Fourty-four of 389 patients with VHL (between 1988-1999) screened positive for pancreatic neuroendocrine tumours (PNETs) either by pathologic analysis of tissue specimens or by characteristic radiographic appearance on CT and MRI. VHL gene germline mutations were determined by quantitative Southern blotting to detect deletions of the gene and gene rearrangements as well as complete gene sequencing. Patient 44 (39 year old male) was found to harbour the c.563T>C mutation in the VHL gene (stated as 776 T to C in the paper which used the Latif sequence as reference) resulting in a Leu to protein change at position 188. The patient presented with two pathologic pancreatic neuroendocrine tumors. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.L188P (c.563T>C) germline variant of the VHL gene was detected in 2 individuals (ID 5730/Family 269 and ID 8828/Family 1005) who both presented with renal cell carcinoma. The paper states that these families are previously reported in PMID 12202531 and/or 9829912.

PatientID: 5730

KindredID: 269

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 1005.

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

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this mutation (L188P (c.563T>C)) was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. This is possibly previously published in PMID: 15300849

GroupID: 51

Case: Age unknown, Sex unknown, French

DiseaseAssertion: VHL

FamilyInfo: None - one member documented here

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: other manifestations are not clearly stated.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Possibly published in PMID:15300849

SupplementalData: N/A

Variant: p.L188P (c.563T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A

PatientID: P34

KindredID: 1

Case: M, 20Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: diagnosed at the age of 20 years with VHL and presented with severe hypertension and a 40 mm PC of the right adrenal gland (pheochromocytoma)

CaseNotHPOs: No positive family history

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB/ SDHD/ RET/ MEN2

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266 https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: also the polymorphism S69S of the SDHD gene.

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: Germline, SDHD, (p.Ser69Ser)

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 L188P (c.563T>C) missense mutation was found in a VHL type 1 (no pheochromocytoma) patient (patient no. V269). Five unaffected family members were negative for the variant.

PatientID: 8828

KindredID: 1005

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 269.

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

Variant: p.L188P (c.563T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625266, https://www.ncbi.nlm.nih.gov/clinvar/variation/625266/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L188P (c.563T>C)

MultipleGeneVariants: N/A