36 VHL-related pheochromocytomas (from 21 patients) and 10 VHL-related CNS hemangioblastomas (from 6 patients) were studied using comparative genomic hybridization (CGH) to detect genetic imbalances. The study identified selective loss of chromosome 11 in pheochromocytomas associated with VHL. Patient XVII and XVIII in VHL-associated pheochromocytoma were found with a germline missense mutation (c.533T>A) in the VHL gene. (stated as c.746T>A in the paper which used the Latif sequence as reference) in the VHL gene. All patients have familial VHL.

Forty-four of the 50 patients with pheochromocytoma and paraganglioma treated at the Christian Medical College, Vellore between January 2010 and June 2012 were included in this study. Four patients were confirmed with VHL disease and with mutations in the VHL gene from DNA obtained from peripheral blood. One patient was a 21Y female who presented with right adrenal tumor confirmed with a VHL germline mutation (c.533T>A; p.Leu178Gln). ACMG: PP4

Of 65 VHL families from central Europe, 53 were identified with germline mutations using SSCP analysis of PCR products by peripheral blood. This missense mutation was found in 2 German, VHL type 2 family, members with retinal angiomas, hemangioblastomas of the central nervous system, and pheochromocytomas (family VHL 29). The L178Q (c.533T>A) mutation was detected in the patient, referred to in the paper by c.746T>A due to a difference in transcript sequence. Each patient's phenotype is highly specific for a disease with a single genetic etiology (ACMG code: PP4).

PatientID: 32

KindredID: 32

Case: M, 14Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient had bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q (c.533T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178Q (c.533T>A)

MultipleGeneVariants: N/A

PatientID: 15

KindredID: 15

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient was found to have multiple benign tumour 7 cm in size in her adrenal gland.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHC/SDHB/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q(c.533T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had LOH of SDHC as indicated in Table 1.

MutationType: missense_variant;transversion

CivicName: L178Q(c.533T>A)

MultipleGeneVariants: N/A

PatientID: 18 (tumour 30,31,32)

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: One other members of this patient's family (patient 17) was found to harbour the same VHL gene mutation.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had three benign pheochromocytomas.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

Variant: p.L178Q(c.533T>A)

LegacyVariant: p.L178Q(c.746T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178Q(c.533T>A)

MultipleGeneVariants: N/A

PatientID: 17 (tumour 29)

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: One other members of this patient's family (patient 18) was found to harbour the same VHL gene mutation.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Benign pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

Variant: p.L178Q(c.533T>A)

LegacyVariant: p.L178Q(c.746T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: L178Q(c.533T>A)

MultipleGeneVariants: N/A

PatientID: 31

KindredID: 31

Case: M, 21Y0M, Asian Indian

DiseaseAssertion: pheochromocytoma

FamilyInfo: None - apparently sporadic

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient had unilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/ SDHB/ SDHD/ NF1

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q (c.533T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: L178Q (c.533T>A)

MultipleGeneVariants: N/A