This study focused on observing SDHx function on the development of PPGLs. DNA was extracted from peripheral blood samples and next generation sequencing of a clinical gene panel included; SDHA, SDHB, SDHC, SDHD, KIT, PDGFRA and NF1 (for GIST) and SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127, VHL, RET, FH for (PPGL). The lowest SDHC expression level was seen in case #0026. This case was a pheochromocytoma with a known pathogenic germline VHL variant (c.499C>G, p.Arg167Gly). She was a 25Y patient who showed an equivocal result on SDHB immunohistochemistry testing, but no evidence of a somatic SDHx mutation. No family history was noted.

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 (R167G (c.499C>G)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 137CA. It was reported in the paper as c.712C>G due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupID/ KindredID: 137CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 137CA. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167G (c.499C>G)

LegacyVariant: p.R167G (c.712C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219

CAID: N/A

gnomAD: N/A

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

MutationType: missense_variant; transversion

CivicName: R167G (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: 30Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as a familial tumor; no other family info present

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma reported with an age at diagnosis of 30 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167W (c.499C>G)

MultipleGeneVariants: N/A

PatientID: 6

KindredID: 2

Case: 15Y0M, Sex and Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Recorded as a familial tumor; One other family member (Patient ID: 5) was a 29 year old patient with a bilateral pheochromocytoma. "Belonging to the same family", although the connection is unclear.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Unilateral pheochromocytoma reported with an age at diagnosis of 15 years of age.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2219 https://www.ncbi.nlm.nih.gov/clinvar/variation/2219/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R167W (c.499C>G)

MultipleGeneVariants: N/A