Case#: II.4 - male, 23, European descent II.5 - male, 28, European descent CasePresentingHPOs: Both patients II.4 and II.5 - HP:0003233 (low HDL cholesterol), HP:0012153 (hypotriglyceridemia), HP:0003563(decreased LDL cholesterol)

CaseMethod1: Exome CaseMethod2: Sanger

Variant: NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)

ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

VariantEvidence: 12 other individuals from the Dallas Heart Study with ANGPTL3 frameshift mutations with phenotypes in Supplementary doc (PMID 19075393), additive dosage model with 2 mutations, 1 mutation and 0 (in supplementary table 5), “key enzymes in the metabolism of circulating triglycerides and HDL cholesterol, respectively, are elevated in Angptl3-knockout mice, suggesting that increased activity of these enzymes may explain the low levels of triglycerides and HDL cholesterol in humans with ANGPTL3 nonsense mutations” (PMIDs 17110602, 12097324, and 17681148)

Case#: 1

Variant: homozygous NM_014495.3:c.286_288del (ANGPTL3) p.Glu96del ← listed in Allele Registry, but paper lists it as p.Glu95del

ClinVar: not in ClinVar

gnomAD: total allele count: 42, allele frequency for African population with an allele count of 16: 0.0006458

Case#: 2

Variant: homozygous NM_014495.3(ANGPTL3):c.439_442del (p.Asn147Terfs)

CAId: CA145485

ClinVar: 91865

gnomAD: 37 allele count, 0.0001966 allele frequency for European with allele count of 23

Case#: 3 (previously report in PMID 20942659)

Variant: compound heterozygous NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)

ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

Case#: 4

Variant: compound heterozygous NM_014495.3(ANGPTL3):c.439_442del (p.Asn147Terfs) and NM_014495.3(ANGPTL3):c.883T>C (p.Phe295Leu)

ClinVar: 91865 and 91867

gnomAD: not in gnomAD

Case#: 5

Variant: heterozygous c.355_360delAACT

ClinVar: not in ClinVar

CAId: none

gnomAD: not in gnomAD

Case#: 6

Variant: heterozygous c.62 insCTCAT

ClinVar: not in ClinVar

CAId: none

gnomAD: not in gnomAD

Case#: 7

Variant: heterozygous NM_014495.3:c.167G>T (ANGPTL3)

ClinVar: not in ClinVar

CAId: CA340600195

gnomAD: not in gnomAD

Case#: 8

Variant: heterozygous NM_014495.3:c.995G>A

CAID: CA886769

ClinVar: not in ClinVar

gnomAD: 0.0001476 total allele freq, 37 allele count, 0.0008191 is largest allele freq for Other population with allele count of 5

Variant: NM_014495.3(ANGPTL3):c.363_367del (p.Asn121Lysfs)

ClinVar: 91866 - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

VariantEvidence: similar fs122 del variant was previously reported in the Dallas Heart Study with ANGPTL3 frameshift mutations with phenotypes in Supplementary doc (PMID 19075393)

PatientID: 1 (case)

KindredID: 1

Case: F, 37Y0M, Ethnicity Unknown

DiseaseAssertion: adrenal pheochromocytoma

FamilyInfo: Her one sister had died just after delivery, following a severe hypertensive crisis. Her 26-year-old niece presented with a 3 cm left adrenal tumor, an 8 cm pancreatic tumor and disseminated hepatic metastasis, evolving to death within a few months. Her liver biopsy was compatible with a moderately differentiated neuroendocrine carcinoma of uncertain origin. Molecular diagnosis was not performed in the affected sister and niece. Her asymptomatic 5Y old daughter tested positive for the mutation: Q164R (c.491A<G).

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: She first presented with paroxisms of severe hypertension associated with headaches, diaphoresis and, ocasionally, fainting, started one year before. She had had acute pulmonary edema and a cardiorespiratory arrest during her first caesarean section. A CT scan revealed a right adrenal tumor (6.0 cm), showing increased 123I-MIBG uptake. After conventional adrenalectomy, a PHEO was immunohistochemically confirmed. Close follow-up has shown no signs of recurrence or evidence of new tumors.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164R (c.491A>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2238 https://www.ncbi.nlm.nih.gov/clinvar/variation/2238/

CAID: N/A

gnomAD: N/A

VariantEvidence: To date, this germline VHL mutation was said to have been described in only 3 cases, with variable phenotypes, and in 2 cases PHEO occurred at a very young age.

MutationType: missense_variant;transition

CivicName: N/A

MultipleGeneVariants: N/A