136Lfs*23 (c.408delT)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43601 https://www.ncbi.nlm.nih.gov/clinvar/variation/43601/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: F136Lfs*23 (c.408delT)

MultipleGeneVariants: N/A

PMID: 15452453

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 10563480 Gene: VHL StandardizedReferenceSequence: NM_000551.3

GroupID: 7

DiseaseAssertion: VHL

Group size: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations. From this pedigree, 6 individuals were suspected of VHL disease. 5/6 individuals developed RH, while 1/6 did not.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: 5/6 patients in this family with VHL disease presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: p.V130P (c.388G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 496061, https://www.ncbi.nlm.nih.gov/clinvar/variation/496061/

CAID: N/A

gnomAD: N/A

VariantEvidence: Chr3(GRCh37): g.10188245G>T

MutationType: missense_variant; transversion

CivicName: V130P (c.388G>T)

MultipleGeneVariants: N/A

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation p.R161Q (c.482G>A) was found in 3 VHL patients. All 3 have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this frameshift mutation p.H191Tfs*11 (c.571delC) was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. This is possibly previously published in PMID: 15300849

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation was found in a 1 patient, without retinal hemangioblastomas, but other manifestations are not clearly stated. No family information or relation was provided. Recorded in paper as c.386insCT, this mutation automaps to NM_000551.3:c.385_386dupCT (p.V130Wfs*30). This is possibly previously published in PMID: 15300849

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation p.R167W (c.499C>T) was found in 15 VHL patients. 5 had retinal hemangioblastomas, and the other 10 were said to not have. Other manifestations are not clearly stated. No family information or relation was provided. Some may be possibly previously published in PMID: 15300849

A 19-year-old female patient was referred to a psychiatric inpatient service due to a suspicion of anorexia nervosa (AN) following severe weight loss, low food intake, and a lack of a menstrual cycle for at least 1 year. The patient is the second child of a non-consanguineous relationship and there were no abnormalities in developmental milestones, but her weight never exceeded 35 kg. Apart from weight loss and weakness, physical and neurological examinations showed no alterations. The patient frequently complained of epigastric burning sensation, nocturnal headaches, postural hypotension and difficulty swallowing. The patient did not meet the necessary criteria for a diagnosis of AN or another psychiatric disorder. The patient experienced episodes of nausea during fasting after waking up, followed by unprovoked vomiting, which is highly uncommon in AN. Blood tests, urinalysis and chest X-ray were all normal. Abdominal CT scan revealed cystic lesions throughout the parenchymatous portion of the pancreas, suggestive of VHL. After 3 weeks of hospitalization, the patient progressively developed gait abnormality and bilateral dysmetria, which was worse on the left side. A brain MRI examination revealed a massive lesion suggestive of a hemangioblastoma (HB) in the fourth ventricle causing hypertensive hydrocephalus. HB and pancreatic cysts support the diagnosis for VHL. Whole blood was obtained for sanger sequencing of all 3 exons of the VHL gene, revealing a nonsense mutation in the VHL gene (c.481C>T; p.Arg161*) that results in a truncated protein. In silico analyses by mutation analyzer 2.0.28 suggests a pathogenic variant. Surgery inserting a ventriculoperitoneal shunt to relieve the hypertensive hydrocephalus only temporarily relieved her appetite; yet she no longer had fasting nausea and vomiting, or nocturnal headaches. Fractionated radiotherapy did not improve appetite or nausea but was successful in controlling tumor growth as an MRI revealed no significant alterations in the size of the lesion six months post-radiotherapy.

Genomic DNA was extracted from whole blood samples for genetic testing of SDHB, SDHC, SDHD, and VHL. 27 patients with urinary bladder paragangliomas, revealed 17 germline mutations, three of which were in the VHL gene. PCR–based bidirectional sequencing was performed along with MLPA on large deletions. This missense mutation (p.T124I) was found in a 12-year-old male (patient no. 22), with his urinary bladder paraganglioma diagnosis at 6Y of age. Family history of pheo or paragangliomas was said to be positive.

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 using the BigDye Terminator Cycle Sequencing Ready Reaction kit on an ABI Prism 3130 genetic analyzer (Applied Biosystems). One 34Y male patient (Patient 15) presented with multiple and/or bilateral RCC and a CNS hemangioblastoma. He had a germline missense mutation in the VHL gene (c.233A>G p.Asn 78 Ser). The patient had a negative family history of VHL disease. The phenotypes of this patient were revised from a previous report in PMID 19270817 and/or 19949673.

PatientID: 15

KindredID: 15

Case: M, 34Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None.

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, HP:0005584 (Hemangioblastoma, renal cell carcinoma )

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19949673

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transition

CivicName: N78S(c.233A>G)

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline p.S183* (c.548C>A) mutation, stated in the paper as c.761C>A due to an older transcript. It was seen in family [pedigree No] 22, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

KindredID: 7

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 7. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L198R (c.593T>G)

LegacyVariant: p.L269R (c.806T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756545 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.593T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L198R (c.593T>G)

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline c.Y98H (c.292T>C) mutation, stated in the paper as c.505T>C due to an older transcript. It was seen in 2 families: [pedigree No] 14 and 15, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

PatientID: II-1

KindredID: 1

Case: M, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Both of the patient’s brothers (Patient II-3 and II-4), the patient’s sister (II-5), and the patient’s nephew (III-3) were clinically diagnosed with VHL disease. Patient II-4 presented with RCCC at age 53, and carried the mutation NM_000551.3:c.269A>T. Patient III-3 presented with CH and carried the same mutation. The patient’s other brother (Patient II‐3) and sister (Patient II‐5) were deceased and had an undetermined mutation. Patient II-3 died of an advanced RCCC, and Patient II‐5 died of a ruptured CH. The patient’s parents (Patient I-1 and I-2) were also deceased from other causes. The patient’s grand-nephew (Patient IV‐1) was healthy and did not carry the mutation.

CasePresentingHPOs: HP:0006770; HP:0006880 (Renal clear cell carcinoma, cerebellar hemangioblastoma)

CaseHPOFreeText: The 45Y male patient was diagnosed with left RCCC at 33Y, but had no symptoms. The patient presented with complaints of headache and dizziness at age 41Y, and was diagnosed with a right cerebellar hemangioblastoma. In the most recent follow‐up, his symptoms had disappeared, and radiological imaging of the brain and abdomen revealed no recurrence.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient.

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

LegacyVariant: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I(c.269A>T)

MultipleGeneVariants: Supplementary Table 1&2 gives information on genetic mutations observed in the CH and RCC tissues of this patient

PatientID: proband

KindredID: D

Case: F, 34Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is said to be positive, however no other members were given. The patient’s son was asymptomatic and negative for the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 34Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Q145* (c.646C>T)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

PatientID: proband

KindredID: C

Case: F, 29Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: Family history is positive. Patient’s sister, and nephew all had the splice mutation, and sister and nephew had CNS hemangioblastomas and adnexal papillary cystadenoma of probable mesonephric origin, and pheochromocytoma phenotypes. Her daughter was asymptomatic and did appear to not carry the mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient had multiple hemangioblastoma of the CNS diagnosed at 29Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+5G>C

LegacyVariant: c.553+5G>C

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

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious).

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma (PC). Deletions. Nonsense, and frameshift mutations were more frequently found in families without PC. Large deletions and mutations predicted to cause truncated protein were associated with lower risk of PC. The mutation of c.214delT was referred to in the paper by c.427delT due to a difference in transcript sequence. This deletion mutation was found in a VHL family without PC (family ID 112). Only moderate evidence for pathogenicity because protein length changes as a result of in-frame deletion in a nonrepeat region or stop-loss variant (ACMG code: PM4).

In a study of 138 unrelated VHL families, 109 germline mutations were found. Missense mutations were more frequently found in families with pheochromocytoma (PC). Deletions, nonsense, and frameshift mutations were more frequently found in families without PC. Large deletions and mutations predicted to cause truncated protein were associated with lower risk of PC. The mutation R177* (c.499C>T) was referred to in the paper by c.712C>T due to a difference in transcript sequence. This missense mutation was found in one of the VHL families (family ID 153).

PatientID: III-8

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This male (III-8) appears to have inherited this disease from his father and has passed it onto to his kin thereafter. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: IV-35

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-35) appears to have inherited this disease from his mother, along with many of his siblings. See Fig. 1 for family pedigree.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: This member had pheochromocytoma which was not further described.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 45

Case: M, 13Y0M, 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:0006770; HP:0000107; HP:0002666; HP:0010797; HP:0030424 (Cerebellar hemangioblastoma, Clear cell renal cell carcinoma, Renal cyst, Pheochromocytoma, Hemangioblastoma, Epididymal cyst)

CaseHPOFreeText: Epididymal cyst was noted as “eH” instead of “eC” in Table 2. Given that “eH” was not explained in the footnotes of the Table as were all other phenotypes; “eH” was taken to be a typo intended to be “eC”.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 14722919

SupplementalData: N/A

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: 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 1-2 Deletion

MultipleGeneVariants: N/A

PMID: 24623741

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

ArticleReferenceSequence: Not specified- Assumption: Nucleotide change is not specified in the paper, only protein coding change is. cDNA variant was inferred based on protein coding change, and reported based on VHL reference sequence NM_000551.3

GenotypingMethod: Samples were paired-end multiplex sequenced on the Illumina HiSeq platform to a median target depth of >100×.

SamplingMethod: blood and tissue samples

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

GenotypingMethod: MLPA, SSCP analysis and qPCR.

SamplingMethod: peripheral blood, tumor tissue

Germline mutations were found in 20 Brazilian, VHL probands and their families. This missense mutation was found in 2 VHL family members (VHL family 3). One had hemangioblastomas of the central nervous system and one had retinal angiomas. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

Germline mutations were found in 20 Brazilian, VHL probands and their families. The S80R (c.238A>C) germline missense mutation was found in a VHL type 1 family of 10 affected individuals (VHL family 2). Seven had hemangioblastomas of the central nervous system, 3 had retinal angiomas, and 3 had renal carcinoma. This variant was not found in 120 alleles from normal subjects in the Brazilian population.

PatientID: None (sister of Patient 9)

KindredID: 2

Case: F, age unknown, Italian

DiseaseAssertion: asymptomatic

FamilyInfo: R167W was detected in her sister as well, who had cerebellar hemangioblastoma.

CasePresentingHPOs: None

CaseHPOFreeText: negative at clinical and instrumental screening

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France). No variants were found in 96 control cases. This stop-gain mutation, c.525C>G, was found in a VHL type 1 patient (patient no. V63). No patient information was provided and no additional family members were screened.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The Y156C (c.467A>G) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V265). One unaffected family member was negative for this mutation.

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The V130L (c.388G>C) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V91). No unaffected family members were tested.

PatientID: 23

KindredID: 16

Case: Sex Unknown, 17Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0030405; HP:0010797; HP:0001737; HP:0009711 (pancreatic endocrine tumor, hemangioblastoma, pancreatic cyst, retinal capillary hemangioma)

CaseHPOFreeText: The patient developed a 2.2 cm PNET at age 17. Patient was also recorded with all of the above manifestations

CaseNotHPOs: HP:0002668, HP:0002666; HP:0005584; HP:0000107 (Paraganglioma, pheochromocytoma, renal cell carcinoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86T (256C>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750624 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.256C%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P25L (c.74C>T) and P86T (c.256C>A)

MultipleGeneVariants: Germline, VHL, c.74C>T (p.Pro25Leu)

PatientID: 21

KindredID: 14

Case: Sex Unknown, 36Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: The patient at 36Y was confirmed with VHL. They had developed the above manifestations

CaseNotHPOs: HP:0009711; HP:0030405; HP:0002668, HP:0002666; HP:0000107 (retinal capillary hemangioma, pancreatic endocrine tumor, paraganglioma, pheochromocytoma, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162* (c.486C>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223226 https://www.ncbi.nlm.nih.gov/clinvar/variation/223226/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: C162* (c.486C>A)

MultipleGeneVariants: N/A

A case report of a 30 year old young Indian female who presented with hypertension and was subsequently diagnosed to have VHL disease with a c.293A>C mutation in the VHL gene, causing the substitution of Tyr with Ser at amino acid 98. Patient presented with adrenal pheochromocytoma, pancreatic mass, and cerebellar hemangioblastoma. Family history is unavailable other than the delivery of a healthy child. ACMG: PP2, PP4

GroupID: 30

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. One registrant from France has this mutation of c.500G>C

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167P (c.500G>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 428799 https://www.ncbi.nlm.nih.gov/clinvar/variation/428799/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167P (c.500G>C)

MultipleGeneVariants: N/A

PatientID: VI-III

KindredID: 6

Case: F, 17Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: Patient first presented with adrenal pheochromocytoma at age 9Y0M and was diagnosed with VHL type 2C (see table 2).

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

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188del (c.562_564del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: L188del (c.562_564del)

MultipleGeneVariants: N/A

An Israeli specialized center identified 32 VHL patients belonging to 16 diferent kindreds. This retorspective collection and analysis of clinical, laboratory and imaging data of VHL patients involved one, 3 generation kindred identified and reported as early as 1980. Genetic analysis via direct VHL gene sequencing and quantitiative Southern blot identified the V166F (c.496G>T) mutation. This kindred (family 1) most recently have a reported 14/32 total patients diagnosed with VHL. One of which (I-31) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree. Note: This kindred was previously published in PMID: 8550742. Since its initial publication in 1996, several asymptomatic carriers developed a neuroendocrine tumor, 7 new children were born where 3 of them carry the mutation. In addition, 2 patients died, one of which was due to metastatic PNEN-related liver failure.

PatientID: None

KindredID: 3

Case: F, 20Y0M, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial/syndromic (FS) association

CasePresentingHPOs: HP:0002666; HP:0030393; HP:0030405; HP:0001737; HP:0000107 (Pheochromocytoma; endolymphatic sac tumor; pancreatic endocrine tumor; pancreatic cysts; renal cyst)

CaseHPOFreeText: Benign unilateral pheochromocytoma at age 20Y0M; as well as ELST, PNETs, pancreatic and renal cysts

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB,SDHC, SDHD, and exons 10, 11, 13, 14, 15 and 16 of RET proto-oncogene

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 1

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Heterozygous deletion of exon 1

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 9 and 10 were found with p.Pro86Leu mutation in the VHL gene. Family 9: the mutation was detected in a 53 years old woman (proband) with asynchronous bilateral renal clear cell carcinomas, multiple renal cysts and pancreatic cysts, an asympomatic member and with (initially) no positive family history. Subsequently, genetic analysis and clinical evaluations showed that the same mutation was also detected in her niece who had no detectable VHL lesions and in her young brother who had pancreatic cysts. Family 10: 1/4 members had CNS hemangioblastoma, 1/4 had retinal angioma, 2/4 had RCC, and 1/4 had a pancreatic lesion. ACMG PP4

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 14 was found with p.Ser111Asn mutation in the VHL gene: 4/5 members had CNS hemangioblastoma, 1/5 had retinal angioma, 3/5 had RCC, and 1/5 had a pancreatic lesion. ACMG PP4

GroupID/ KindredID: 18

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 2 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0005584; HP:0001732 (hemangioblastoma; renal cell carcinoma; pancreatic lesion)

GroupHPOFreeText: both (2) members had CNS hemangioblastomas, 1 had RCC, 1 had a pancreatic abnormality

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

GroupNotHPOFreeText: No family members appeared to have the above manifestations.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162Y (c.485G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.C162Y (c.698G>A)

ClinVarID: 223225 https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

PMID: 31368132

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

ArticleReferenceSequence: NM_000551.3

GenotypingMethod: Genetic testing was done through a variety of methods depending on the availability of genetic techniques at the time of testing. Note: Patients with a clinical diagnosis of VHL, regardless of confirmatory genetic testing, or those with a positive VHL family history and confirmed genetic variant were included in the analysis.

SamplingMethod: Data found using medical records; therefore genetic testing was completed through a variety of methods depending on the availability of genetic techniques at the time of testing

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. 7 patients were found with this germline mutation (c.496_506del), belonging to two pedigrees (but no data stated to determine which individuals belong together). Patient ID 44 had CNS hemangioblastoma and clear cell renal cell carcinoma; Patient ID 65 was found with the same mutation and only CNS hemangioblastoma; Patient ID 82 had retinal capillary hemangioma and hemangioblastoma; Patient ID 85 had hemangioblastoma, clear cell renal cell carcinoma and retinal capillary hemangioma; And patient ID 69, 83, 84 were all asymptomatic. Patients' age, and sex data was not reported.

PatientID: V-30

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: DIII7

KindredID: D

Case: F, 16Y0M, Chinese

DiseaseAssertion: pancreatic cysts

FamilyInfo: A 3-generation family is given with 3 confirmed members with this mutation. 2 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0001737 (pancreatic cysts)

CaseHPOFreeText: initially diagnosed by genetic analysis and further verified radiologically, to be found with pancreatic cysts at 16Y.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F76del (c.226_228delTTC)

LegacyVariant: p.F76del (c.439delTCT)

CaseProblemVariantFreeText: NM_000551.3:c.226_228delTTC automaps to NM_000551.3:c.227_229delTCT

ClinVarID: N/A

CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.226_228delTTC

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.227_2289delTCT)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: M, 12Y0M, Asian Indian

DiseaseAssertion: assumed VHL

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0000107; HP:0001737 (pheochromocytoma; paraganglioma; renal cyst; pancreatic cysts)

CaseHPOFreeText: unilateral pheochromocytoma with sympathetic paraganglioma. Renal and pancreatic cysts

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 219160 https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: Y98S (c.293A>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 5

Case: Sex Unknown, 60Y0M, 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:0009713; HP:0000107; HP:0002666; HP:0001737 (Retinal capillary hemangioma, Spinal hemangioblastoma, Renal cyst, Pheochromocytoma, Pancreatic cysts)

CaseHPOFreeText: VHL Type 2a/b.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 24132471

SupplementalData: Table 1

Variant: p.G93S (c.277G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2237, https://www.ncbi.nlm.nih.gov/clinvar/variation/2237/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93S (c.277G>A)

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.277G>A germline mutation of the VHL gene. They presented with a retinal hemangioblastoma, spinal hemangioblastoma, renal cyst, pheochromocytoma and pancreatic cysts. Their age at the last follow-up was 60. Previously published in: PMID 24132471.

GroupID: 8

DiseaseAssertion: VHL

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

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0001737 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Pancreatic cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: assumed VHL

GroupSize: 9

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 9 of the 573 patients discussed in this paper were found to the mutation belonging to 3 families, all with this mutation

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

GroupHPOFreeText: 7 patients had retinal angiomas diagnosed at a mean age of 23Y, and 3 patients had cerebellar hemangioblastomas diagnosed at a mean age of 29Y. 5 patients had RCCs with a mean age of diagnosis of 43Y.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). A missense mutation, S65W(c.194C>G), affecting residue within the pVHL protein core, was found in a VHL family with 8 affected individuals including 6 with retinal hemangioblastomas, 5 with cerebellar hemangioblastomas, and 1 with renal cell carcinoma. ACMG codes as follows: supporting evidence for pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

KindredID: 116

GroupID: 41

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.116 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene. Family history indicates that pheochromocytoma is present in this kindred.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: This study investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. No other information about disease presentation within members of a kindred could be inferred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.712C>T (p.R238W)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PMID: 7987306

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 28006088

Gene: VHL

StandardizedReferenceSequence: NM_000551.3