PMID: 41647802

Gene: MYBPC3

HGNC ID: 7551

case1: male, 40 weeks,

DiseaseAssertion: sudden-onset acute heart failure

FamilyInfo: Both parents suspected of being heterozygous carriers of a pathogenic MYBPC3 variant

ParentalTesting: Both parents were identified as heterozygous carriers of a pathogenic MYBPC3 variant

CasePresentingHPOs: HP: 0001639, HP: 0001631, HP: 0001635

“Hypertrophic cardiomyopathy, atrial septal defect, acute heart failure”

CaseHPOFreeText: Absence of significant interstitial fibrosis, extensive myocardial disarray and contraction band necrosis

CaseNotHPOs: N/A

CaseNotHPOFreeText: normal fetal growth and anatomy reported

CasePreviousTesting: Targeted gene panel for pathogenic variants in MYBPC3

Genotyping Method: Whole-exome sequencing (WES)

FunctionalAnalysis: N/A

Variant: NM_000256.3:c.2905+1G>A

Case6: 48 year old male

DiseaseAssertion: Carried the MYBPC3 E619K mutation

FamilyInfo:Three unaffected children were examined (IV:1, IV:2 and IV:3), all with normal echocardiography without signs of hypertrophy or dilatation. Both affected individuals as well as a 26-year-old unaffected daughter (M29, IV:3) carried the MYBPC3 E619K mutation

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:0011713, HP:0001635

CaseHPOFreeText: Onset of symptoms in their third decade; the index case required heart transplantation 3 years after the onset of symptoms. Has onset at the age of 37. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with the value of 79 mm and 3.2 cm/m2. They have a 20% of left ventricular ejection fraction. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1855G>A

ClinVar:161303

CAID:CA011336

gnomAD: gnomAD v2: 11:47362731 C / T gnomAD v3: 11:47341180 C / T gnomAD v4: chr11-47341180-C-T

AdditionalInfo:NR

PatientID: 11

KindredID: 11

Case: 30Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: No family history

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

CaseHPOFreeText: Aged 30Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. CNS angiomas, retinal angiomas, renal cysts and pancreatic cysts all diagnosed at 30Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88* (c.263G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 22

KindredID: 22

Case: 13Y0M, Sex Unknown, Argentinian

DiseaseAssertion: hemangioblastoma

FamilyInfo: No family history

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Aged 13Y at diagnosis (genetic testing); does not fulfil type 1 VHL clinical diagnosis. Solitary CNS angiomas diagnosed at 13Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: did not develop other manifestations of the disease during a 5- year follow-up.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88* (c.264G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 936684 https://www.ncbi.nlm.nih.gov/clinvar/variation/936684/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.264G>A)

MultipleGeneVariants: N/A

PatientID: 21

KindredID: 12

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated.

CasePresentingHPOs: HP:0002893; HP:0002666 (Pituitary adenoma, Pheochromocytoma)

CaseHPOFreeText: Pituitary adenoma presented at age 27. Pheochromocytoma age of presentation unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX/RET/TMEM127/SDHA/SDHB/SDHC/SDHD/SDHAF2

PreviouslyPublished: N/A

SupplementalData: Table 1, Supplementary Table 6

Variant: p.D197N (c.589G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756524, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351756524

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: D197N (c.589G>A)

MultipleGeneVariants: Germline, SDHA, c.91C>T (p.Arg31*)

GroupID: 23

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 41 non-related patients with retinal angiomatosis between 1988 and 1999 were evaluated.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

41 non-related patients with retinal capillary hemangioma presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline splicing mutation (c.464-1G>C) mutation in the VHL gene. This variant was reported as c.677-1G>C (AF010238.1) and mapped to c.464-1G>C (NM_000551.3).

PatientID: 30

KindredID: PM

Case: M, 49Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001737 (Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: CNS hemangioblastoma and multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 9

KindredID: AD

Case: F, 38Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0001737 (Pancreatic cysts)

CaseHPOFreeText: Multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0030393; HP:0009711; HP:0010797 (Renal cell carcinoma, Pheochromocytoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114D (c.340+1G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transition

CivicName: G114D (c.340+1G>A) and c.340+5G>C

MultipleGeneVariants: N/A

Germline sequencing of the VHL gene was performed on patients who presented with VHL syndromic hemangioblastomas, and germline results were compared to sequencing results from matched tumor tissue samples. Patients were only identified by their tumor sample number. Sample 1 (patient 1) had a Gln96_Pro102 deletion (c.287_307del) in the VHL gene. Genetic analysis was conducted as follows: peripheral blood samples were collected from patients, and genomic DNA was extracted, amplified, and purified using ExoSAP IT (ExoSAP IT (Thermo Scientific Inc., MA, USA). Sanger sequencing was performed on samples (Bigdye direct cycle sequencing v3.1, Life Technologies, CS, USA) and capillary electrophoresis was performed on an ABI Genetic Analyzer (ABI 3130xl, Life technologies, CS, USA). Deletion and duplication analysis of the VHL gene spanning the chr3p.25.3 locus was tested by the Multiplex Ligation-dependant Probe Amplification (MLPA) procedure. VHL gene locus-specific probes (P016-C2 VHL) were purchased from MRC Holland (MRC Holland, Amsterdam, Netherlands). ACMG evidence codes: PP4- Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

PatientID: III:4

KindredID: 1

Case: M, 56Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: A 5-generation family with VHL in 15 members. Both second generation children (presumed), 5 third generation, and 8 further generation individuals were affected and haplotyping was conducted using three polymorphic microsatellite markers. All of the 5th generation children (9 total at time of publication) had been sequenced and haplotyped as unaffected.

CasePresentingHPOs: HP:0006880; HP:0002666 (cerebellar hemangioblastoma; pheochromocytoma)

CaseHPOFreeText: patent had a combination of cerebellar HB and bilateral pheo, age of onset at 38Y, and operated on the same year

CaseNotHPOs: HP:0006880; HP:0002666; HP:0030405; HP:0001737; HP:0000107; HP:0002668 (pancreatic endocrine tumor, pancreatic cysts, renal cysts, paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). 

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263). The microsatellite markers were amplified by PCR using fluorescently labeled primers. Mutation screening was performed by directly analyzing the DNA sequence output. The exons of VHL were amplified with primers flanking the exon‑intron boundaries

SamplingMethod: peripheral blood leukocytes

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.395A>C), affecting a residue on surface of pVHL, was found in a VHL family of 2, 1 with retinal angiomas diagnosed at 18Y, 1 with cerebellar hemangioblastomas at 37Y, and 1 with renal cell carcinoma at 49Y.

GroupID: 1

DiseaseAssertion: assumed VHL

GroupSize: 113

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 113 of the 573 patients discussed in this paper were found to have the following mutation belonging to 39 families altogether

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

GroupHPOFreeText: 68 patients had retinal angiomas diagnosed at a mean age of 25Y, 61 had cerebellar hemangioblastomas diagnosed ad a mean age of 31Y, 34 had RCC diagnosed at a mean age of 45Y, and 4 had pheochromocytoma diagnosed at a mean age of 33Y

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: exonic deletions

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Exon Deletion

MultipleGeneVariants: N/A

GroupID: 80

DiseaseAssertion: assumed VHL

GroupSize: 33

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.500G>A)

MultipleGeneVariants: N/A

GroupID: 61

Case: Age Unknown, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.262T>A) was found in 1 VHL family with a single patient.

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

CaseHPOFreeText: patient had retinal angioma diagnosed at 23Y, cerebellar hemangioblastoma diagnosed at 54Y, and RCC at 54Y.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this nonsense mutation. c.529A>T was found in 3 VHL families total. 2 families were grouped and detailed as affected with a total of 10 patients, 8 with retinal angioma, 4 with cerebellar hemangioblastoma, 1 with renal cell carcinoma (diagnosed at 50Y), and 1 with pheochromocytoma (diagnosed at 27Y). Another individual belonging to a separate family was written with the same nonsense mutation and retinal angiomas diagnosed at 28Y, cerebellar hemangioblastomas diagnosed at 22Y, and renal cell carcinoma diagnosed at 37Y.

Genotype-phenotype correlations of 573 VHL patients were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this nonsense mutation (c.375insT: p.Glu55*) in a VHL family with 2 affected members. They both had hemangioblatomas. No other info was given.

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

GroupID: 8

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

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.D92G (c.275A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA351750765 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.275A%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: D92G (c.275A>G)

MultipleGeneVariants: N/A

GroupID: 11

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: UK (country)

GroupAgeRange: N/A

GroupInfo: 2 registrants from the UK were grouped in this study via the mutation of c.332G>A

GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

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.256C>G), which was found in 1 individual from Italy.


GroupID: 22

Case: Sex unknown, Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

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.T157I (c.470C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 223223 https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: T157I (c.470C>T)

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 inframe mutation (c.224_226delTCT) was recorded in the paper as c.437delTCT due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any relation between patients is unknown. No other phenotypes described.

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.194C>G) was recorded in the paper as c.407C>G due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any relation is unknown. No other phenotype described.

PatientID: 7

KindredID: 2656

Case: F, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with one pathologic pancreatic neuroendocrine tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: V62Cfs*5 (c.180delG)

MultipleGeneVariants: N/A

Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for pancreatic neuroendocrine tumours (PNETs) either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. Five patients presented with the c.500G>A VHL gene mutation (stated as 713 G to A in the paper which used the Latif sequence as reference) causing a change of Arg to Gln at protein position 167. From family 5960, patient 38 (41-year-old male) presented with a single radiologic PNET and patient 39 (39-year-old female) presented with a single pathologic PNET. From family 5069, patient 41 (48-year-old male) presented with five pathologic PNETs, and patient 42 (16-year-old male) presented with a three pathologic PNETs. Unrelated patient 40 (31-year-old female) presented with a single pathologic PNET. No ACMG code.

GroupID: 3770

DiseaseAssertion: assumed VHL

GroupSize: 6

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 6 family members recorded with this mutation.

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

GroupHPOFreeText: all members had CNS hemangioblastomas, 5 have RCC and 4 members had retinal angioma (hemangioma)

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

Variant: p.E186* (c.556G>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.E257* (c.769G>T)

ClinVarID: 381602 https://www.ncbi.nlm.nih.gov/clinvar/variation/381602/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E186* (c.556G>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4398

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Familial VHL stated; although only 1 family member recorded.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78H (c.232A>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N149H (c.445A>C)

ClinVarID: 625225 https://www.ncbi.nlm.nih.gov/clinvar/variation/625225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78H (c.232A>C)

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 detected in a VHL type 2B patient (family ID 4422), using PCR and SSCP sequencing. The mutation of c.482G>A was referred to in the paper by c.695G>A due to a difference in transcript sequence. The patient had  retinal hemangioblastoma, renal cell carcinoma, and pheochromocytoma. Only supporting evidence for pathogenicity because patient's phenotyoe is highly specific for a disease with a single genetic etiology (ACMG code: PP4).

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 4 VHL type 2 families of 51 individuals altogether (family IDs 2338, 3490, 4477, 4405). 36 of 51 individuals had retinal hemangioblastomas, 17 had CNS hemangioblastomas, 16 with renal cell carcinoma, and 36 with pheochromocytomas. This mutation was also detected in an additional family with 1 single member, with retinal angiomas (family ID 3699). Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

GroupID/ KindredID: 21CA, 56CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from two databases: the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database. There was an unknown number of members belonging to Family IDs: 21CA and 56CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

LegacyVariant: p.Q195* (c.796C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 428794 https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (G57fs (c.167_168insA)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 110CA. It was reported in the paper as c.380insA due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 3710NCI

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3710NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

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

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID/ KindredID: 8CE, 59CA, 21CE

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family IDs 8CE, 59CA, 21CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.L89P (c.479T>C)

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

GroupID/ KindredID: 91CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 91CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158V (c.472C>G)

LegacyVariant: p.L158V (c.685C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 567944 https://www.ncbi.nlm.nih.gov/clinvar/variation/567944/

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transversion

CivicName: L158V (c.472C>G)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S111fs (c.331delA)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3669NCI. It was reported in the paper as c.544delA due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

PatientID: 1 (case)

KindredID: 1

Case: F, 30Y0M, Vietnamese

DiseaseAssertion: VHL

FamilyInfo: None - The diagnosis of VHL had not been established in her parents or her relatives, who lived in Vietnam without further evaluation.

CasePresentingHPOs: HP:0009711; HP:0001737 (retinal capillary hemangioma; pancreatic cysts)

CaseHPOFreeText: At 28Y presented with multiple retinal capillary hemangioma (complicated tractional retinal detachment and multiple large angiomas) and multiple pancreatic cysts. Underwent PPV combined with relaxing retinectomy.

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: 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

PatientID: DHPLC 1

KindredID: 1

Case: M, 51Y0M, Unknown Ethnicity

DiseaseAssertion: Assumed VHL

FamilyInfo: The patient’s daughter (DHPLC 1) had a pheochromocytoma at 11Y. At 18Y, she had a pheochromocytoma in the contralateral adrenal gland and two concurrent paragangliomas of the abdominal aorta and urinary bladder. At 25Y, she was found to have a right frontal meningioma. A family history obtained from his daughter’s other parent, one son and one other daughter (not DHPLC 1) was uninformative. The patient’s relatives (except for his daughter) were normal both clinically and biochemically.

CasePresentingHPOs: HP:0001028; HP:0000277; HP:0009715; HP:0000107 (Angioma, abnormality of the mandible, papillary cystadenoma of the epididymis, renal cyst)

CaseHPOFreeText: The patient had an attenuated VHL phenotype caused by mosaicism which led to what initially appeared to be a de novo mutation in his daughter (DHPLC 3). The patient was found to have an angioma of the glans penis and had had surgery for a mandibular cyst and epididymal cystadenomas at age 43Y. Abdominal ultrasonography and total-body magnetic resonance imaging (MRI) conducted at the time of the study (51Y) revealed a 2.3-cm cyst in his right kidney. His blood pressure and levels of plasma free metanephrines, fractionated urinary metanephrines, chromogranin A were normal.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R161Q (c.695G>A)

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: V209

KindredID: V209

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The E46* (c.136G>T) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V65).

ArticleReferenceSequence: NM_000551.3

GenotypingMethod: Sanger sequencing of PCR-amplified coding sequences of the VHL gene.

SamplingMethod: peripheral blood

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.R82P (c.245G>C) was found in 3 VHL patients. 1 member was said to have retinal hemangioblastomas, while the other 2 were said not to have this phenotype. 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 mutation p.Y156* (c.468T>G) was found in 3 VHL patients. All 3 were said not to have retinal hemangioblastomas, while other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

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.Q73* (c.217C>T)) was found in 5 VHL patients. 4 members were said to have retinal hemangioblastomas, while the other was said not to have this phenotype. 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 mutation p.W117C (c.351G>T) was found in 5 VHL patients. 4 members were said to have retinal hemangioblastomas, while the other member was said not to have this phenotype. Other manifestations are not clearly stated. No family information or relation was provided. This is possibly previously published in PMID: 15300849

PatientID: 290

KindredID: 114

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 38, and at age 41 presented with a retinal angioma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 118

KindredID: 42

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: The proband (patient 42) had four family members confirmed with the mutation: his son (CNS hemangioblastoma at 12, retinal angioma at 11); his sister 1 (patient 116) presented with multiple pancreatic cysts/tumors at 53; his niece (daughter of sister 2) was asymptomatic at the time of assessment, and his nephew (son of brother 2) presented with a CNS hemangioblastoma at 12, and pheochromocytoma and multiple pancreatic cysts/tumors at 18. The proband also had three family members who passed away before diagnosis/ before they could be confirmed with the mutation: his sister 2 (patient 117) had multiple pancreatic cysts/tumors at 46, his brother 1 presented with a CNS hemangioblastoma at 47, renal cell carcinoma at 59, and multiple pancreatic cysts/tumors at 59; and his brother 2 presented with a retinal capillary hemangioma at 43, and CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 44.

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's niece (daughter of sister 2) was genetically confirmed with the mutation but was asymptomatic at the time of assessment.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0010797; HP:0009711; HP:0001732; HP:0001737 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the pancreas, Pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336).

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

Variant: p.W117G (c.349T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 862346; https://www.ncbi.nlm.nih.gov/clinvar/variation/862346/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W117G (c.349T>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. This familial mutation was confirmed in family #42. A male proband (patient 114) was diagnosed with CNS hemangioblastoma at 36Y, retinal angioma at 44Y, RCC at 44Y, and multiple pancreatic lesions at 44Y. His son (patient 115) was diagnosed with CNS hemangioblastoma at 12Y and retinal angioma at 11Y. His first sister (patient 116) was diagnosed with multiple pancreatic lesions at 53Y. His second sister (patient 117), who was not genetically confirmed for the mutation, was diagnosed with multiple pancreatic lesions at 46Y. His niece (daughter of second sister) (patient 118) was asymptomatic. His first brother (patient 119), who was not genetically confirmed for the mutation, was diagnosed with CNS hemangioblastoma at 47Y, RCC at 59Y, and multiple pancreatic lesions at 59Y. His second brother (patient 120), who was not genetically confirmed for the mutation, was diagnosed with CNS hemangioblastoma at 44Y, retinal angioma at 43Y, RCC at 44Y, and multiple pancreatic lesions at 44Y. His nephew (son of second brother) (patient 121) was diagnosed with CNS haemangioblastoma at 12Y, multiple pancreatic lesions at 18Y, pheochromocytoma at 18Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). Wang et al., 2018 reported 8 patients from 1 family who were genetically confirmed with this germline mutation. Wang et al., 2014 reported 4 patients from 1 family who were genetically confirmed with the mutation. It is likely that all three papers published the same family.

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This frameshift mutation was found in the VHL gene of family #15. The proband (patient 42) has four family members confirmed with the mutation, and two family members who passed away before diagnosis/ genetic confirmation of the mutation. Family members confirmed with the mutation include: the proband's daughter (patient 43) who had retinal angioma (age 17), renal cell carcinoma (21), multiple pancreatic cysts/tumors (18), and a pheochromocytoma (19). His son (patient 44) who was asymptomatic at the time of assessment. His niece 1 (patient 47) who had a retinal angioma and renal cell carcinoma (22). And his niece 2 (patient 28) who had a CNS hemangioblastoma (19) and a retinal angioma (18). Family members who passed away before diagnosis and were not genetically confirmed include: his sister (patient 45) who had a CNS hemangioblastoma (22), and his brother (patient 46) who had a retinal angioma and renal cell carcinoma at 52. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336). It is likely that the same family was published in both papers, with two additional members added in the 2018 paper.

PatientID: 132

KindredID: 50

Case: F, 45Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: Q145fs (c.433_437delCAGCC)

MultipleGeneVariants: N/A

PatientID: 109

KindredID: 37

Case: M, 20Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at 19, renal cell carcinoma and multiple pancreatic cysts/tumors at 20.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as a later paper by Wang et al., 2018 (PMID: 29330336).

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

Variant: p.S111Tfs*48 (c.332delG)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: S111fs (c.332del)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A female proband, patient 111 from kindred 39, was found with this germline splice site mutation (c.340+5G>C). She was diagnosed with a CNS hemangioblastoma at 35Y. This kindred was likely published in a later paper by Wang et al., 2018 (PMID: 29330336).

PatientID: 107

KindredID: 36

Case: M, 18Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother presented with a CNS hemangioblastoma and retinal angioma at age 29, but passed away before the mutation could be confirmed.

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

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma and retinal angioma at age 18.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: p.H110Pfs*49 (c.329delA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 560741, https://www.ncbi.nlm.nih.gov/clinvar/variation/560741/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: H110PFS*49 (c.329delA)

MultipleGeneVariants: N/A

PatientID: 37

KindredID: 12

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had the same germline mutation as her brother (the proband) and father. Her brother presented with CNS Hemangioblastoma, Renal cell carcinoma, and multiple pancreatic cysts/tumors at the age of 34. Her father presented with renal cell carcinoma at 55. The patient's uncle passed away before diagnosis and presented with a CNS hemangioblastoma at age 19, but could not be genetically confirmed for the mutation.

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

CaseHPOFreeText: The patient presented with multiple pancreatic cysts/tumors at the age of 27.

CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

PatientID: 291

KindredID: 115

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0002666 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Pheochromocytoma)

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

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. A male patient was confirmed for nonsense mutation in the VHL gene (c.217C>T; p.Gln73*). He was diagnosed with CNS haemangioblastoma at 66Y, retinal angioma at 66Y, renal cell carcinoma at 37Y, and multiple pancreatic cysts or tumours at 54Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 24581539) and Wang et al., 2014 (PMID: 29330336). It is likely that all three papers reported on the same individual.

PatientID: 141

KindredID: 52

Case: F, 69Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 138) had multiple family members affected with the mutation. Their daughter (pt 139) was asymptomatic at the time of assessment; their son (pt 140) was also asymptomatic at the time of assessment; their mother (pt 141) presented with a CNS hemangioblastoma at 66, renal cell carcinoma at 69, and multiple pancreatic cysts/tumors at 66; their sister 1 (pt 142) presented with a CNS hemangioblastoma at 32, renal cell carcinoma at 36, and multiple pancreatic cysts/tumors at 36; the son of sister 1 was asymptomatic at the time of analysis; the daughter of sister 1 was asymptomatic at the time of analysis; the proband's sister 2 presented at age 39 with CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors; and the son of sister 2 was asymptomatic at the time of analysis. All members of this family were genetically confirmed to have this mutation.

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

CaseHPOFreeText: The proband's mother (patient 141) had a CNS hemangioblastoma and multiple pancreatic cysts/tumors at 66, and renal cell carcinoma at 69.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220; https://www.ncbi.nlm.nih.gov/clinvar/variation/223220/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>C)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0100634; HP:0009711 (hemangioblastoma, neuroendocrine neoplasm, retinal capillary hemangioma)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma, a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), and a retinal hemangioblastoma.

CaseNotHPOs: HP:0030421; HP:0006770; HP:0030405 (epididymal tumour, clear cell renal cell carcinoma, pancreatic endocrine tumour)

CaseNotHPOFreeText: Patient was recorded without the manifestations of: an epididymal tumor, CCRCC, and a pancreatic endocrine tumour (pancreatic neuroendocrine neoplasm)

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. Patients ID 3 and 25 had this germline mutation (p.D92V). Patient 3 had: CNS hemangioblastoma. Patient 25 pheochromocytoma/paraganglioma (recorded here as a neuroendocrine neoplasm). Whether patients were related, age, and sex data was not reported. ACMG PP4

PatientID: 63

KindredID: 63

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405; HP:0100634 (pancreatic neuroendocrine neoplasm, Neuroendocrine neoplasm)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R107G (c.319C>G)

MultipleGeneVariants: N/A

75 individuals pre-diagnosed with pheochromocytoma and/or paraganglioma were referred for molecular genetic testing. Genomic DNA of each participant was isolated from peripheral blood samples to look for germline mutations in pheochromocytoma and paraganglioma targeted susceptibility genes. 6 targeted genes (IF1B, RET, SDHB, SDHD, TMEM127, and VHL) were sequenced and identified variants were confirmed by sanger sequencing. Sequencing identified a germline S68P(c.202T>C) missense variant in the VHL gene of 3 patients: 4, 5 and 6. Patient 4 (29, M) was pre-diagnosed with pheochromocytoma (bilateral renal and eyes, pancreatic cysts) and had two affected family members, his mother (without any described phenotype or genotype) and his brother (patient 5). Patient 5 (32Y, M) was pre-diagnosed with pheochromocytoma (right kidney-clear cell carcinoma). Lastly, patient 6 was a 33Y male pre-diagnosed with paraganglioma and liver cysts. This patient's cousin was an affected family member described (without genotype or phenotypes details).

PatientID: 65

KindredID: 65

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

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

CaseHPOFreeText: CNS hemangioblastoma and retinal hemangioblastoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete deletion)

MultipleGeneVariants: N/A

PatientID: 8

KindredID: 8

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.T157I (c.470C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223223, https://www.ncbi.nlm.nih.gov/clinvar/variation/223223/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T157I (c.470C>T)

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.3

GenotypingMethod: Polymerase chain reaction (PCR) amplification, denaturating high-performance liquid chromatography (DHPLC), and direct sequence analysis were used to analyze the entire coding sequence and intron-exon boundaries.

SamplingMethod: peripheral blood

PatientID: 44

KindredID: 44

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Retinal hemangioblastoma and renal cystic lesion.

CaseNotHPOs: HP:0002666; HP:0010797; HP:0006770; HP:0001732 (Pheochromocytoma, Hemangioblastoma, Clear cell renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, 43Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

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

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V155G (c.464T>G)

MultipleGeneVariants: N/A

PatientID: 214

KindredID: 214

Case: Sex Unknown, 33Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2, S3.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA020099 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.194C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType:missense_variant;transversion

CivicName: S65W(c.194C>G)

MultipleGeneVariants: N/A

atientID: II.1

KindredID: F6

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Splenomegaly

FamilyInfo: N/A

CasePresentingHPOs: HP:0001744 (Splenomegaly)

CaseHPOFreeText: Diagnosed with splenomegaly at age 6 months (DOB: 2014).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+574A>T

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1040488, https://www.ncbi.nlm.nih.gov/clinvar/variation/1040488/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: Q164H (c.492G>T) and c.340+574A>T

MultipleGeneVariants: Germline, VHL, c.492G>T (p.Gln164His)

PatientID: 84

KindredID: 84

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1b.

Variant: p.R107H (c.320G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223184, https://www.ncbi.nlm.nih.gov/clinvar/variation/223184/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R107H (c.320G>A)

MultipleGeneVariants: N/A

A study investigated paraganglioma/pheochromocytoma tumors in a retrospective cohort and a prospective cohort. Tumour tissue samples were sequenced by next-generation sequencing using a custom gene panel. In some cases, Sanger sequencing was used to detect germline mutations. Some of these tumors were found with germline VHL mutations. Patient ID 100, from the prospective cohort, presented with multiple paragangliomas and a germline mutation in the VHL gene c.191G>C. Other phenotypic and demographic information was not available. The paper performed carbonic anhydrase IX immunohistochemistry and immunostaining with CA9 was observed in patient 100.

PatientID: III-3

KindredID: 1

Case: M, Age Unknown, Korean

DiseaseAssertion: hemangioblastoma

FamilyInfo: His family members had features apparently related to VHL disease. His grandmother was troubled with severe headache during her lifetime, though the cause of death was unclear. His father was diagnosed with brain hemangioblastoma, which was his cause of death. In addition, his sister had various VHL phenotypes. His sister was tested with the same mutation, while whereas his other, clinically unaffected sister did not.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: underwent brain surgery in his teens due to brain hemangioblastoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: Not diagnosed with diabetes mellitus

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98Tfs*61 (c.291delC)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432420512 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.291delC

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: Y98fs (c.291delC)

MultipleGeneVariants: N/A

3-year-old white male child presented with hematuria of two days and a CT scan showed a right renal mass determined to be renal cell carcinoma. A nephrectomy was done and the tumour tissue was sent for karyotyping. Peripheral blood samples were also taken and sent for sequence analysis of the VHL gene. Genetic testing confirmed 2 mutations: a translocation between chromosome X and 1 t(X;1)(p11.2; p34.3) and a germline missense mutation, c.562C>G (p.Leu188Val) in the VHL gene. Family history was remarkable for a renal tumour in the paternal grandmother at age 65, treated by nephrectomy in 1998. Furthermore, a maternal uncle had a history of thyroid cancer, and a maternal cousin had a history of breast cancer. The patient’s parents and a 13-year-old half-brother were healthy.

PatientID: 13 (tumour 21)

KindredID: 14

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

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

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

VariantEvidence: Refer to Table 1 for LOH information.

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PMID: 17001110

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

A case report reveals a 3Y girl with right adrenal malignant pheochromocytoma, with the mother diagnosed with von Hippel-Lindau syndrome. The mother was 38Y when diagnosed with bilateral pheochromocytoma that was resected when she was 18Y. She presented several relapses, the most recent one at 32Y when she was also diagnosed with cerebral angioma. Genetic tests revealed the presence of the VHL c 244 C>G (p. Arg 82 Gly) heterozygote mutation in the mother, as well as in the child. Genetic tests for mutations in RET, SDHB, SDHC and SDHD in the mother were negative. After 6 months from the complete resection of the tumor, the daughter is without any clinical symptoms, with normal blood pressure, normal ophthalmoscopy, no tumor markers and no evidence of tumor on cerebral or abdominal MRI.

PatientID: None

KindredID: 50

Case: F, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: Patient information was extracted from Table 1 of Supplementary.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

GroupID: 47

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have the c.712C>T (R167W) germline variant of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: HP:0002666 (Pheochromocytoma)

GroupHPOFreeText: Number of family affected members is not specified.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151 and/or 8956040

SupplementalData: N/A

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: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 20

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: N/A

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

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

SupplementalData: N/A

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

LegacyVariant: c.430C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

93 families examined at the Clinical Center of the National Institutes of Health (Bethesda, MD) underwent genetic testing for germline mutations of the VHL gene. Whole blood was extracted and genomic DNA was amplified by PCR and products were sequences using a cycle sequencing kit with dye-labeled terminators and automatically sequenced. This missense mutation was found in a VHL type 1 family (lineage 132). The variant was reported as c.440T>C (AF010238.1) and was mapped to F76S (c.227T>C) (NM_000551.3).

GroupID: 88

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.500G>A variant causing a Arg167Gln missense mutation (noted in the paper as c.713G>A due to Latif reference transcript being used). It was noted that this family had patients with pheochromocytoma's.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified. It was noted that this family had patients with pheochromocytoma's.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

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

CAID: N/A

gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients. All patients had VHL germline mutations. Age is at the time of surgery. Patients #15 (male) was found with this germline VHL mutation (p.R82P (c.245G>C)) and pancreatic endocrine tumours. The last known age of the patient was 48Y. Other phenotypes and demographics were unknown. ACMG PP4

15 Dutch VHL patients from 5 families were taken to measure the expression of vascular endothelial growth factor (VEGF). Nine patients were found to harbour the VHL germline mutation V170D, referred to in the paper by V241D due to a difference in transcript sequence. Patient 1, a 57 year old female, presented with pancreatic cysts. Patient 4, a 31 year old male, presented with a kidney cyst and a brain hemangioblastoma and no signs of eye lesions. Patient 5, a 28 year old female, presented with a kidney cyst, brain hemangioblastoma, renal cell carcinoma and a left eye angioma. Patient 7, a 28 year old female, presented with a kidney cyst and a right eye angioma. Patient 8, a 28 year old female, presented with pancreatic cysts and a right eye angioma. Patient 9, a 61 year old male, presented with pancreatic and liver cysts, a brain hemangioblastoma and a left eye angioma. Patient 11, a 38 year old male, presented with pancreatic, liver and kidney cysts, brain and spinal cord hemangioblastomas and a right eye angioma. Patient 12, a 50 year old male, presented with kidney & pancreatic cysts, a pheochromocytoma and a brain hemangioblastoma as well as no sign of eye lesions. Patient 13, a 34 year old male, presented with pancreatic cysts, brain and spinal cord hemangioblastomas and right and left eye angiomas. ACMG: 'PP1' since we have cosegregation with the disease in multiple affected family members, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

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

GenotypingMethod: N/A

SamplingMethod: N/A

PatientID: 10b

KindredID: 8

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was positive with 3 other members of unknown relation (10a, 10c, 10d) presenting with the mutation, with various phenotypes, however one member being asymptomatic as of age 3Y.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711; HP:0030405 (Pheochromocytoma; Paraganglioma; Retinal capillary hemangioma; Pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5a

KindredID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: An unspecified relative (5b) has the same familial mutation with renal cell carcinoma, pancreatic, and renal cysts.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0000107 (Hemangioblastoma; pancreatic cyst; renal cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: S111N (c.332G>A)

MultipleGeneVariants: N/A

PatientID: 47 (Uncle)

KindredID: 18

Case: M, 39Y0M, 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:0009711 (Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (30 and 42Y) and retinal angioma (26Y). Patient died at 39Y.

CaseNotHPOs: HP:0005584; HP:0000077; HP:0001732; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Abnormality of the pancreas, Pheochromocytoma)

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: 3 (Father)

KindredID: 13

Case: M, 46Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 5 members of this family were found to harbour the deletion of one VHL allele. The proband (ID 1), sister (ID 2) and uncle (ID 5) were all asymptomatic. The grandmother (ID 9) presented with CNS hemangioblastoma (34Y).

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: This patient presented with CNS hemangioblastoma (34Y).

CaseNotHPOs: HP:0002666; HP:0005584; HP:0009711; HP:0000077; HP:0001732 (Pheochromocytoma, Renal cell carcinoma, Retinal capillary hemangioma, Abnormality of the kidney, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Reported as “del one vHL allele”.

MutationType: deletion

CivicName: Null (del one VHL allele)

MultipleGeneVariants: N/A

PatientID: 1 (Proband)

KindredID: 10

Case: M, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: 2 members of this family presented with the c.712C>T/c.499C>T germline variant of the VHL gene. ID 3 presente with CNS hemangioblastoma, retinal angioma and renal cell carcinoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000077; HP:0002666; HP:0001732; HP:0010797; HP:0005584; HP:0009711 (Abnormality of the kidney, Pheochromocytoma, Abnormality of the pancreas, Hemangioblastoma, Renal cell carcinoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

20 unrelated VHL families were retrospectively identified in SickKids Genetics and Cancer Genetics Program SHIRE genetics database, with data entered between 30 August 1984 and 8 August 2016. Family 9 had one patient with the missense mutation c.257C>T in the VHL gene (legacy notation c.470C>T). The proband (male) was diagnosed with CNS hemangioblastoma at 16Y and was 23Y at the end of the study. This patient was later published in 31368132- updated phenotypes available.

PatientID: A-V6

KindredID: A-V6

Case: M, 30Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: 2 affected individuals (twin brothers) in this family but no further details provided. Twin brother of proband died of VHL.

CasePresentingHPOs: HP:0002666; HP:0006880 (Pheochromocytoma, Cerebellar hemangioblastoma)

CaseHPOFreeText: Cerebellar hemangioblastomas and bilateral pheochromocytoma. Diagnosed with VHL type 2.

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 25078357

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected to c.499C>T. This assumption was made due to later publications referencing this mutation and paper. Variant is reported in Table 1 as c.499G>T which was assumed to be a typo and was corrected due to future publications' reference to this paper regarding this patient and mutation as c.499C>T

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 2 patients were found to have the above mutation (c.208G>T). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PVS1' because they observe a nonsense variant in a gene where loss of function is a known mechanism of disease.

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 2 patients were found to have the above mutation (c.472C>G). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

GroupID: 7

Case: Age, Sex, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 1 individual belonging to 1 family was mentioned with this VHL mutation. No other family info was provided.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Other manifestations aside from pheochromocytoma are possible; but not specified.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: 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: 14

KindredID: 8

Case: M, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No details regarding family information is provided.

CasePresentingHPOs: N/A

CaseHPOFreeText: Patient has VHL disease characterized by tumours, but specific types of tumours were not indicated

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

CaseNotHPOFreeText: Patient did not have CNS hemangioblastoma or Retinal capillary hemangiomas.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E52* (c.154G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182982, https://www.ncbi.nlm.nih.gov/clinvar/variation/182982/

CAID: N/A

gnomAD: 0.00001795, https://gnomad.broadinstitute.org/variant/3-10183685-G-T

VariantEvidence: N/A

MutationType: stop_gained

CivicName: E52* (c.154G>T)

MultipleGeneVariants: N/A

GroupID: 4

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 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 2-3 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 2-3 deletion

MultipleGeneVariants: N/A

GroupID: 25

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

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

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88R (c.262T>A)

MultipleGeneVariants: N/A

GroupID: 24b

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

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

GroupPresentingHPOs: N/A

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

GroupNotHPOs: HP:0009711 (retinal capillary hemangioma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86H (c.257C>A)

MultipleGeneVariants: N/A