A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The V155M (c.463G>A) germline missense mutation was found in a VHL type 1 family of 9 affected individuals who presented with CNS hemangioblastoma (5/9), retinal angioma (1/9), renal cell carcinoma (9/9) and pancreatic tumor or cyst (unspecified) (2/9) (family ID 32). This family was previously reported in PMID 8634692.

GroupID: 5

DiseaseAssertion:VHL

GroupSize: 2

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: There were two patients described in this family.

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

GroupHPOFreeText: Both patients had CNS hemangioblastoma and retinal capillary hemangioma but only one patient had renal cell carcinoma.

GroupNotHPOs: HP:0001737 (pancreatic cysts)

GroupNotHPOFreeText: Neither patient had pancreatic cysts or lesions.

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: 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

GroupID: 45

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 2 individuals from a single family (ID 45).

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

GroupHPOFreeText: Pheochromocytoma (1/2) and renal cell carcinoma (2/2).

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

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

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

LegacyVariant: c.683C>T

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

PatientID: 11

KindredID: 9

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Two other members of this family (patients 13 and 17) had the same VHL gene mutation. Patient 13 presented with cerebellar hemangioblastoma. Patient 17 presented with hemangioblastoma of the spinal cord and hemangioblastoma of the medulla oblongata.

CohortInfo: A total of 42 CNS haemangioblastoma samples were obtained from 31 patients, who were consecutively treated between 1993 and 1997 at the Department of Neurosurgery of the Freiburg University Medical Centre.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: N/A

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

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: W

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Parents unavailable for testing. No prior family history of VHL.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711, HP:0002894, HP:0002666 (retinal capillary hemangioma, neoplasm of the pancreas, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: c.677-1G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.464-1G>A

MultipleGeneVariants: N/A

Two unrelated patients were screened for VHL mutations using SSCP and sequence analysis. Patient W was found with a germline splice site variant mutation c.464-1G>A (stated as 677-1G>A in the paper which used the Latif sequence as reference). They had no prior family history but parents were not available for genetic testing. The patient had hemangioblastoma and renal cell carcinoma.

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: 10

KindredID: 1

Case: Sex Unknown, 23Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: 13Y at first pheochromocytoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: 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: 1

KindredID: 1

Case: Sex Unknown, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Significant family history. Pedigree follows 8 generations (see Figure 3). Family immigrated to Iowa, US, from Baden-Baden, Germany, in 1832; Likely sharing a common ancestor to the traced lineage of the Black Forest region of Germany.

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

CaseHPOFreeText: 11Y at first pheochromocytoma and ocular angioma (retinal capillary hemangioma). Total of 4 ocular angiomas.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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: 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

Genomic DNA was extracted from peripheral blood and PCR amplifications of the three exon regions were performed. 4 of 5 families presenting with non-syndromic familial pheochromocytomas were found to have VHL germline mutations. The mutation R167W (referred to in the paper by c.712C>T due to a difference in transcript sequence) of the VHL gene was found in one proband and was confirmed to occur in other members of their family. The patient and their familial members had no clinical manifestation of hereditary syndromes, including MEN 2A, MEN 2B, VHL disease, and NF1. The laboratory and image examinations also excluded the presence of the above-mentioned hereditary syndromes. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

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 (Q164* (c.490C>T)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 65CE. It was reported in the paper as c.703C>T due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (Q73* (c.217C>T)) was taken from the Cambridge, Department of Pathology database as well as the National Cancer Institute database, with an unknown number of members belonging to Family ID 38CA, 74CA, and 2753NCI. It was reported in the paper as c.430C>T 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. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

GroupID/ KindredID: 53F

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 Neuro Olcologie database in Paris, with an unknown number of members belonging to Family ID 53F. 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.F136S (c.407T>C)

LegacyVariant: p.F136S (c.620T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3738NCI, 4874NCI

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 two family IDs: Family 3738NCI and 4874NCI. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as 2 VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151; 8863170

SupplementalData: N/A

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

LegacyVariant: p.Y112H (c.547T>C)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 31CE

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 Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 31CE. 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: (c.464-2A>G)

LegacyVariant: Splice (c.677-2A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/

CAID: N/A

gnomAD: N/A

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

MutationType: splice_site_variant

CivicName: Splice Site (c.464-2A>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: P30

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: a pheochromocytoma was detected in this patient

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: p.R167W (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-T

VariantEvidence: Tested the tumors for somatic mutations but did not detect any

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: P1

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: One other patient belonging to the same family (P1) had this mutation. They had 1 HB and 1 pheochromocytoma

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: two cerebellar hemangioblastomas were detected in this patient

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: p.R167W (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-T

VariantEvidence: Tested the tumors for somatic mutations but did not detect any

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

GroupID: 150

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.699C>G (C162W) 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

SupplementalData: N/A

Variant: p.C162W (c.486C>G)

LegacyVariant: c.699C>G

CaseProblemVariantFreeText: N/A

ClinVarID: 223227, https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

GroupID: 69

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: N/A

SupplementalData: N/A

Variant: p.C162F (c.485G>T)

LegacyVariant: c.698G>T

CaseProblemVariantFreeText: N/A

ClinVarID: 43604, https://www.ncbi.nlm.nih.gov/clinvar/variation/43604/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: C162F (c.485G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Positive.

CohortInfo: Between September 1994 and December 1997, 16 unrelated individuals were referred to Genetic Services of Western Australia by local clinicians and by similar genetic services in other States, for VHL gene mutation analysis because of clinical manifestations suggestive of the diagnosis.

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584, HP:0001737 (renal cell carcinoma, pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V84L (c.250G>T)

LegacyVariant: p.V84L (c.463G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 2236 https://www.ncbi.nlm.nih.gov/clinvar/variation/2236/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V84L (c.250G>T)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The C162W (c.486C>G) germline missense mutation of the VHL gene was found in a 29 year old VHL patient with pancreatic cysts or tumors (index case 78).

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.

In the analysis of 63 clinically diagnosed VHL patients, 55 patients were found with pancreatic involvement. Genetic tests on 35 of 55 VHL patients revealed VHL variants in 28 patients. Of the 55 enrolled patients, hemangioblastomas of the central nervous system were previously documented in 47 patients, renal cell carcinoma in 25, and pheochromocytoma in 11 patients. Peripheral blood samples were extracted and PCR sequencing was used to identify point mutations and multiplex ligation-dependent probe amplification (MLPA, P016-C2, MRC-Holland, Amsterdam, Netherlands) analysis was used to detect large rearrangements of the VHL gene. This missense mutation, c.208G>A, was found in 37-year-old female (case no. 1) who presented with pancreatic endocrine tumour and underwent a pylorus-preserving pancreaticoduodenectomy. The patient was followed up 27.7 months later.

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.395A>C) was recorded in the paper as c.608A>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system, one of which had primary asymptomatic tumors. Any family information or relations is unknown. No other phenotypes described.

PatientID: 24

GroupID/ KindredID: 24

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F136S (c.407T>C)

LegacyVariant: p.F136S (c.620T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID: 32

DiseaseAssertion: VHL

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: The seven patients are grouped based on both having the c.463+1G>A mutation. They are unrelated to one another.

GroupPresentingHPOs: HP:0005584, HP:0010797 (renal cell carcinoma, hemangioblastoma)

GroupHPOFreeText: Four of seven members had a hemangioblastoma of the CNS. All seven members had renal cell carcinoma.

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

GroupNotHPOFreeText:N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+1G>A

LegacyVariant: c.676G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 526679 https://www.ncbi.nlm.nih.gov/clinvar/variation/526679/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.463+1G>A

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline 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.

GroupID/ KindredID: VHL 6

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Italian

GroupAgeRange: N/A

GroupInfo: 3 patients with the given mutation belonging to VHL family 6

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts)

GroupHPOFreeText: all 3 patients have pancreatic cysts, 2 had retinal capillary hemangiomas, hemangioblastoma, and renal cysts, and 1 had RCC

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183* (c.548C>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.S183* (c.761C>A)

ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

Of 65 VHL families from central Europe, 53 were identified with germline mutations, using SSCP analysis of PCR products by peripheral blood. The mutation of c.464-1G>A was referred to in the paper by c.677-1G>A due to a difference in transcript sequence. This splice mutation was found in a German, VHL type 1 patient with hemangioblastomas of the central nervous system (family VHL 48). This study contains very strong evidence of pathogenicity in the form of a canonical -1 splice site variant in a gene where loss-of-function is a known mechanism of disease (ACMG code: PVS1).

This case report documented the promising short-term radiological response to somatostatin analog therapy of multiple nonmetastatic, nonfunctional PNETs in a patient with VHL. A 24 year old woman was confirmed with a germline VHL mutation (c.499C>T). She was diagnosed with bilateral pheochromocytomas and a pancreatic neuroendocrine tumour. Her aunt also had a pancreatic neuroendocrine tumour, but was not confirmed with the variation.

Through blood sample testing, ten affected individuals from 7 families in Singapore were identified with VHL disease. One patient of Chinese ethnicity was found with the c.499C>T (p.Arg167Trp) mutation in the VHL gene and presented with retinal angioma, pheochromocytoma, pancreatic tumour. ACMG: PM1, PP4

A 55-year-old male presented to the emergency room due to shortness of breath, chest pain, and coughing. A chest X-ray and CT scan found a perihilar mass on the left lung, as well as a left renal lesion. A CT scan of the abdomen and pelvis revealed a mass on the left kidney and right adrenal gland. A biopsy showed that the left kidney mass was a renal cell carcinoma. The patient had a left-sided radical nephrectomy and right-sided adrenalectomy. Pathology confirmed clear cell renal cell carcinoma (ccRCC) and pheochromocytoma. Two pieces of lung tissue were orally expelled and examination supported metastatic ccRCC. Spinal MRI and chest CT identified both bone metastases and two spinal lesions consistent with spinal hemangioblastomas. Histology also confirmed liver metastases from the ccRCC. 10 months after his initial presentation, the patient succumbed to his disease 10 months. The patient had no family history of VHL and no other VHL-associated manifestations. The patient was clinical diagnosis with Type 2B VHL. Germline DNA from peripheral blood leukocytes was isolated and sent for gene panel genetic testing targeting known hereditary renal cell cancer and hereditary paraganglioma-pheochromocytoma genes. The gene panel targeted FH, FLCN, MET, MITF, MLH1, MSH2, MSH6, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, TP53, TSC1, TSC2, MAX, MEN1, NF1, RET, SDHAF2, TMEM127, and VHL. The patient tested negative for both single nucleotide or copy number variants in any of the genes. The variant allele threshold for this germline panel was >10%. Subsequent sequencing analysis of all four postmortem tumor tissues revealed an L198P(c.593T>C) missense VHL mutation at varying allele fractions (range: 10–55%) in all four tissues. Both of the patient's daughters underwent germline genetic analysis of VHL and were negative. However, due to family history, both daughters underwent full VHL screening including ophthalmologic assessment, brain, spine, and abdominal MRI. They have no VHL manifestations at the ages of 25 and 30. The germline genetic testing results of the proband's blood sample were re-analyzed and the VHL missense variant was detected at 6% variant allele frequency (below the standard 10% threshold), strongly suggesting that this case is a result of somatic mosaicism.

GroupID/ KindredID: F26

Case: Sex unknown, 31Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: Noted of familial antecedents of phaeochromocytoma and CNS hemangioblastoma.

CasePresentingHPOs: HP:0009711; HP:0000107 (retinal capillary hemangioma, renal cysts)

CaseHPOFreeText: Age of onset is 31Y0M.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0006880; HP:0001737 (clear cell renal cell carcinoma, pheochromocytoma, cerebellar hemangioblastoma, pancreatic cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121G (c.362A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223200 https://www.ncbi.nlm.nih.gov/clinvar/variation/223200/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: D121G (c.362A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: F61

Case: Sex unknown, 15Y0M, Spanish

DiseaseAssertion: assumed VHL

FamilyInfo: familial antecedents found of clear cell RCC

CasePresentingHPOs: HP:0009711; HP:0002666; HP:0000107 (retinal capillary hemangioma, pheochromocytoma, renal cysts)

CaseHPOFreeText: Unilateral pheo. Age of onset is 15Y0M.

CaseNotHPOs: HP:0006880; HP:0006770; HP:0001737 (cerebellar hemangioblastoma, clear cell renal cell carcinoma, pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/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

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

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.

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 missense mutation, c.486C>G, was found in a VHL type 2B patient (patient no. V345). No patient information was provided and no additional family members were screened.

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: IV-5

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-5) appears to have inherited this disease from his father, 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

Patients' records in a tertiary care university hospital were reviewed. Fifty-four Black patients presenting with phaeochromocytoma between 1980 and 2009 were included. Two patients had VHL syndrome (submitted for publication). This diagnosis of VHL syndrome was made in the pregnant woman (Case 9) who had bilateral adrenal phaeochromocytomas. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine. Genetic testing revealed a missense mutation (c.499C>T) in the VHL gene, located on chromosome 3p26-p25. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother and daughter will be investigated further and monitored long-term. ACMG PP4

PatientID: 37

KindredID: 37

Case: M, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CohortInfo: Patients with apparently sporadic pheochromocytomas.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: The patient had a benign adrenal pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L63P(c.188T>C)

LegacyVariant: p.L63P(c.401T>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 2227 https://www.ncbi.nlm.nih.gov/clinvar/variation/2227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L63P(c.188T>C)

MultipleGeneVariants: N/A

Tissue specimens of apparent sporadic pheochromocytoma were retrieved from the archives of the Department of Pathology of the Erasmus MC (Rotterdam), the Radboud University Nijmegen Medical Center, and the University Hospital Zurich (Switzerland). Mutation analysis was performed using SSCP analysis and BigDye® Terminator V3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA). 136 VHL cases and six germline VHL mutations were found. A c.188T>C, p.Leu63Pro mutation (stated as 401T>C in the paper which used the Latif sequence as reference) was found in one 26Y male patient (patient ID 37) with benign adrenal pheochromocytoma. No other phenotypes, patient demographics, or family history was described.

Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. Patient no.30 from family 64 had a nonsense mutation (c.217C>T) and presented with pancreatic endocrine tumour and renal carcinoma. The patients' phenotypes are highly specific to VHL disease (PP4) and nonsense mutation supports PVS1.

The patient, a 45 year-old male, had a history of 2 weeks of progressive fatigue and intermittent left-upper and lower-extremity weakness. MRI showed bilateral chronic infarcts resulting from multiple cryptogenic strokes in his past medical history. Blood tests revealed unexplained lymphocytosis and thrombocytosis. CT scan showed abnormal uptake in the adrenal glands and bilateral 18F-fluorodeoxyglucose-avid adrenal masses. He was diagnosed with bilateral pheochromocytomas (6 cm on the left side and 8.5 cm on the right). He had no personal or family history of genetic syndromes or endocrine disorders. He was found to have a heterozygous for the c.292T>C germline mutation of the VHL gene. A further MRI of the spine showed hemangioblastomas in the spinal cord at T11 and in the cauda equina at L2 and abdominal imaging showed multiple intraductal papillary mucinous neoplasms. The patients fatigue, lymphocytosis and thrombocytosis was resolved with adrenalectomy. The patient had no personal or family history of genetic syndromes or endocrine disorders.

PatientID: 7

KindredID: III

Case: Sex Unknown, Age Unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: Patient had three other family members with additional CNS hemangioblastomas and the same splice site mutation. Their one family member, patient 4, also presented with pancreatic tumors.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Patient was recorded with 3 labelled CNS hemangioblastoma tumors (a, b, and c).

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). Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

26 VHL patients from 18 families, who had undergone a partial adrenalectomy for pheochromocytoma were retrospectively analyzed. 2 patients from 2 families were confirmed to have the mutation (R167W). Additional manifestations aside from pheochromocytoma are possible, but were not discussed.

PatientID: 22

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S3 describes 9 patients with splice site mutations, including this patient.

Variant: c.464-1G>A

LegacyVariant: c.677-1G>A

CaseProblemVariantFreeText: N/A

ClinVarID: 43603; https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

KindredID: 95

GroupID: 40

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.95 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

Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for 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. Patient 18, a 19 year old female, was found to harbour the c.257C>G mutation in the VHL gene (stated as 470 C to G in the paper which used Latif sequence as reference) leading to an amino acid change of Pro to Arg at protein position 86. She presented with a single radiologic pancreatic neuroendocrine tumor. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

Through peripheral blood sequencing and PCR/MLPA, 5 Bulgarian patients and their families underwent molecular genetic testing for clinically suspected VHL. A female patient and her mother both had bilateral pheochromocytoma and retina hemangioblastoma, consistent with Type 2a VHL disease. Both were confirmed with a c.500G>A (p.Arg167Gln) germline mutation in the VHL gene. Further patient demographics were not reported.

Tissues embedded in paraffin blocks were collected from 203 cHAB patients operated in different Medical Centres in Poland. Eight of these harboured germline mutations in unrelated patients from distinct undiagnosed VHL families. Various variants were unverified as somatic or germline as they were detected in tumour but blood samples were not tested. Other phenotypes and demographic information is not known. Patient 37 was found with a splice mutation in the VHL gene.

PatientID: V-1

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

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

CaseHPOFreeText: CNS hemangioblastoma and renal cyst. Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

Pathogenic variants from 10,389 individuals across 33 cancer types were examined from The Cancer Genome Atlas (TCGA) cohort. 12 of these individuals had a germline mutation in the VHL gene. The E134*(c.400G>T) nonsense VHL mutation was found in a white 29Y0M female diagnosed with clear cell renal cell carcinoma. No family information was provided.

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. Family 5 has one affected member. Genetic analysis reveals mutation E70K(c.208G>A)in the VHL gene. The patient presented with bilateral retinal capillary hemangioma. The patient does no have a family history of VHL disease. The genetic information of the patient's parents are not available, as the patient was adopted. This patient was previously reported in PMID: 9829912.

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 V166F (c.496G>T) was referred to in the paper by c.709G>T due to a difference in transcript sequence. This missense mutation was found in a VHL family with PC (family ID 50).

PatientID: None

KindredID: 1

Case: F, 18Y0M, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's grandmother presented with retinal angiomas, renal and pancreatic cysts, bilateral pheochromocytoma and a paraganglioma. The patient's father carried the mutation and presented with pheochromocytoma. The patient's brother also carried the mutation and presented with pheochromocytoma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

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

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (c.430G>T) was detected by direct sequencing and MLPA. This nonsense mutation was found as sporadic germline in a VHL case with bilateral renal cell carcinoma and hemangioblastoma (case no. 442). This was suggested to be de novo but it could not be confirmed. There is very strong evidence of pathogenicity in the form of a nonsense variant in a gene where loss-of-function is known mechanism of disease (ACMG code: PSV1).

Peripheral blood from unrelated patients with pheochromocytoma was tested for mutations of proto-oncogene RET, tumor suppressor gene VHL, succinate dehydrogenase subunit D (SDHD) gene, and the succinate dehydrogenase subunit B (SDHB) gene. Of 271 patients with nonsydromic pheochromocytoma and no family history of the disease, 30 mutations were found in VHL. Multiple pheochromocytomas were statistically more frequent among patients with mutations than among patients without mutations (21 of 66 vs. 5 of 205, P<0.001). The G93S (c.277G>A) mutation was detected in the patient, referred to in the paper by c.277G>A due to a difference in transcript sequence. This missense mutation was found in the VHL gene and two patients with pheochromocytoma. Any relation is unstated.

Case#: 203 6.1yrs male, age at initial diagnosis 4.9 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 1.7 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months

CaseBMT: No PreviouslyPublished Don't know Variant1:p.R621X Variant1ClinVarID: 11917 Variant1CAID: Variant2:IVS9-12_4delCAGGCCCCG . However the sequence at this location corresponds to "cccgccccg" Variant2ClinVarID: Variant2CAID:

Case#: 211 2.5 yrs male, age at initial diagnosis 2.4 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: Nil, study drug, valanafusp alpha, also called AGT-181 for 12 months

CaseBMT: No PreviouslyPublished Don't know Variant1:p.G208D Variant1ClinVarID: 554590 Variant1CAID: Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:

Case#: Patient D2, Druze religious group, located in lower Galilee.

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.928C>T (p.Q310X)

Variant1ClinVarID: 11915

Variant1CAID: N/A

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient D4, Druze religious group, located in lower Galilee.

DiseaseAssertion: N/A

FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1096A>C (p.T366P)

Variant1ClinVarID: 11916

Variant1CAID: CA:256117

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient D5, Druze religious group, located in lower Galilee.

DiseaseAssertion: N/A

FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1096A>C (p.T366P)

Variant1ClinVarID: 11916

Variant1CAID: CA:256117

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient M2, Muslim religious group, located in lower Galilee.

DiseaseAssertion: MPS1-H

FamilyInfo: Parents of M2 were found to be heterozygous for this mutation.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1096A>C (p.T366P)

Variant1ClinVarID: 11916

Variant1CAID: CA:256117

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2 of family B: Female DiseaseAssertion:MPS1 FamilyInfo:Consanguinity Yes CasePresentingHPOs: NA CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: enzyme values lower than the cut-off values CaseUrineGAGs: NA CaseERT: NA CaseBMT:Nil Variant1:c.1469T>C ,Leu490Pro Variant1ClinVar ID: 11919 Variant1CAID: Variant2:c.1469T>C ,Leu490Pro Variant2ClinVarID:11919 Variant2CAID: AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

Case#: Eldest child, female, age at diagnosis and onset are unknown, age at treatment is 6, age at report is 11 DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0000280, HP:0008800, HP:0010501, HP:0006467, HP:0001659, HP:0001653, HP:0001634 (Coarse facial features, Limited hip movement, Limited shoulder movement, Limitation of knee mobility, Aortic regurgitation, Mitral regurgitation, Mitral valve prolapse) CaseHPOFreeText: Corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

Case#: Youngest child, Female, age at diagnosis and onset are unknown, age at treatment is 4 months, age at report is 5 years, 4 months DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: N/A CaseHPOFreeText: Mild corneal clouding, this study is to examine the efficacy of enzyme replacement therapy at different stages of teh disease, and it is assumed this patient is not yet old enough to have develped symptoms CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

Case#: Middle child, Male, age at diagnosis and onset are unknown, age at treatment is 2.5 years, age at report is 7.5 years DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0001634, HP:0001653 (mitral valve prolapse, mitral regurgitation) CaseHPOFreeText: Mild corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

Case: IP #8 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 71

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #62

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 87

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #16 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #9 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 85; VWF:Ac [IU/dL] = 56; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3917G>T p.Arg1306Leu

HGVS:

ClinVarID: 100301

CAID:

gnomAD: 6.196e-7 (1 in 1613956) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019501-C-A?dataset=gnomad_r4

Case: IP #23 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 55

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4022G>A p.Arg1341Gln

HGVS:

ClinVarID: 291

CAID:

gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case: IP #1 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3845T>C p.Leu1282Pro

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #15 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 25.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3923G>A p.Arg1308Pro

HGVS:

ClinVarID: 100303

CAID:

gnomAD: absent

Case: IP #17 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 64; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #19 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 58; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 54

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #9 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 93; VWF:Ac [IU/dL] = 107; FVIII:C [IU/dL] = 18

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2446C > T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVar: 296

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #43

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 29

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #46

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 64; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 66

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #7 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 35; FVIII:C [IU/dL] = 35

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #21 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 31

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #12 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 59; VWF:Ac [IU/dL] = 59; FVIII:C [IU/dL] = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #61

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #15 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 28

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #5 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 44; VWF:Ac [IU/dL] = 25; FVIII:C [IU/dL] = 135

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #22 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 51

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4022G>A p.Arg1341Gln

HGVS:

ClinVarID: 291

CAID:

gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case: IP #16 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 93; VWF:Ac [IU/dL] = 48; FVIII:C [IU/dL] = 76

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #18 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 25; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #2 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 37

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #21 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 53

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #20 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 10; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 12

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #6 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 22

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #8 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 61; VWF:Ac [IU/dL] = 59; FVIII:C [IU/dL] = 25

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2446C > T p.Arg816Trp

HGVS:

ClinVarID: 295

CAID:

gnomAD: 0.00001983 (32 in 1613930) no homozygotes https://gnomad.broadinstitute.org/variant/12-6036488-G-A?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

ClinVar: 296

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #36

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 51

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4541T>G p.Phe1514Cys

HGVS:

ClinVarID: 304

CAID:

gnomAD: absent

Case: IP #18

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19.3; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #11 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 74; VWF:Ac [IU/dL] = 79; FVIII:C [IU/dL] = 18

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #1 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 49

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2435del p.Pro812Argfs*31

HGVS:

ClinVarID: 303

CAID:

gnomAD: 0.00007187 (116 in 1613916) no homozygotes https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.3797C>T p.Pro1266Leu

ClinVarID: 314

gnomAD: 0.0006678 (1077 in 1612852) 2 homozyogotes https://gnomad.broadinstitute.org/variant/12-6019621-G-A?dataset=gnomad_r4

Case: IP #49

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 47

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #14 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 39

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4