PatientID: N/A

KindredID: 1

Case: F, 66Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Patient’s nephew (index case) is a 52Y0M man diagnosed with five cancers (clear cell renal cancer, glioma, low-grade urothelial tumour, Cutaneous basal cell cancer, Multifocal bilateral papillary thyroid cancer) from the age of 40Y0M. The nephew had a heterozygous CHEK2 variant but no VHL mutation. Patient’s sister (mother of index case) died of non-Hodgkin’s lymphoma at 47Y0M in 1993. The patient’s niece (sister of index case) was diagnosed with breast cancer at the 26Y0M and died at 27Y0M in 1999. Neither the patient’s sister nor niece had genetic testing.

CasePresentingHPOs: HP:0002666; HP:0003002 (pheochromocytoma, breast carcinoma)

CaseHPOFreeText: Patient was diagnosed with pheochromocytoma at the age 56Y0M and breast cancer at age 66Y0M.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: next-generation sequencing for MAX, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and multiplex ligation-dependent probe amplification (MLPA) for VHL, SDHA, MAX, SDHB, SDHC and SDHC.

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330, https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988, https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense varaint, transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: None (Proband)

KindredID: 1

Case: M, 74Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo:Mother with a brain tumor of unconfirmed pathology, and both brothers (70Y and 79Y) with renal cell carcinoma with the same VHL gene mutation as this patient. One son (44Y) has the same mutation but was asymptomatic. Daughter (40Y) had a brain hemorrhage, niece had hematologic malignancy, nephew has pancreatic cancer; genetic information is unclear or not provided for these family members.

CasePresentingHPOs: HP:0010797; HP:0000822; HP:0000518; HP:0000572; HP:0000646; HP:0000819; HP:0040276; HP:0006770; HP:0032118, HP:0030439; HP:0009713; HP:0002672; HP:0006880 (Hemangioblastoma, Hypertension, Cataract, Visual loss, Amblyopia, Diabetes mellitus, Adenocarcinoma of the colon, Clear cell renal cell carcinoma, Retinitis, Anal canal adenocarcinoma, Spinal hemangioblastoma, Gastrointestinal carcinoma, Cerebellar hemangioblastoma)

CaseHPOFreeText: History of arterial hypertension and retinitis causing loss of vision in the left eye due to cataract and amblyopia in the right eye. History of retinal hemangioblastoma was presumed. Diagnosed with diabetes mellitus at the time of the study. MRI showed multiple enhancing nodular lesions of the spinal canal, later confirmed to be a hemangioblastoma. Whole body PET scan showed a heterogeneous mass in the right kidney and focal mural thickening in the sigmoid colon. Colonoscopy showed an ulceroinfiltrative lesion in the sigmoid colon and a polypoid lesion in the rectum subsequently confirmed as a adenocarcinoma and high grade tubular adenoma with focal carcinoma, respectively. Histologic examination of the kidney revealed renal clear cell carcinoma. In the sigmoid colon, gross pathology showed an ulcerofungating tumor and some regional lymph nodes were metastasis. The rectum specimen was confirmed to be a well differentiated adenocarcinoma. Brain MRI showed three enhancing lesions in bilateral cerebellar hemispheres and left cerebellar tonsil, suggesting hemangioblastomas. Histologic examination of liver revealed a metastatic adenocarcinoma. Pathologic finding indicated that the aortocaval lymph node was metastatic carcinoma, favoring renal clear cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: M, 75Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's brother had hypertension at age 77 and was found to carry the mutation. The patient's niece had breast cancer at age 33. Refer to Figure 4 for Pedigree.

CasePresentingHPOs: HP:0006770, HP:0040276, HP:0006748, HP:0001407, HP:0002716, HP:0032618, HP:0100526, HP:0100598 (clear cell renal cell carcinoma, adenocarcinoma of the colon, adrenal pheochromocytoma, hepatic cysts, lymphadenopathy, renal necrosis, neoplasm of the lung, pulmonary edema)

CaseHPOFreeText: Patient admitted at age 64 for intermittent abdominal pain, loss of appetite and constipation. He was found to have a solid tumor with areas of colliquative necrosis in the upper pole of the left kidney. The scans also showed distension of the colon with concomitant wall thickening, indicating possible neoplasia. Colonoscopy revealed a small polyp in the rectum-sigmoid junction, and a subsequent histological exam confirmed a diagnosis of adenocarcinoma. Both tumours were removed via a left hemicolectomy and left radical nephrectomy. A histologic examination of the kidney revealed renal clear cell carcinoma. Five years later, an abdominal CT scan revealed an adrenal pheochromocytoma in the right adrenal gland and multiple hepatic cysts in the right kidney and liver. The patient underwent a right adrenalectomy which found no convincing evidence of malignancy. At age 73 total body positron emission tomography (PET)-CT revealed the presence of several metastatic sites (both lungs, a 12×10 mm right sovraclaveare lymphadenopathy, and a 32×12 mm lesions at the mediastinum). An agobiopsy and cytologic broncholavage showed lymphocytes and epithelial cells with voluminous clear cytoplasm and large nuclei with prominent nucleoli, confirming the presence of metastatic lesions of clear cell renal carcinoma. In the same year, CT imaging revealed progression of pulmonary disease. One year later, a new CT scan revealed hepatic metastases and worsening of the mediastinal adenopathy and pulmonary metastases. At age 75, a new CT scan showed stable disease at various metastatic sites with minimal pleural effusion. Later in the month the patient was hospitalized for severe dyspnea, fatigue, and lower limb edema and died a few days later.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: Fundoscopy revealed no vascular abnormalities of the retina.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: II-1

KindredID: Family C

Case: M, 45Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Only this one member was studied at have the L198P mutation, however the asymptomatic father of patient C II-1 was also a carrier of the same polymorphism (c.74C>T, p.P25L).

CasePresentingHPOs: HP:0006748; HP:0030405; HP:0009711 (Adrenal pheochromocytoma; pancreatic neuroendocrine tumour; retinal capillary hemangioma)

CaseHPOFreeText: At the age of 15, patient had pancreatic tumor (malignant pancreatic neuroendocrine tumor). At the age of 16, MRI revealed suprarenal tumor masses bilaterally (pheochromocytomas in the adrenal glands), as well as optic nerve hemangioblastomas of the right eye. At the age of 25, he shows no signs of metastases or new VHL-associated tumors, but since the age of 23, he has been suffering from HLAB27-positive ankylosing spondylitis.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L198P (c.593T>C) AND P25L (c.74C>T)

MultipleGeneVariants: Germline, VHL, c.593T>C (p.Leu198Pro)

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: The proband was part of a cohort of apparently sporadic cases of pheochromocytoma/ paraganglioma, implying this individual had no family history of VHL disease or pheochromocytoma.

CasePresentingHPOs: HP:0006748 (Adrenal Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330, https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988, https://gnomad.broadinstitute.org/variant/3-10183605-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 125

GroupNumberMales: 58

GroupNumberFemales: 67

GroupEthnicity: German

GroupAgeRange: 4-86 Y

GroupInfo: The subjects included 64 patients belonging to 15 families with a known VHL c.505 T/C mutation. From their test programme, another 10 c.505 T/C mutation carriers were identified. As well, all consenting first degree relatives (at risk subjects) of mutation carriers, irrespective of disease status, were subjected to mutation analysis, resulting in another 51 mutation carriers detected.

GroupPresentingHPOs: HP:0002666, HP:0009713, HP:0009711, HP:0010797, HP:0006748, HP:0006737, HP:0006770, HP:0002893, HP:0100616, HP:0030357, HP:0002894 (pheochromocytoma, spinal hemangioblastoma, retinal capillary hemangioma, hemangioblastoma, adrenal pheochromocytoma, extraadrenal pheochromocytoma, clear cell renal cell carcinoma, pituitary adenoma, testicular teratoma, small cell lung carcinoma, neoplasm of the pancreas)

GroupHPOFreeText: 96 patients had clinical manifestations of VHL. 55 subjects (31 males, 24 females) developed pheochromocytoma during their lifetime. Overall penetrance for pheochromocytomas was estimated to be 31% by age 35 and 60% by age 70. Other frequent lesions were retinal angioma (36%), hemangioblastoma of the spine (36%), and, to a lesser extent, hemangioblastoma of the brain (16%). One patient with angiomatosis retinae developed at least 25 retinal angiomas, whereas the remaining patients had an average of two angiomas with no more than five lesions in one patient. 15 patients had bilateral and 25 unilateral involvement of the retinae. Pheochromocytoma was observed as a single tumour with adrenal or extra-adrenal localization in 32 patients, but 23 mutation carriers developed multiple pheochromocytomas. Four patients developed renal clear cell carcinoma (estimated overall penetrance 13% by the age of 70). Two of these patients died of metastases. All renal clear cell carcinomas were unilateral, single tumours, and no kidney showed renal cysts. Three of the patients with renal cell carcinoma were female. The kidney tumours were detected at the ages of 46 (male patient), 48, 63, and 74 years. Two patients with renal cell carcinoma also had multiple spinal hemangioblastomas. Other rare tumours were one pancreatic islet cell tumour and one pituitary adenoma; both neoplasms had been incidentally found in a dead 34 year old woman at necropsy. One 68 year old male patient was noted to have small cell lung cancer, and two other males developed testicular teratocarcinoma both at 39 years of age.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: 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: IIII-6

KindredID: 1

Case: F, 44Y0M, Hungarian

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's mother (II-5) carried the Ser80Asn mutation and presented with renal cell carcinoma. The patient's siblings (III-7 and III-8) both carried the Ser80Asn mutation. Patient III-7 presented with hemangioblastoma of the brain and retina hemangioblastoma and her children carried the Ser80Asn mutation with clinical presentation. Patient III-8 presented with brain hemangioblastoma, pheochromocytoma, and retina hemangioma. The patient's maternal aunt (II-1) carried both Ser80Asn and Pro25Leu mutation but was asymptomatic. She passed on the Ser80Asn mutation to her daughter (III-1), the proband and this patient's cousin. Refer to figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: CA020538 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.74C%3ET

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: 12

KindredID: 12

Case: 32Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Family history unremarkable; Patient was confirmed to have a de novo mutation.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0000107; HP:0030424 (hemangioblastoma; retinal capillary hemangioma; renal cyst; epididymal cyst)

CaseHPOFreeText: Aged 32Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. Retinal hemangioblastomas and CNS hemangioblastomas diagnosed at 32Y, renal cysts were also diagnosed at 32Y, while epididymal cysts were diagnosed first at 23Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA2497423672 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2497423672

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V74Sfs*53 (c.219_232delGGTCATCTTCTGCA)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: F, 40Y0M, Ethnicity Unknown

DiseaseAssertion: Cerebellar Hemangioblastoma

FamilyInfo: N/A

CohortInfo: The cohort included a series of 20 capillary haemangioblastomas of the central nervous system for mutations of the VHL gene.

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.P25L (c.74C>T)

LegacyVariant: p.P25L (c.287C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: Refer to Table 1 for abnormal SSCP or heteroduplex patterns.

MutationType: missense_variant;transition

CivicName:P25L(c.74C>T)

MultipleGeneVariants: N/A

PatientID: IV-3

KindredID: 1

Case: M, 77Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother and two brothers had died with cerebellar hemangioblastoma, although genetic testing was not performed. One of the patient’s four children, a 46Y male, also presented with a small renal tumour, renal cysts, and pancreatic cysts; he was found to carry the same mutation the patient carried. One of the patient’s grandsons, a 10Y male, was also found to carry the same mutation as the patient but was asymptomatic. Genealogical inquiry also revealed that the patient was distantly related to a known VHL family; one member, a 47Y male, was previously operated on for CNS hemangioblastoma, RCC and symptomatic pheochromocytoma and was found to carry the same mutation as the proband. Another female member had previously presented with retinal hemangioblastoma before becoming deceased at 37Y. The paper also asserted that the patient’s grandmother and two distant relatives carried the mutation, although genotyping was not performed and phenotypic information was not provided.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0006770; HP:0006748; HP:0000479 (Cerebellar hemangioblastoma, pancreatic serous cystadenoma, clear cell renal cell carcinoma, adrenal pheochromocytoma, retinal lesions)

CaseHPOFreeText: The patient was originally diagnosed with metastatic bilateral clear cell renal cell carcinoma at 68Y and underwent chemotherapy for three months. The metastases were later reinterpreted to be a cystic hemangioblastoma and a benign serous cystadenoma. The patient was also found to have a non-secreting adrenal pheochromocytoma at 73Y and a clear cell renal cell carcinoma metastasis in the thyroid at 74Y. The patient had also previously presented with retinal lesions, although detailed records were unavailable.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R82P(c.245G>C)

LegacyVariant: N/A

ClinVarID: 193118, http://www.ncbi.nlm.nih.gov/clinvar/variation/193118

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P(c.245G>C)

MultipleGeneVariants: N/A

PatientID: IV:6

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient had two siblings both of whom carried the P25L mutation. One was asymptomatic (IV:4) whereas another (IV:2) presented with retinal hemangioma and renal cysts. Her cousin (IV:7) was diagnosed at the age of 47 years with renal cell carcinoma and subsequently died at the age of 48 years. Her great grandmother (I:2) had died of a brain tumor in her late 50s. Her grandfather (II:3) had a brain tumor at the age of 53 years and died aged 78 years. As well, her grandfather's sister (II,1) reportedly died of stomach cancer in her 80s. Of the 13 family members tested, V:2, IV:4, IV:6, III:2, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: III:11

KindredID: 1

Case: F, 75, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:2 and III:3). The patient's sister (III:2) had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her niece, (IV:2) had three children and one was found to carry the mutation. The patient's brother (III:3) had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation (IV:7). The patient had three unaffected children who did not carry the mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Ongoing clinical follow up of the individuals with P25L over a period of 5 years has continued to show no evidence of additional clinical involvement of VHL disease.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: III:2

KindredID: 1

Case: F, 62, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (II:3) had a brain tumour at age 53 and died at age 78. The patient's paternal aunt (II:1) died of stomach cancer at age 80. The patient's paternal grandfather died at age 50 due to a brain tumour. The patient had three children all of whom carried the P25L mutation and were asymptomatic (IV:4 and IV:6) except patient IV:2 who presented with a retinal hemangioma and renal cyst. Her daughter (IV:2) had three children and one was found to carry the mutation. The patient had seven siblings, five of whom underwent genetic testing. Two were found to carry the mutation but both were asymptomatic (patient III:3 and III:11). Patient III:3 had six children one of whom died due to clear cell renal carcinoma at age 48 but did not carry the P25L mutation. Of the 13 family members tested, V:2, IV:4, IV:6, III:3, and III:11 were all found to carry the P25L mutation in the VHL gene. Refer to Figure 1 for pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName:P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 68Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None.

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

CaseHPOFreeText: Patient was found observed to have retinal angioma (retinal capillary hemangioma) and a right kidney cortex cyst (30mm). Patient's pheochromocytoma was found incidentally and he remained asymptomatic with steady weight.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Chinese

GroupAgeRange: N/A

GroupInfo: With a family history, 3 family members were recorded in this group with the given mutation.

GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0001732 (hemangioblastoma; retinal capillary hemangioma; pancreatic lesion)

GroupHPOFreeText: 2 members had CNS hemangioblastomas, 1 member had retinal angiomas, and 1 had pancreatic cysts or tumors (an abnormality of the pancreas)

GroupNotHPOs: HP:0005584; HP:0002666 (renal cell carcinoma, pheochromocytoma)

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

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V74G (c.221T>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.V74G (c.434T>G)

ClinVarID: N/A

CAID: CA70042528 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A

PatientID: RCC-23

KindredID: 1

Case: Sex and Age unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P25L (c.74C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 93330 https://www.ncbi.nlm.nih.gov/clinvar/variation/93330/

CAID: N/A

gnomAD: 0.002988 https://gnomad.broadinstitute.org/variant/3-10183605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P25L (c.74C>T)

MultipleGeneVariants: N/A

PatientID: 25

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 S1 describes 19 patients with missense mutations, including this patient.

Variant: p.V74G(c.221T>G)

LegacyVariant: c.434T>G

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: 53CE

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 53CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

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.V74G (c.221T>G)

LegacyVariant: p.V74G (c.434T>G)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA70042528 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.221T>G

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V74G (c.221T>G)

MultipleGeneVariants: N/A