c.531C>G
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.531C>G (p.P177L)
Variant1ClinVarID: 2432729
Variant1CAID: CA2801983
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.898G>A
Case#: Functional assay variant with a clinical significance of having conflicting interpretations.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.898G>A (p.A300T)
Variant1ClinVarID: 11923
Variant1CAID: CA121772
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.1706C>T
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1706C>T (p.S569L)
Variant1ClinVarID: N/A
Variant1CAID: CA355965250
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Functional assessment of IDUA variants of uncertain significance identified by newborn screening
PMID: 39702574
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
c.719A>G
Case#: Functional assay variant with a clinical significance of pathogenic.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.719A>G (p.H240R)
Variant1ClinVarID: 947028
Variant1CAID: CA355962127
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
22
Case#: Patient 22, female, 4 years (age at presentation).
DiseaseAssertion: MPS1-H/S
FamilyInfo: Consanguinity in the family not present for this patient.
CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, sleep disturbance, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0002360, HP:0001744)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1898C>T (p.S633L)
Variant2ClinVarID: 556406
Variant2CAID: CA355966010
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
28
Case#: Patient 28, female, 2 months (age at presentation).
DiseaseAssertion: MPS1-H
FamilyInfo: Consanguinity in the family present for this patient. Sister is unaffected.
CasePresentingHPOs: Coarse facial features, dysostosis multiplex, global developmental delay, hepatomegaly, joint contractures, splenomegaly (HP:0000256, HP:0000943, HP:0001263, HP:0002240, HP:0100790, HP:0001744)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1855C>T (p.R619X)
Variant1ClinVarID: 280976
Variant1CAID: CA2802455
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: Mother and father are both carriers but does not specify for which variants.
PreviouslyPublished N/A
30
Case#: Patient 30, female, 3 years (age at presentation).
DiseaseAssertion: MPS1-H/S
FamilyInfo: Consanguinity in the family present for this patient. Family had a prenatal diagnosis "CVS-unaffected"
CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint stiffness, splenomegaly, short stature, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0001744, HP:0004322, HP:0001537)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1861C>T (p.R621X)
Variant1ClinVarID: 11917
Variant1CAID: CA256118
Variant2: c.1861C>T (p.R621X)
Variant2ClinVarID: 11917
Variant2CAID: CA256118
AdditionalVariants: N/A
ParentalGenotype: Mother and father are both carriers but does not specify for which variants.
PreviouslyPublished N/A
c.1240_1240delA
Case#: No additional case information provided
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.09 umol/g hr, reference range 10–50 umol/g hr.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1240_1240delA (p.S414AfsTer26)
Variant1ClinVarID: N/A
Variant1CAID: CA645372298
Variant2: c.614G>A (p.C205X)
Variant2ClinVarID: 1468875
Variant2CAID: CA355961928
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.41T > G
Case#: No additional case information provided
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Not detectable
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.41T>G (p.L14R)
Variant1ClinVarID: N/A
Variant1CAID: CA355945322
Variant2: c.386-2A>G
Variant2ClinVarID: 222994
Variant2CAID: CA356991
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
To assess the potential utility of these genotype–phenotype relationships, the associations suggested were applied to test cohort derived from a previously published cohort of MPS I patients (Beesley et al., 2001). This study described the variants identified in a cohort of 85 families with MPS I, and identified nine common variants. Phenotypic information was available for a subset of individuals in whom neither or only one variant was a common variant. Up to date genotypes and phenotypic classification was obtained for 31 such individuals in whom both IDUA variants were identified (Clare Beesley, personal communication), and this was used as the test cohort (Supp. Table S5).
This variant can be found in supp table s5, mentioned from a previous publication (Beesley et al., 2001).
c.506_513delinsGGAA
Case#: No additional case information provided
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Not detectable
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.506_513delinsGGAA (p.L169RfsTer24)
Variant1ClinVarID: N/A
Variant1CAID: CA645372296
Variant2: c.506_513delinsGGAA (p.L169RfsTer24)
Variant2ClinVarID: N/A
Variant2CAID: CA645372296
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
P3-IDUAMNorth AfricaMorocco1.774.4IDUAc.1598C > G/wtp.Pro533Arg/wtMissenseHurler/wt
Case#: P3-IDUA, M, North Africa, Morocco DiseaseAssertion: MPS1 - Hurler/wt FamilyInfo: CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: NBS 1.77 triplex / 4.4 single CaseUrineGAGs: CaseERT: CaseBMT: Variant1: c.1598C>G Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2: wt Variant2ClinVarID: Variant2CAID:<br /> AdditionalVariants: ParentalGenotype: PreviouslyPublished
Case#: TW1-1 ID number, Table S1.1 of Supplementary Material. Stored Frozen (-20ºC). Other identifying factors N/A
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 301 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1874A>C (p.Y625S)
Variant1ClinVarID: 2910181
Variant1CAID: CA355965961
Variant2: c.300-3C>G
Variant2ClinVarID: 551563
Variant2CAID: CA549265042
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: MN-400 ID number, Table S1.1 of Supplementary Material. Female, 1.5 months old (age at diagnosis). Stored frozen (-20ºC) 0.7 yr
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Probable heart features, small curve in the spine
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1632 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: NY-605 ID number, Table S1.1 of Supplementary Material. Additional health information not provided.
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1412 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: NJ-500 ID number, Table S1.1 of Supplementary Material. Male, 1 year and 4 months (age at first symptoms), 1 year and 4 months old (age at diagnosis). Stored ambient 3 yr
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, umbilical hernia, hypertension (HP:0000256, HP:0001537, HP:0000822)
CaseHPOFreeText: Some heart issues
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1343 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
missense mutations
Case#: Patient 61, Spain
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1475G>C (p.R492P)
Variant1ClinVarID: 11918
Variant1CAID: CA256120
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
distinct mutant IDUA alleles
Case#: Patient 23, Italy
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1487C>G (p.P496R)
Variant2ClinVarID: 496861
Variant2CAID: CA2802275
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
distinct mutant IDUA alleles
Case#: Patient 92, Turkey, patient belong to the same geographical region as patients 86, 90, and 98
DiseaseAssertion: MPS1-H/S - S (Unsure what this phenotype means)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.494-1G>A
Variant1ClinVarID: 557942
Variant1CAID: CA355961634
Variant2: c.826G>A (p.E276K)
Variant2ClinVarID: 3233261
Variant2CAID: CA355962355
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 3, male, 12.2 months (age at HSCT), 8.5 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: RSV pneumonitis, pneumothoraces
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.14 (at diagnosis), 49.9 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 96 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the PBSC (peripheral blood stem cells)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 7, female, 13.2 months (age at HSCT), 10.2 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Norovirus gastroenteritis
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.09 (at diagnosis), 17.1 (after ERT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 113 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 4, female, 8.3 months (age at HSCT), 4.5 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText: Cy-induced acute cardiomyopathy
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.31 (at diagnosis), 15.7 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 114 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the BM (bone marrow).
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 2, male, 11.5 months (age at HSCT), 9.2 months (age at ERT)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Renal tubular acidosis (HP:0001947)
CaseHPOFreeText: Veno occlusive disease (VOD), skin graft-versus-host disease (GVHD)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.22 (at diagnosis), 27.6 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 64 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients
PMID: 25256405
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
9/m
Case#: 9, Male, Han Chinese
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)
CaseHPOFreeText: Skeletal Deformities
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)
Variant1: c.1190-1G>A
Variant1ClinVarID: 1204494
Variant1CAID: CA355963511
Variant2: c.792+1G>T
Variant2ClinVarID: N/A
Variant2CAID: CA355962278
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: F602I
Variant1ClinVarID:
Variant1CAID: CA355965569
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: A300T
Variant1ClinVarID: 11923
Variant1CAID: CA121772
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: W626R
Variant1ClinVarID:
Variant1CAID: CA355965965
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Pro533Arg
Case#: Variant not associated with a proband in this paper.
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: Pro533Arg
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: C205Y
Variant1ClinVarID: 1468875
Variant1CAID: CA355961928
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: T364M
Variant1ClinVarID: 11925
Variant1CAID: CA256126
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: T366P
Variant1ClinVarID: 11916
Variant1CAID: CA256117
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
16/M
Case#: 16, Male, Infancy (onset), 2,5 years (diagnosed), 3 years (report), deceased (at 5y)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0000256, HP:0002240, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly (hydrocephalus), Hepatomegaly (moderate), Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)
CaseHPOFreeText: (Mental Development (Delayed since infancy; developmental quotient 68 at 3y), Mild LV Hypertrophy, Frequent respiratory infections, After ERT: decreased illness (obstructive bronchitis), decreased organomegaly, increased mobility)
CaseNotHPOs: HP:0004322, HP:0001744 (Short Stature, Splenomegaly)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: Decreased excretion of GAGs in the urine
CaseERT: Had an ERT
CaseBMT: N/A
GenotypingMethod: Not Provided
Variant1: p.A327P
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.1727+2T>G (splicing error)
Variant2ClinVarID: N/A
Variant2CAID: CA355965300
AdditionalVariants: p.Q33H
ParentalGenotype: N/A
PreviouslyPublished N/A
5/M
Case#: 5, Male, 1 year (onset), 3 years (diagnosed), 3 years (report)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0001387, HP:0002240, HP:0001744, HP:0000501, HP:0000280, HP:0000943, HP:0007957 (Joint Stiffness, Hepatomegaly (moderate), Splenomegaly (moderate), Glaucoma, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)
CaseHPOFreeText: Mental Development (delayed since 2y), LV hypertrophy (at 3y)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Not Provided
Variant1: p.W402X
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: p.V620F
Variant2ClinVarID: 1067173
Variant2CAID: CA355965934
AdditionalVariants: p.R105Q, p.N181, p.A314, p.T410, p.V454I, p.R489
ParentalGenotype: N/A
PreviouslyPublished N/A
Taiwan National Newborn Screening Program by Tandem Mass Spectrometry for Mucopolysaccharidoses Types I, II, and VI
PMID: 30409495
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
MPS I_Case 02
Case#: MPS I_Case 02, female newborn
DiseaseAssertion: MPS type I, MPS I, MPS-I, attenuated MPS I
FamilyInfo: MPS I_Case 02 and MPS I_Case 03 are twins
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText: This proband is believed to be an affected MPS-patient however, the proband did not have any obvious clinical symptoms to date (up to two years of age). The paper states that this attenuated MPS I case will need a long term follow up.
CaseEnzymeAssay: Proband identified by newborn screening. alpha-L-iduronidase activity in dried blood spot sample is 0.59 umole/L/Hr; this is below the study's DBS enzyme activity cutoff value of 3 umol/L/h
CaseUrineGAGs: Urine DMB GAG ratio is 204.7mg/mmol creatinine. 99.60 ug/ml dermatan sulfate in urine (<0.41 ug/ml is the reference cutoff for dermatan sulfate in this study). 13.31 ug/ml heparan sulfate in urine (<0.8 ug/ml is the reference cutoff for heparan sulfate in this study). 0.83 ug/ml keratan sulfate in urine.
CaseERT: Don't know (would assume no since the proband is a newborn)
CaseBMT: Don't know (would assume no since the proband is a newborn)
Variant1: c.1037T>G, p.L346R
Variant1ClinVarID: 11927
Variant1CAID: CA256128
Variant2: c.1091C>T, p.T364M
Variant2ClinVarID: 11925
Variant2CAID: CA256126
AdditionalVariants: No additional variants mentioned
ParentalGenotype: No parental testing results are available
PreviouslyPublished No statement from the author indicating the proband is previously published. Since this is a newborn study, I strongly believe this is the proband’s first time being published.
PKMPS1P7
Case#: PKMPS1P7, 10 months old (age at presentation), 2.4 years old (age at report), male, Pakastani. He underwent ventriculoperitoneal shunting at the age of 18 months due to significant hydrocephalus.
DiseaseAssertion: MPS-I
FamilyInfo: Parents had a consanguineous marriage
CasePresentingHPOs: Coarse facial features, macrocephaly, rhinorrhea, hydrocephalus, mild to moderate developmental delay, umbilical hernia (HP:0000256, HP:0000256, HP:0031417, HP:0000238, HP:0001263, HP:0001537)
CaseHPOFreeText: Poor growth potential, widening of the wrist and elbow. The abdomen was distended. The liver span was 3 cm.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.784delC (p.H262Tfs*55)
Variant1ClinVarID: 956890
Variant1CAID: CA2802083
Variant2: c.784delC (p.H262Tfs*55)
Variant2ClinVarID: 956890
Variant2CAID: CA2802083
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
PKMPS1P12
Case#: PKMPS1P12, 2.6 years old (age at presentation), male, Pakastani
DiseaseAssertion: MPS-I
FamilyInfo: Born to a non-consanguineous couple
CasePresentingHPOs: Significant developmental delay, stridor, coarse facial features, recurrent chest infections, umbilical hernia, corneal clouding (HP:0001263, HP:0010307, HP:0000256, HP:0002783, HP:0001537, HP:0007957)
CaseHPOFreeText: Running nose, skeletal stigmata were consistent with MPS1, and a liver span on 3 cm.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1469T>C (p.L490P)
Variant2ClinVarID: 11919
Variant2CAID: CA220503
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
PMID: 31473686
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Case#: Patient W3, 10 years old, Chinese. The patient had normal intelligence based on their performance in school.
DiseaseAssertion: MPS1-H/S
FamilyInfo: Patient received the p.M1I mutation from their mother and received the p.Y343X from their father.
CasePresentingHPOs: Short stature, coarse facial features, severe skeletal deformities (HP:0004322, HP:0000280, HP:0000924)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Expression of Y343X in COS-7 cells showed retention of a very low level of IDUA activity
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.3G>A (p.M1I)
Variant1ClinVarID: 557150
Variant1CAID: CA355945212
Variant2: c.1029C>A (p.Y343X)
Variant2ClinVarID: 222997
Variant2CAID: CA356984
AdditionalVariants: The patient has one IDUA allele with the variant c.3G>A (p.M1I) and an in frame deletion of the whole of exon 2, whereas the other allele has Y343X (an in frame deletion of nucleotides 1061-1117 in exon 8).
ParentalGenotype: Maternal - p.M1I, Paternal - p.Y343X
PreviouslyPublished N/A
two boys
Case#: Boy 3, male, 5 years old, born of normal pregnancy with a birth weight of 3,200 grams
DiseaseAssertion: MPS-I H/S
FamilyInfo: Boy 1 was born to a Chinese family of five members, with a total of 3 boys. Genetic testing was conducted on all 5 family members. The first and third child (boy 1 and boy 3) have MPS I. The second son had a normal phenotype and genotype.
CasePresentingHPOs: N/A
CaseHPOFreeText: Lesions (similar to elder brother; noted at 3 years old)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 3.29 nmol/h/mg (reference range >21)
CaseUrineGAGs: Positive for urinary polysaccharide toluidine blue staining test
CaseERT: N/A
CaseBMT: N/A
Variant1: c.265C>T (p.R89W)
Variant1ClinVarID: 580286
Variant1CAID: CA2801156
Variant2: c.1633G>T (p.E545X)
Variant2ClinVarID: N/A
Variant2CAID: CA355965099
AdditionalVariants: N/A
ParentalGenotype: Mother carries c.265C>T and father carries c.1633G>T.
PreviouslyPublished N/A
Hurler
Case#: 0.1% residual activity at 37 °C
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.2 ± 0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Scheie
Case#: 0.3% residual activity at 37 °C
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.8 ± 0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.979G>C (p.A327P)
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.1148G>A (p.R383H)
ClinVarID: 558189
Variant2CAID: CA2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: c.1403-1G>T/c.1728-1G>C
ClinVar: 556064
CAID: CA355965306
SupplementalData: Table S1 has the genotypes listed
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: c.1728-1G>C/W402X
ClinVar: 556064
CAID: CA355965306
SupplementalData: Table S1 has the genotypes listed
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: Q70X/Y343X
ClinVar: 222997
CAID: CA356984
SupplementalData: Table S1 has the genotypes listed
p.Q310X [37]
This paper references a pt from PMID: 12865757 which can no longer be accessed. Links/DOI say they're no longer found.
263
Case#: Patient 26 (see Table 2), 40 weeks (Gestational age)
DiseaseAssertion: MPS1-S
FamilyInfo: Sibling of Patient 25 (see Table 2)
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1148G>A (p.R383H)
Variant2ClinVarID: 558189
Variant2CAID: CA:2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
6
Case#: Patient 6 was biochemically diagnosed with MPS I because they showed an increase in urinary GAGs and a reduction in IDUA activity in leukocytes. Patient 6 was diagnosed at 1 year.
DiseaseAssertion: MPSI-H/S
FamilyInfo: N/A
CasePresentingHPOs: Coarse facies, corneal clouding, hernias, intellectual disability, skeletal abnormalities, cardiac abnormalities, and hepatosplenomegaly (HP:0000256, HP:0007957, HP:0100790, HP:0001249, HP:0002360, HP:0001627, HP:0001433)
CaseHPOFreeText: N/A
CaseNotHPOs: Growth delay (HP:0001510)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity of 1.78 nmol/mg/protein/hr. No reference range provided.
CaseUrineGAGs: 2517.8 CPC unit/g creatinine. No reference range provided.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1487C>G (p.P496R)
Variant1ClinVarID: 496861
Variant1CAID: CA2802275
Variant2: c.1854C>A (p.Y618X)
Variant2ClinVarID: 554826
Variant2CAID: CA355965929
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 43, 2 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0001249, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 34, 5 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0000943, HP:0001249, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1373T>C (p.Leu458Pro)
Variant1ClinVarID: N/A
Variant1CAID: CA355964255
Variant2: c.1373T>C (p.Leu458Pro)
Variant2ClinVarID: N/A
Variant2CAID: CA355964255
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 48, 6 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections (HP:0001433, HP:0002828, HP:0007957, HP:0002719)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 25, 28 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0000943)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.5% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1148G>A (p.Arg388His)
Variant1ClinVarID: 558189
Variant1CAID: CA2802205
Variant2: c.1148G>A (p.Arg388His)
Variant2ClinVarID: 558189
Variant2CAID: CA2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4F41.23.3
Case#:Patient Sample unique ID 2
DiseaseAssertion:MPS type I-Hurler children
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:Obstructive sleep apnea, HP:0002870
CaseNotHPOFreeText:None
CaseEnzymeAssay:None
CaseUrineGAGs: Tested but amounts not reported
CaseERT:No
CaseBMT:Hematopoietic stem cell transplantation
Variant1:c.208C>T
Variant1ClinVarID:11909
Variant1CAID:CA204563
Variant2:c.1413C>G
Variant2ClinVarID:1094781
Variant2CAID:CA417702021
AdditionalVariants:None
ParentalGenotype:None provided
PreviouslyPublished:N/A
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:Q70X
Variant1ClinVarID:
Variant1CAID:
Variant2:Q380R
Variant2ClinVarID:550799
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Prenatal diagnosis of mucopolysaccharidosis type I on hepatosplenomegaly and coarse features: a case-report
PMID: 39754079
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
H240R
Case#: Family 29, UK
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The Scheie phenotype is characterized by aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation. This is a general assessment and not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
α-L-iduronidase activity in COS-7 cells transiently transfected with wild-type or mutagenised cDNAs. α-L-iduronidase activity: 5.6 nmol/h/mg cell protein; values are the means of two experiments.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.719A>G (p.H240R)
Variant2ClinVarID: 947028
Variant2CAID: CA355962127
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Q70X
Case#: Family 19, Slovenia
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
R619X
Case#: Family 5, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
IDUA gene mutations in mucopolysaccharidosis type-1 patients from two Pakistani inbred families
PMID: 31400021
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
22
Case#: Patient 22, born in 1995 (paper published in 2017), 8 months (age at first treatment). 2 years and 2 months (age at last treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 49.94 ng/mol (38.49 weight matched enzyme reference assay)
CaseUrineGAGs: 0.43 DS/CS
CaseERT: No
CaseBMT: Yes, Sib
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors
PMID: 33287330
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
T141S in exon 4, and IVS2+6c>t
Case#: Patient 3, Egyptian, female, 3 years old
DiseaseAssertion: MPS1-H
FamilyInfo: Parents were nonconsanguineous
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.421A>T (p.T141S)
Variant1ClinVarID: N/A
Variant1CAID: CA355961378
Variant2: c.299+6C>T (in the paper the variant is labeled as c.IVS2+6C>T which is old nomenclature)
Variant2ClinVarID: 92640
Variant2CAID: CA145880
AdditionalVariants: A8A, A20A, N297N, IVS11 (3318)C>A, IVS10 (3122)T>C - these are not the current nomenclatures for these variants but they are identified as polymorphisms in the article
ParentalGenotype: All mutations were confirmed in the parental DNA
PreviouslyPublished N/A
P10
Case#: P10, Female, 11.4 years (diagnosed), 15.8 (report), 31 kg (weight), 131 cm (height), Algerian
DiseaseAssertion: Hurler-Scheie Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0001433, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatosplenomegaly, Hernia(Ombelical), Deafness(perceptive), Corneal Opacity, Hydrocephalus)
CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Stenosis)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)
CaseUrineGAGs: GAG quantitation 46 (fold change to the reference range mean according to age)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Direct DNA Fragments Sequencing
Variant1: c.1598C>G (p.Pro533Arg)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.Pro533Arg)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
33/M
Case#: Patient 33, male, Han origin, 7 year 5 months old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay (HP:0001263)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 0.7 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.792+1G>C
Variant1ClinVarID: N/A
Variant1CAID: : CA355962280
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
31/F
Case#: Patient 31, female, Han origin, 9 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0000256, HP:0001387, HP:0001433, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Mongolian macula, Hernia (HP:0001263, HP:0011369, HP:0100790)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.3 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1037T>G (p.L346R)
Variant1ClinVarID: 11927
Variant1CAID: CA256128
Variant2: c.1037T>G (p.L346R)
Variant2ClinVarID: 11927
Variant2CAID: CA256128
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed by parental testing.
PreviouslyPublished N/A
3/M
Case#: Patient 3, male, Han origin, 1 year and 5 months old (age at diagnosis).
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 1.0 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.536C>G (p.T179R)
Variant1ClinVarID: 556358
Variant1CAID: CA355961718
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
Treatment of latent tuberculosis in a child with mucopolysaccharidosis type I receiving enzyme replacement therapy: A case report
PMID: 36052356
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Patients of family B
Case#: Family B proband, male, 1 year and 4 months old (age of onset), 3 years old (age at report), Tunisia.
DiseaseAssertion: MPS1-H
FamilyInfo: Three affected maternal cousins (one of them, 13 years old, was followed for convulsing encephalopathy and infirmity matrix, the other cousin, 3 years old, was followed in the same Pediatric Unit for encephalopathy). Parents were 2nd degree relatives (second cousins) (See Table 1).
CasePresentingHPOs: HP:0000256, HP:0001433, HP:0001263, HP:0002463, HP:0000470, HP:0000687, HP:0030812, HP:0000158, HP:0012471, HP:0001513 (Macrocephaly, hepatosplenomegaly, global developmental delay, language impairment, short neck, widely spaced teeth, enlarged tonsils, macroglossia, thick lips, obesity)
CaseHPOFreeText: Short trunk
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity (0.08 nmol/h/mg) (usual values: 1-5).
CaseUrineGAGs: Glycosaminoglycans (120 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.
CaseERT: No
CaseBMT: No
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Comment on “report of 5 novel mutations of the α-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I”
PMID: 30286738
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal Dominant
4
Case#: 4, Female, 0.3 years (diagnosed), 7.2 years (report), 23 kg (weight), 112 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0000943, HP:0001387 (Multiple Dysostosis, Joint Stiffness)
CaseHPOFreeText: HM/HSM
CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 1.27 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 13.27 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D257A
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
11
Case#: 11, Female, 0.5 years (diagnosed), 6.2 years (report), 14.5 kg (weight), 100 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are not consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0100790, HP:0000365, HP:0007957 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia, Deafness, Corneal Opacity, Hydrocephalus)
CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea
CaseNotHPOs: HP:0000238 (Hydrocephalus)
CaseNotHPOFreeText: Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 1.04 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 7.82 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D301E
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
16
Case#: 16, Male, 0.6 years (diagnosed), 5.5 years (report), 11.0 kg (weight), 66 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0100790 (Mental Retardation, Facial Dysmorphic Features, Hernia)
CaseHPOFreeText: HM/HSM
CaseNotHPOs: HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 0.89 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 8.5 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D301E
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Efficacy of recombinant human alpha-L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I patients
PMID: 20217237
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
730.248 (3.0)9.6DS 3.3heterozygous VUS: c.1744G>A; p.E582KNormal examinationHS 4.9heterozygous PD: c.235G>A; p.A79Theterozygous PD: c.296C>T; p.T99I
Case#:Patient Sample unique ID 73, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.248 (3.0) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 9.6 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 3.3 g/mol creatinine and HS 4.9 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:heterozygous VUS: c.1744G>A; p.E582K (Normal examination)
Variant1ClinVarID:538474
Variant1CAID:CA1944440
Variant2:heterozygous PD: c.235G>A; p.A79T
Variant2ClinVarID:41682
Variant2CAID:CA000358
AdditionalVariants:heterozygous PD: c.296C>T; p.T99I (ClinVarID:53610, CAID:CA326991)
ParentalGenotype:None provided
PreviouslyPublished:N/A
530.351 (4.2)6.9DS 4.6heterozygous PD: c.235G>A; p.A79TNormal examinationHS 3.3heterozygous PD: c.667G>A; p.D223N
Case#:Patient Sample unique ID 53, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.351 (4.2) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 6.9 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 4.6 g/mol creatinine and HS 3.3 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:heterozygous PD: c.235G>A; p.A79T (Normal examination)
Variant1ClinVarID:41682
Variant1CAID:CA000358
Variant2:heterozygous PD: c.667G>A; p.D223N
Variant2ClinVarID:2220838
Variant2CAID:CA363422841
AdditionalVariants: None
ParentalGenotype:None provided
PreviouslyPublished:N/A
patient
Case#: 20 months old, Male, 78 cm of height (-3 S.D.), 10 kg of weight (-3 S.D.), head circumference of 50.5 cm (>90th percentile).
DiseaseAssertion: Severe MPS-I
FamilyInfo: First son of healthy non-consanguineous parents with an unremarkable family history.
CasePresentingHPOs: Snoring, noisy breathing (since 3 months old), sleep apnea, upper airway obstruction, breathing cessation, cyanosis, facial dysmorphic features, short stature (since 8 months old), coarse facial features, scaphocephaly, mild corneal clouding, depressed nasal bridge, wide nose, anteverted nares, nasal congestion, long philtrum, thick lips, small and spaced teeth, low set ears, short neck, gibbus deformity, umbilical hernia, claw hands, global developmental delay, frontal bossing, Mongolia spots, dysostosis multiplex, scoliosis, broad ribs bilaterally (HP:0025267, HP:0010307, HP:0010535, HP:0002781, HP:0005943, HP:0000961, HP:0001999, HP:0004322, HP:0000256, HP:0030799, HP:0007957, HP:0005280, HP:0000445, HP:0000463, HP:0001742, HP:0000343, HP:0000219, HP:0000687, HP:0000369, HP:0000470, HP:0002808, HP:0001537, HP:0034337, HP:0001263, HP:0002007, HP:0011369, HP:0000943, HP:0002650, HP:0000885)
CaseHPOFreeText: Had neonatal complications such as being late in crying and breathing. Hyporeactive Apgar 5/8 Silverman-Anderson 3/2. Upper airway infections, bulging frontal bone, enlarged tongue, short trunk, protruding abdomen. The liver edge was palpated 2 cm below the right costal margin and had blue cutaneous pigmentation with dorsal distribution. Limited extension of the arms and small joints. No ability to walk or speak at the age of 20 months. Lumbar gibbus with vertebral hypoplasia. Hand bullet-shaped phalanges and widened metacarpals pointed proximally. Widened diaphysis and cortical thinning of long bones. Pelvis with rounded or flared iliac wings.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity of 0.24 μmol/L/h, enzymatic IDUA activity was 10 times less than the reference minimum level of this enzyme (2.02–16.10 μmol/L/h).
CaseUrineGAGs: N/A
CaseERT: Yes - at 2 years of age
CaseBMT: N/A
Variant1: c.1898C>G (p.S633W)
Variant1ClinVarID: 286242
Variant1CAID: CA10605410
Variant2: c.1898C>G (p.S633W)
Variant2ClinVarID: 286242
Variant2CAID: CA10605410
AdditionalVariants: N/A
ParentalGenotype: Sequence analysis of parental genomic DNA showed that both parents are heterozygous for c.1898C>G variant, with no clinical phenotype of MPS I. Enzymatic IDUA activity was 1.29 μmol/L/h and 3.25 μmol/L/h for the father and the mother, respectively. These levels were 5.4 and 13.5 higher than the ones observed in the patient, respectively. The low enzyme activity observed in the father, which would be expected to be greater because he is a heterozygous with a normal allele, could be explained by a condition known as pseudodeficiency, in which clinically normal individuals shows levels of enzyme activity below the normal levels.
PreviouslyPublished N/A
1
Case#: Patient 1: Enrolled in study at 18 years, male, onset at 3 years, diagnosed at 14.8 years, ERT started 16.7 years DiseaseAssertion:MPS1 H-S FamilyInfo:Consanguinity Yes CasePresentingHPOs:Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), CaseHPOFreeText: CaseNotHPOs: Hepatosplenomegaly (HP:0001433), Macrocephaly (HP:0000256) CaseNotHPOFreeText: CaseEnzymeAssay: CaseUrineGAGs: 1.07(min)-3.08(max) mg GAG/mmol creatinine while on ERT CaseERT: Laronidase dose-optimization trial : standard regimen – 0.58 mg/kg/week; biweekly regimen – 1.2 mg/kg every two weeks CaseBMT:Nil Variant1:P533R Variant1ClinVarID:11910 Variant1CAID:CA256112 Variant2:P533R Variant2ClinVarID:11910 Variant2CAID:CA256112 AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA
Patient 1
Case#:2.2 year female, diagnosed at 0.9 years DiseaseAssertion:MPS1H FamilyInfo:NA CasePresentingHPOs:NA CaseHPOFreeText:NA CaseNotHPOs:NA CaseNotHPOFreeText:NA CaseEnzymeAssay:Undetectable CaseUrineGAGs:NA CaseERT:NA CaseBMT:Yes, Unrelated cord blood, Post HSCT <br /> 29.3 nmol/h/mg of protein ( α-l-Iduronidase Levels) Variant1:IDUA : c.457A>T Variant1ClinVarID:917689 Variant1CAID: Variant2:IDUA: c.1205G>A Variant2ClinVarID: 11908 Variant2CAID:CA220498 AdditionalVariants: ParentalGenotype: PreviouslyPublished
12 base pairs
Case#: One patient from Norway
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.134del12 (p.Arg45ProfsTer?)
Variant1ClinVarID: N/A
Variant1CAID: CA3064219537
Variant2: c.134del12 (p.Arg45ProfsTer?)
Variant2ClinVarID: N/A
Variant2CAID: CA3064219537
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
1 nonsense mutation
Case#: One patient whose country of origin is not identifiable.
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1861C>T (p.R621X)
Variant1ClinVarID: 11917
Variant1CAID: CA256118
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
6
Case#: Patient 6 (see Table 2), male, 16.7 years old (age at report), 10.4 years (duration of treatment), 4 surgeries
DiseaseAssertion: MPS1-HS
FamilyInfo: N/A
CasePresentingHPOs: HP:0002360 (Sleep abnormality)
CaseHPOFreeText: Psychiatric problems
CaseNotHPOs: HP:0000238, HP:0002176 (Hydrocephalus, spinal cord compression)
CaseNotHPOFreeText: Shunt placement
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.712T>A (p.L238Q) CDNA and protein change do not match. Known variant p.L238Q has a CDNA change of c.713T>A.
Variant1ClinVarID: 265418
Variant1CAID: CA2802065
Variant2: (Int3-2a>g) Current HGVS nomenclature is c.386-2A>G.
Variant2ClinVarID: 222994
Variant2CAID: CA356991
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
older sibling
Case#: OS of sibship 3, female, 1 year old (age at diagnosis), 12 years old (age at ERT enrollment), 8 years (duration of ERT)
DiseaseAssertion: MPS1-HS
FamilyInfo: Affected female YS (YS of sibship 1)
CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0010862, HP:0002194 (Corneal opacity, dysostosis, joint contractures, cognitive delay, delayed fine motor development, delayed gross motor development)
CaseHPOFreeText: Cardiac disease, moderate musculoskeletal disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes - After ERT all existing symptoms persisted or progressed in this sibling except for improvement in organomegaly.
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/a
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease
PMID: 34257302
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal Recessive
D5
Case#: Patient D5, Druze religious group, located in lower Galilee.
DiseaseAssertion: N/A
FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1096A>C (p.T366P)
Variant1ClinVarID: 11916
Variant1CAID: CA:256117
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
M3)
Case#: Patient M3, Muslim religious group, located in Gaza. The cells of the patient were listed in the catalog of the Human Genetic Mutant Cell Repository as "Hurler/Scheie". However, the patient at age 6 years had been described as having a typical MPS1-H phenotype except for apparently normal intelligence (measured across a language barrier).
DiseaseAssertion: MPS1-H/S or MPS1-H
FamilyInfo: Parents were found to have both mutations were found in heterozygous form in the DNA. Affected brother deceased at age 9.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1225G>A (p.G409R)
Variant1ClinVarID: 1084956
Variant1CAID: CA91169920
Variant2: (p.X654C)
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
M1
Case#: Patient M1, Muslim religious group, located in lower Galilee.
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.192C>A (p.Y64X)
Variant1ClinVarID: 11914
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
26
Case#: Patient 26 (Table 3)
DiseaseAssertion: Severe naïve MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
38
Case#: Patient 38 (Table 3)
DiseaseAssertion: Severe MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 59.4 DBS protein concentration determined by Immuno-SRM (pmol/L).
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
40
Case#: Patient 40 (Table 3)
DiseaseAssertion: Severe MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 7 nmol/h/mg per DBS (dried blood spots) determined during NBS. 469.4 DBS protein concentration determined by Immuno-SRM (pmol/L). 15.98 relative protein abundance, expressed as the ratio between IDUA/GAA (amol / fmol) in buccal swabs.
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
10 MPS I patients
Case#: MPS 1 patient
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1918_1927del p.E640Cfs
Variant2ClinVarID: N/A
Variant2CAID: CA2586965997
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Growth in individuals with attenuated mucopolysaccharidosistype I during untreated and treated periods: Data from theMPS I registry
PMID: 35869927 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive
Two other IDUA mutations occurred in CpG dinucleotides (678 G→A and Y202X) and were found in the same patient, along with M133I. The analysis of parental DNA showed that the mutation M133I was linked to the Y202X mutation in the father whereas the other mutation (678 G→A) was maternally inherited. The 678 G→A mutation, a transition in the first base of intron 6, is also a splice site mutation that would cause the change of a glycine to an aspartic acid in position 196 of the protein. However, since skin fibroblasts from this patient were not available, it was not known whether mutant mRNA coding for the G197D α-l-iduronidase was produced. Therefore, this IDUA change was considered only as a splice mutation and was not expressed in CHO-K1 cells.
Case#: Patient #19, Brazilian
DiseaseAssertion: MPS1, severe(Hurler)
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: underwent bone marrow transplant
CaseNotHPOs:
CaseNotHPOFreeText:
Genotyping Method: Patients were screened for 10 known mutations using PCR and restriction enzymes and all 14 exons of the IDUA gene were amplified and analyzed by single strand conformational polymorphism (SSCP) analysis. PCRs were performed and sequenced using the big dye terminator kit and an ABI 373 automated sequencer (Applied Biosystems). Mutations were confirmed by sequencing the reverse strand using the same method.
PreviouslyPublished: n/a
Variant: allele 1: M133I/ Y202X (father); allele 2: 678 G→A (mother)
other changes: A8, A20, Q33H, L118
ClinVar: CA355961907
215
Case#: 215 12.1 yrs male, age at initial diagnosis 3.6 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 5.6 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months
CaseBMT: No PreviouslyPublished Don't know Variant1:p.P533R Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:
213
Case#: 213 15.7 yrs male, age at initial diagnosis 3.7 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 12 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months Variant1: p.R383H Variant1ClinVarID: 558189 Variant1CAID: Variant2:p.W402X Variant2ClinVarID: 11908 Variant2CAID: CA220498 AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA
4
Case#: Patient 4, male
DiseaseAssertion: MPS I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Low IDUA enzyme activity 2.06 (Ref. 4.87 ~ 54.70 μmol/g protein/h)
CaseUrineGAGs: Negative GAG tests
CaseERT: N/A
CaseBMT: N/A
Variant1: c.355G>T (p.D119Y)
Variant1ClinVarID: 2432701
Variant1CAID: CA2801882
Variant2: c.617C>T (p.S206L)
Variant2ClinVarID: 1436435
Variant2CAID: CA2802033
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N//A
7
Case#: Patient 7 (see Table 1), 13 years old (age at report), 5 years old (age at onset), female, height of 110 cm, weight of 15 kg, location at Djerba: Land
DiseaseAssertion: MPS1 - intermediate
FamilyInfo: One affected siblings (Patient 6), parents were 1st cousins (see Table 2), parents have the same grandfather but with a different wife (see Table 4), aged 40 yrs (M) and 49 yrs (F).
CasePresentingHPOs: HP:0004322, HP:0001999 (Short stature, moderate facial dysmorphia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA:256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA:256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4/f
Case#: Patient 4, female, 10.9 months (age at diagnosis), 16.5 months (age at HSCT), 8.3 - 17.3 months (age at ERT), 7 MRI + neuropsychological observations over the course of 11 years.
DiseaseAssertion: MPS-1H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 67.7 nmol/h/mg (Normal values: 11-43 nmol/h/mg)
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: Yes
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1487C>G (p.P496R)
Variant2ClinVarID: 496861
Variant2CAID: CA2802275
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
case 2
Case#: Case 2, male, 5 years old (age at diagnosis).
DiseaseAssertion: MPS1
FamilyInfo: Proband's mother was pregnant and her genomic DNA was extracted from cultured amniocytes, her fetus acquired the same pathogenic gene as the proband and was affected.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Proband was diagnosed using enzymatic detection. IDUA enzyme activity in the mother's amniotic fluid cells in the 2nd pregnancy was 0.5 nmol/(h·mg protein).
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.530dupT, in the article this is written as c.531insT (old nomenclature). Various variants from Wang articles have nomenclature errors that are 1 base pair off from the described variant.
Variant1ClinVarID: N/A
Variant1CAID: CA2586973520
Variant2: c.1037T>G (p.Leu346Arg)
Variant2ClinVarID: 11927
Variant2CAID: CA256128
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 10, Turkish
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1882C>T (p.R628X)
Variant1ClinVarID: 550421
Variant1CAID: CA2802462
Variant2: c.1882C>T (p.R628X)
Variant2ClinVarID: 550421
Variant2CAID: CA2802462
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3/F
Case#: Patient 3, female, Russian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Severe intellectual disability, corneal clouding, skeletal deformities, hepatosplenomegaly (HP:0010864, HP:0007957, HP:0000924, HP:0001433)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.05 nmol/mg/h (reference range 135 ± 57 nmol/mg/h)
CaseUrineGAGs: 265.24 mg GAG/mmol/creatinine (reference range 6.17 ± 3.79 mg GAG/mmol creatinine)
CaseERT: No
CaseBMT: No
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
PM 29 35 F ? ? - - - - - VHL FLD – BRK1, FANCD2
PatientID: 29
KindredID: PM
Case: F, 35Y0M, Indian
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0001737 (Pancreatic cysts)
CaseHPOFreeText: Multi-cystic pancreatic lesions.
CaseNotHPOs: HP:0010797; HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Hemangioblastoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Complete Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.
MutationType: deletion
CivicName: Deletion
MultipleGeneVariants: N/A
NS 21 35 M ? - ? ? ? - - Exon 3 del – a, distal b
PatientID: 21
KindredID: NS
Case: M, 35Y0M, Indian
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0009711; HP:0010797; HP:0005584 (Retinal capillary hemangioma, Hemangioblastoma, Renal cell carcinoma)
CaseHPOFreeText: RCC, retinal angioma and CNS hemangioblastoma.
CaseNotHPOs: HP:0001737; HP:0030393; HP:0002666 (Pancreatic cysts, Endolymphatic sac tumor, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Exon 3 Deletion (c.464-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 3 Deletion
MultipleGeneVariants: N/A
We applied our custom NGS panel to samples from 12 patients previously diagnosed by Sanger sequencing as having the diseases or diagnosed clinically by meeting the diagnostic criteria in this study.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: gene panel of 23 genes selected according to the ACMG recommendations for reporting of incidental findings, but excluding genes not related to hereditary tumors. Exons of target genes were amplified and sequenced.
SamplingMethod: peripheral blood
VON HIPPEL-LINDAU SYNDROME PRESENTING AS PHEOCHROMOCYTOMA COMPLICATED WITH MYOCARDIAL INFARCTION: A CASE REPORT
PMID: N/A - No PMID
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
Locate: Abstract can be found at: https://journals.lww.com/jhypertension/Abstract/2021/04001/VON_HIPPEL_LINDAU_SYNDROME_PRESENTING_AS.761.aspx
Cite: Yu, Huizhen, Lin, Lichao, Yu, Peng, Chen, Qing, Deng, Chaochao. Von Hippel-Lindau Syndrome Presenting as Pheochromocytoma Complicated with Myocardial Infarction: A Case Report. Journal of Hypertension: April 2021 - Volume 39 - Issue - p258 doi: 10.1097/01.hjh.0000747400.32772.50
Patient and Tissues All tissue specimens were obtained from an autopsy of one VHL patient. The patient had a documented VHL germline mutation (partial deletion). Specimens of several neoplastic lesions and grossly normal-appearing tissues were fixed in formalin and embedded in paraffin. The patient had been treated in compliance with the National Institutes of Health Internal Review Board (protocol number 03N0164).
PatientID: 1
KindredID: 1
Case: Sex Unknown, Age Unknown (deceased), Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009713; HP:0002894 (hemangioblastoma; renal cell carcinoma; pancreatic cyst; spinal hemangioblastoma; neoplasm of the pancreas)
CaseHPOFreeText: All tissue specimens (kidney, brain, spinal cord, and pancreas) were obtained from an autopsy of this VHL patient. The 16 lesions from the autopsy included 3 central nervous system hemangioblastomas, 7 renal cell carcinomas, 3 cystic renal structures, 2 pancreatic tumors, and 1 pancreatic cyst.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Partial deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: By studying several VHL-associated tumors and precursor lesions from this patient, there is possible biological effects of the “second hit” independent of the germline mutation (first hit).
MutationType: deletion
CivicName: Null (Partial deletion)
MultipleGeneVariants: N/A
In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family
PatientID: 21
KindredID: 1
Case: F, 23Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: This patient was a member of family 1, where 14/32 total patients were diagnosed with VHL. One of which (I-32) was a mutational carrier with down syndrome. The other 13 patients had varying phenotypes, including adrenal pheochromocytoma, pancreatic endocrine tumors, liver and bone metastases, paraganglioma, cerebellar, spinal, and retinal hemangioblastomas, polycythemia, and chondrosarcoma. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0006748; HP:0009711 (adrenal pheochromocytoma; retinal capillary hemangioma)
CaseHPOFreeText: Patient presented with his initial VHL-related clinical manifestations at 11Y0M. She had adrenal pheochromocytoma and retinal capillary hemangioma. She was diagnosed with VHL subtype 2A(see table 1).
CaseNotHPOs: HP:0002668 (paraganglioma)
CaseNotHPOFreeText: Patient does not have paraganglioma.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.V166F (c.496G>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: V166F (c.496G>T)
MultipleGeneVariants: N/A
PatientID: N/A
KindredID: 2034
Case: Age unknown, Sex unknown, Ethnicity unknown
DiseaseAssertion: assumed VHL
FamilyInfo: Paper states familial VHL; germline mutation
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (hemangioblastoma; retinal capillary hemangioma; renal cell carcinoma)
CaseHPOFreeText: Patient had CNS HB, RA and a Grawitz tumor (RCC)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 32179488
SupplementalData: Yes (Specifically Supp. Table S2)
Variant: p.F76del (c.227_229delTCT)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: F76del (c.227_229delTCT)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 14482
Case: Age unknown, Sex unknown, Belgian
DiseaseAssertion: VHL
FamilyInfo: Paper states: Belgian family; Germline mutation
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: None (Son 2)
KindredID: 25
Case: M, Age Unknown, Korean
DiseaseAssertion: VHL
FamilyInfo: Familial VHL. Two sons and a daughter presented with the same VHL germline mutation. All of these children presented with CNS hemangioblastomas. One of these sons also had renal cell carcinoma and was noted to have further unspecified phenotypes. His sister also had co-occurring unspecified phenotypes.
CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.
CasePresentingHPOs: HP:0005584; HP:0010797 (Renal cell carcinoma, Hemangioblastoma)
CaseHPOFreeText: Multiple or bilateral CNS hemangioblastomas and renal cell carcinoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).
CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 19270817 and/or 19949673
SupplementalData: N/A
Variant: c.340+5G>C
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/
CAID: N/A
gnomAD: 0.01119, https://gnomad.broadinstitute.org/variant/3-10183876-G-C?dataset=gnomad_r2_1
VariantEvidence: This variant has a large allele frequency and therefore is likely non disease causing (polymorphism).
MutationType: missense_variant;transversion; splice_site_variant
CivicName: Splice Region (c.340+5G>C)
MultipleGeneVariants: N/A
Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced. Patient 29, 47Y female, and her daughter presented with multiple and/or bilateral pheochromocytoma. The proband also presented with CNS and retinal hemangioblastomas. Both family members had the c.361G>A (p.D121N) germline VHL variant. The probands phenotypes were revised from a previous report in PMID 16142346 and was previously reported by Yang et al., in 2005 (reference 20 in the current paper). The proband was diagnosed with VHL Type 2A and her daughter with VHL Type 2C.
GroupID: 28
Case: 24Y0M, Sex Unknown, Ethnicity Unknown
DiseaseAssertion: retinal capillary hemangioma
FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.
CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)
CaseHPOFreeText: patient had retinal capillary hemangioma diagnosed at 24Y
CaseNotHPOs: HP:0002666; HP:0006880; HP:0005584 (pheochromocytoma; cerebellar hemangioblastoma; renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.L153Tfs*21 (c.456dupA)
LegacyVariant: c.455_456insA
CaseProblemVariantFreeText: c.455_456insA automaps to c.456dupA due to redundancy
ClinVarID: N/A
CAID: CA2499307154 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499307154
gnomAD: N/A
VariantEvidence: N/A
MutationType: duplication
CivicName: T152fs (c.455insA)
MultipleGeneVariants: N/A
GroupID: 18
Case: 28Y0M, Sex Unknown, Ethnicity Unknown
DiseaseAssertion: retinal capillary hemangioma
FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation was found in 1 VHL family with a single patient.
CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)
CaseHPOFreeText: patient had retinal angiomas diagnosed at 28Y
CaseNotHPOs: HP:0005584; HP:0002666; HP:0006880 (renal cell carcinoma; pheochromocytoma; cerebellar hemangioblastoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table S1.
Variant: p.R113Efs*46 (c.337del)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: CA432420675 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.337del
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_1_frameshift_variant
CivicName: R113FS (c.337delC)
MultipleGeneVariants: N/A
We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families
GroupID: 3
DiseaseAssertion: VHL
GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A
GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.
GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0001737; HP:0030405 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Pancreatic cysts, Pancreatic neuroendocrine tumor)
GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst, Retinal capillary hemangioma (2), Hemangioblastoma/cerebellum/brain (2), Pancreatic cysts (2), Pancreatic neuroendocrine tumor (1).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplemental Table 2, Table 1, Table 3
Variant: Exon 1 Deletion (c.1-?_340+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1 Deletion
MultipleGeneVariants: N/A
We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families.
GroupID: 37
DiseaseAssertion: VHL
GroupSize: N/A GroupNumberMales: 0 GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A
GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.
GroupPresentingHPOs: HP:0005584; HP:0009711; HP:0009713 (Renal cell carcinoma, Retinal capillary hemangioma, Spinal hemangioblastoma)
GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Retinal capillary hemangioma (1), Spinal hemangioblastoma (1)
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplemental Table 2, Table 1, Table 3
Variant: Exon 1-3 Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: Exon 1-3 Deletion
MultipleGeneVariants: N/A
Meanwhile, it was also found that the guanine replaced the 559th cytosine on one patient and two carriers from the third family, which made the 116th leucine replaced by valine.
This study shows the clinical characteristics of three large Chinese families with VHL disease and evaluates the consequence of the genetic test for the diagnosis of VHL disease and clinical screening of the family members. DNA is extracted from peripheral blood in 43 members from three large families with VHL disease and amplified by PCR to three exons of the VHL gene. The PCR products were directly sequenced and the mutations compared with the Human Gene Mutation Database. The ages of the patients who are given the initial diagnosis ranged from 16 to 47 years (mean: 31 years), and the mean time was 17.3 months (2-30 months) from the emergence of the symptom to patients' first visit. Furthermore, the gender distribution was 20% female (4) and 80% male (16). VHL phenotypes of the disease is seen in 8 members of a Chinese family. Molecular diagnosis is confirmed in only 3 family members, as 5 died prior to genetic testing. These 5 could be assumed due to pedigree showing future linear relations of this mutation. The mutation p.L116V (c.346C>G) was referred to in the paper by c.559C>G due to a difference in transcript sequence. Manifestations in this family include CNS hemangioblastoma, and renal cysts. The proband (female) had renal cysts and hemangioblastoma, and 2 of her brothers and their 3 children (2 male; 1 female) had hemangioblastomas. The clinical manifestations were characterized by early morbidity, rapid progress, high relapse rate, and high mortality rate. There are two members who are asymptomatic, but they are young (likely before the age of onset). ACMG evidence codes: 'PP1' based on segregation results, 'PP2' because they observe a missense variant in gene where missense variants are common mechanism of disease, 'PP4' because the patients phenotypes and family history are highly specific for a disease with single genetic etiology.
Meanwhile, it was also found that the guanine replaced the 559th cytosine on one patient and two carriers from the third family, which made the 116th leucine replaced by valine.
PatientID: III-2
KindredID: 3
Case: F, Age Unknown (deceased), Chinese
DiseaseAssertion: CNS Hemangioblastoma
FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including III-2, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L116V (c.346C>G) [assumed]
LegacyVariant: p.L116V (c.559C>G) [assumed]
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG
gnomAD: N/A
VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this deduction
MutationType: missense_variant;transversion
CivicName: L116V (c.346C>G)
MultipleGeneVariants: N/A
P9PCC VHL c.292T>C
PatientID: P9
KindredID: 6
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 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: None (Maternal Grandmother)
KindredID: 1
Case: F, 33Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Look to proband for more information on family history.
CasePresentingHPOs: HP:0006880; HP:0009711 (Cerebellar hemangioblastoma, Retinal capillary hemangioma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 25494863
SupplementalData: Figure 1
Variant: p.G114R (c.340G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223193, https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/
CAID: N/A
gnomAD:
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: G114R (c.340G>C)
MultipleGeneVariants: N/A
One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). The c.224_226del (p.F76del) in-frame deletion (noted as c.440delTCT (p.F147del) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred no.48, and kindred no. 75. The affected patient(s) in both kindreds had VHL type 1 (no pheochromocytoma). Pheochromocytoma was not observed in any members of either kindred. ACMG evidence codes: none.
c.241C>T2 (2)2a/b47 (34–59)HBr, HBc, HBsc, RCC, pNET, Pheo, Cr
GroupID:None
DiseaseAssertion:VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Dutch
GroupAgeRange: 34-59
GroupInfo: 2 out of 82 individuals were grouped together based on all having the c.241C>T mutation. This group was classified as 2a/b meaning that it included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.
GroupPresentingHPOs: HP:0009711, HP:0006880, HP:0009713, HP:0005584, HP:0030405, HP:0002666, HP:0000107 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Pancreatic endocrine tumor, Pheochromocytoma, Renal cyst)
GroupHPOFreeText: It is unclear if both patients in this group had all of these presentations or if they were only affected by a subset.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.P81S (c.241C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/
CAID: N/A
gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: P81S (c.241C>T)
MultipleGeneVariants: N/A
Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene
PMID: 28849724 Gene: VHL StandardizedReferenceSequence: NM_000551.3
PatientID: 114
KindredID: 114
Case: Sex Unknown, 27Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the pancreas)
CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pancreatic cyst or tumor.
CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished:N/A
SupplementalData: Table S1, S2 and S3
Variant: Partial Deletion (12kb)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Partial deletion of 12kb
MultipleGeneVariants: N/A
PatientID: 218
KindredID: 218
Case: Sex Unknown, 17Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Positive VHL family history.
CasePresentingHPOs: HP:0010797 (hemangioblastoma )
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0009711, HP:0001737, HP:0002666, HP:0000107, HP:0006770 (retinal capillary hemangioma, pancreatic cyst, pheochromocytoma, renal cyst, clear cell renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Table S1, S2, S3.
Variant: p.R161* (c.481C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: CA020408 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.481C%3ET
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R161*(c.481C>T)
MultipleGeneVariants: N/A
PatientID: 384
KindredID: 384
Case: Sex Unknown, 40Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family history is positive but no details provided.
CasePresentingHPOs: HP:0001732; HP:0006770 (Abnormality of the pancreas, Clear cell renal cell carcinoma)
CaseHPOFreeText: Clear cell renal cell carcinoma and pancreatic cyst or tumor.
CaseNotHPOs: HP:0010797; HP:0002666; HP:0000107; HP:0009711 (Hemangioblastoma, Pheochromocytoma, Renal cyst, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished:N/A
SupplementalData: Table S1, S2 and S3
Variant: Complete Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Null (Complete deletion)
MultipleGeneVariants: N/A
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: N/A - not specified
SamplingMethod: N/A - not specified
PatientID: 147
KindredID: 53
Case: F, 18Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband's mother presented with a CNS hemangioblastoma at age 17. She passed away before she could be diagnosed/ genetically confirmed with the same mutation as her daughter.
CasePresentingHPOs: HP:0010797 (Hemangioblastoma)
CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 18.
CaseNotHPOs: HP:0009711; HP:0002666; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: c.464-1G>A
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43603, https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.464-1G>A)
MultipleGeneVariants: N/A
PatientID: 218
KindredID: 81
Case: M, 26Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The patient's sister (the proband) had the same germline mutation, and presented with a CNS hemangioblastoma at 24, renal cell carcinoma at 32, and multiple pancreatic cysts/tumors at 33. The proband's mother had a CNS hemangioblastoma at 35, however no genotyping information is available for her.
CasePresentingHPOs: HP:0010797; HP:0002666 (Hemangioblastoma, Pheochromocytoma)
CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at age 20, and a pheochromocytoma at age 26.
CaseNotHPOs: HP:0009711; HP:0005584; HP:0001737; HP:0001732 (Retinal capillary hemangioma, Renal cell carcinoma, Pancreatic cysts, Abnormality of the pancreas)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: 2
KindredID: 2
Case: M, 48Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: The proband's son also had this mutation, and presented with a CNS hemangioblastoma at age 22. The proband's mother presented with a CNS hemangioblastoma at age 61, and his brother presented with a CNS hemangioblastoma at age 33. His mother passed away before diagnosis, and there was no DNA sample available for his brother.
CasePresentingHPOs: HP:0005584; HP:0001732; HP:0001737 (Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts)
CaseHPOFreeText: The proband presented with renal cell carcinoma and pancreatic cysts at the age of 48.
CaseNotHPOs: HP:0010797; HP:0009711; HP:0002666 (Hemangioblastoma, Retinal Capillary Hemangioma, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).
SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.
Variant: p.S65W (c.194C>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43597, https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/
CAID:
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: S65W (c.194C>G)
MultipleGeneVariants: N/A
1p.F76del>18YAffected3 Hb, KC+ PC
PatientID: None (I)
KindredID: 1
Case: Sex and Ethnicity unknown; Age >18Y0M
DiseaseAssertion: assumed VHL
FamilyInfo: Total of 4 family members belonging to Family 1 (see Table 2; or follow KindredID 1)
CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001737 (hemangioblastoma, renal cyst, pancreatic cysts)
CaseHPOFreeText: 3 HB, 1 kidney cyst at first screening, as well as now pancreatic cyst at final screening (5 year follow up).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 16572651
SupplementalData: N/A
Variant: p.F76del (c.227_229del)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 223166 https://www.ncbi.nlm.nih.gov/clinvar/variation/223166/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: p.F76del
MultipleGeneVariants: N/A
4 France c.500G>A p.Arg167Gln Italy
GroupID: 29
DiseaseAssertion: VHL
GroupSize: 4
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: Four registrants from France or Italy have the same mutation of c.500G>A
GroupPresentingHPOs: HP:0030393 (Endolymphatic sac tumor)
GroupHPOFreeText: N/A
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PARS PLANA VITRECTOMY IN ADVANCED CASES OF VON HIPPEL–LINDAU EYE DISEASE
PMID: 26308528
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
GroupID: 63
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Japanese
GroupAgeRange: N/A
GroupInfo: 3 individuals from a single family (ID 63).
GroupPresentingHPOs: HP:0001732; HP:0005584; HP:0010797 (Abnormality of the pancreas, Renal cell carcinoma, Hemangioblastoma)
GroupHPOFreeText: CNS hemangioblastoma (2/3), renal cell carcinoma (3/3) and pancreatic cyst or tumor (unspecified) (1/3).
GroupNotHPOs: HP:0009711 (Retinal capillary hemangioma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.S168Tfs*2 (c.503_513del)
LegacyVariant: c.716_726del (c.716del11bp)
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA2573131812, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2573131812
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion; minus_2_frameshift_variant
CivicName: S168Tfs*2 (c.503_513del)
MultipleGeneVariants: N/A
Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: an extended study of 77 families
PMID: 10761708
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: None
KindredID: 80
Case: Sex Unknown, Age Unknown, Japanese
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797; HP:0001732; HP:0005584 (Hemangioblastoma, Abnormality of the pancreas, Renal cell carcinoma)
CaseHPOFreeText: CNS hemangioblastoma, renal cell carcinoma and pancreatic tumor or cyst (unspecified).
CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.F76del (c.227_229del)
LegacyVariant: c.437_439del
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA357012, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229del
gnomAD: N/A
VariantEvidence: Variant reported as c.437_439del and mapped to c.224_226del which is equivalent to c.227_229del.
MutationType: inframe_deletion; deletion
CivicName: F76del (c.227_229del)
MultipleGeneVariants: N/A
A 40-year-old woman was admitted to our hospital for further evaluation of a left RCC that had been found during a routine checkup. Computed tomography of the abdomen showed multiple, small tumors (≤10 mm in diameter) in the head of the pancreas as well as a left renal mass, measuring 8×7×6 cm in size (Fig. 1a). Selective abdominal angiography (via the celiac and supramesenteric arteries) disclosed numerous small tumor stains in the pancreatic head (Fig. 1b). Multiple pancreatic metastases from the left RCC were first suspected. Pancreatic microadenomatosis of MEN1 syndrome was also suggested, but no other lesions related to this syndrome (such as pituitary adenoma, parathyroid adenoma, or adrenocortical tumor) were observed. This patient had no clinical symptoms of inappropriate pancreatic hormone secretions such as insulin, glucagon, and gastrin.
PatientID: None
KindredID: 1
Case: F, 43Y0M, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: None
CasePresentingHPOs: HP:0006770, HP:0030405, HP:0004510 (clear cell renal cell carcinoma, pancreatic endocrine tumour, Pancreatic islet-cell hyperplasia)
CaseHPOFreeText: At age 40 the patient presented with left sided clear cell renal cell carcinoma, islet cell hyperplasia, and pancreatic endocrine tumour. 46 months later the patient has no evidence of recurrence.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: Both the hyperplastic islet cells and pancreatic microadenomas stained negatively for marker upon immunohistochemical testing for hypoxia-inducible factor (HIF)-1α.
MutationType: missense_variant; transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
226_228delTTC76F76del
A study of 34 Polish families revealed germline mutations in 30 families using DNA isolated from peripheral blood luykocytes to sequence through PCR and Quantitative Southern analysis. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This mutation was found in a VHL patient and 2 additional families. The patient had hemangioblastomas of the central nervous system and retina (family no. 6). In a family with two affected family members, 2 had hemangioblastomas of the central nervous system and 1 had retinal hemangioblastomas (family no. 7). A VHL family of 3 had 2 with hemangioblastomas of the central nervous system and 3 with retinal hemangioblastomas (family no. 5). Two members were published in a future publication: PMID: 32179488.
Complete deletion
GroupID/ KindredID: 28
PatientID: III
Case: 40Y0M, Sex unknown, Polish
DiseaseAssertion: VHL
FamilyInfo: Family 28 consisted of 4 members; one relative (age 27Y) was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs, another was diagnosed with a single cerebellar HAB at 24Y, and a final relative (62Y), diagnosed with a single HAB.
CasePresentingHPOs: HP:0009713; HP:0006880 (spinal hemangioblastoma, cerebellar hemangioblastoma)
CaseHPOFreeText: Patient was diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs
GroupNotHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma; renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: complete deletion of VHL gene
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Haplotype analysis information in Table 3
MutationType: deletion
CivicName: deletion
MultipleGeneVariants: N/A
Complete deletion
GroupID/ KindredID: 28
PatientID: I
Case: 27Y0M, Sex unknown, Polish
DiseaseAssertion: VHL
FamilyInfo: Family 28 consisted of 4 members; one relative (age 24Y) diagnosed with a single cerebellar HAB, another (40Y) diagnosed at 30Y with multiple cerebellar HABs, and multiple spinal HABs, and a final relative (62Y), diagnosed with a single HAB.
CasePresentingHPOs: HP:0009713; HP:0006880 (spinal hemangioblastoma, cerebellar hemangioblastoma)
CaseHPOFreeText: Patient was found with multiple cerebellar HABs at 25Y, and multiple spinal HABs
GroupNotHPOs: HP:0009711; HP:0005584 (retinal capillary hemangioma; renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: complete deletion of VHL gene
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Haplotype analysis information in Table 3
MutationType: deletion
CivicName: deletion
MultipleGeneVariants: N/A
KindredID: 4885
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666; HP:0005584; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma)
CaseHPOFreeText: The patient was also described to have cysts but the type or location was not specified.
CaseNotHPOs: HP:0009711; HP:0030405 (Retinal capillary hemangioma, Pancreatic endocrine tumor)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161* (c.481C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.R161* (c.694C>T)
ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: N/A
gnomAD: N/A
VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).
MutationType: stop_gained; missense_variant;transition
CivicName: R161* (c.481C>T)
MultipleGeneVariants: N/A
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: The entire coding and flanking regions of VHL underwent PCR and long PCR amplification and the products sequenced and re-sequenced to confirm.
SamplingMethod: peripheral blood
2. Presentation of CaseA 17-year-old girl was referred to our department for the investigation of a newly diagnosed diabetes mellitus and a severe arterial hypertension. She was the first child of consanguineous parents. Her past medical history was unremarkable. Her family history was notable for type 2 diabetes and dyslipidemia but no history of pheochromocytoma, paraganglioma, unexplained sudden death, or condition that may lead to thinking about VHL disease was reported.As symptoms, the patient complained of headaches, palpitations, diaphoresis, and hot flashes since one month. She reported also asthenia and body weight loss of five kilograms in two weeks.On examination, she had a body weight of 50 kg, a body height of 154 cm, a body mass index of 21.1 kg/m2, a blood pressure of 200/100 mmHg without orthostatic hypotension, a regular pulse of 120 bpm, and a large abdominal café-au-lait spot (Figure 1). Thyroid, abdominal, and neurological examinations were normal.Open in a separate windowFigure 1A large abdominal café-au-lait spot.Twenty-four-hour blood pressure monitoring confirmed the diagnosis of hypertension and the presence of peaks of 230/110 mmHg. Electrocardiogram showed a sinus tachycardia. Capillary glucose level was 2.68 g/l without ketosis.Fundoscopy showed grade 3 hypertensive retinopathy without any other abnormalities.The results of biological investigations are shown in Table 1.Table 1Biological parameters before and after surgery. Before surgeryAfter surgeryReference rangesFasting glucose level (mmol/l)16.394.784.12–5.55Glycated hemoglobin (%)10.125.91≤5.6Total cholesterol (mmol/l)11.835.233.1–5.18Triglycerides (mmol/l)2.431.210.57–1.71Natremia (mmol/l)135140135–145Kalemia (mmol/l)3.343.6–5Creatinine (mg/L)664–13Calcium (mg/L)111.29888–105Phosphate (mg/L)443627–45Albumin (g/l)47.22—35–52Intact PTH∗ (μg/L)1825411–62TSH (mUI/L)0.625—0.12–3.4FT4 (ng/dl)1.31—0.71–1.85Calcitonin (ng/L)2.70—<10.0024 h-urine NMN (μg/24)315057030–60024 h-urine MN (μg/24)40.21220–34524 h-urine sodium (mmol/24 h)88.5— 24 h-urine potassium (mmol/24 h)60— 24 h-urine calcium (mg/24 h)200— 24 h-proteinuria (g/24)0.3—<0.3Open in a separate windowPTH: parathormone, TSH: thyroid stimulating hormone, FT4: free-T4, NMN: normetanephrines, MN: metanephrines. ∗The intact PTH dosage was made using 3rd generation chemiluminescence immunoassay.The diagnosis of clinically suspected pheochromocytoma was confirmed by the dosage of urinary methoxylated derivatives at 5 times the upper limit of normal. In addition, the diagnosis of diabetes mellitus, dyslipidemia, and primary hyperparathyroidism were made.The abdominal computed tomography (CT) showed two adrenal masses: the first on the right measuring 35 × 55 × 70 mm with a spontaneous density of 30 HU heterogeneously enhanced in the arterial time showing areas of necrosis with an absolute washout of 40%, the second on the left measuring 24 × 27 mm with the same characteristics as the first one (Figure 2). There were neither other localizations nor lymph nodes. Metaiodobenzylguanidine (MIBG) scintigraphy exhibited a high accumulation of the tracer in both adrenal tumors with no other localization. Cervical ultrasound and 99mTc-sestamibi scintigraphy were normal. Cardiac ultrasound was normal.Open in a separate windowFigure 2Abdominal computed tomography showing the two adrenal masses (two white arrows).
PatientID: N/A (case)
KindredID: 1
Case: F, 18Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Not relevant - She was the first child of consanguineous parents. Her family history was notable for type 2 diabetes and dyslipidemia but no history of pheochromocytoma, paraganglioma, unexplained sudden death, or condition relevant to VHL. However, the family screening for VHL has not been performed.
CasePresentingHPOs: HP:0006748; HP:0000819; HP:0008200 (adrenal pheochromocytoma; Diabetes mellitus; hyperparathyroidism)
CaseHPOFreeText: First brought to clinic for newly diagnosed diabetes mellitus and severe arterial hypertension. As symptoms, the patient complained of headaches, palpitations, diaphoresis, and hot flashes since one month. She reported also asthenia and body weight loss of five kilograms in two weeks. Pheochromocytoma was confirmed. CT showed adrenal masses: Right measuring 35×55×70mm, and left measuring 24×27mm. She underwent a bilateral adrenalectomy in two steps. Pathological examination confirmed bilateral adrenal pheochromocytomas. 12 months post, follow up is clear.
CaseNotHPOs: N/A
CaseNotHPOFreeText: Thyroid, abdominal, and neurological examinations were normal.
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R64P (c.191G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2226 https://www.ncbi.nlm.nih.gov/clinvar/variation/2226/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: R64P (c.191G>C)
MultipleGeneVariants: N/A
Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients (Table 1).
PatientID: 2
KindredID: 2
Case: F, 28Y0M, Ethnicity unknown
DiseaseAssertion: pancreatic endocrine tumor
FamilyInfo: None
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)
CaseHPOFreeText: See Table 1 for more information
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
Eighteen VHL patients who underwent pancreatectomy for one or several endocrine tumors at Beaujon hospital from 1997 to 2008 were retrieved from the file of VHL patients (Table 1).
PatientID: 7
KindredID: 7
Case: M, 26Y0M, Ethnicity unknown
DiseaseAssertion: pancreatic endocrine tumor
FamilyInfo: None
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)
CaseHPOFreeText: See Table 1 for more information
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: N/A; Null (large rearrangement)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: rearrangement_region
CivicName: Rearrangement
MultipleGeneVariants: N/A
PatientID: V262
KindredID: V262
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
PatientID: 83 (Cousin)
KindredID: 18
Case: F, 50Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.
CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the pancreas)
CaseHPOFreeText: This patient presented with CNS hemangioblastoma (25Y), retinal angioma (16Y) and pancreatic tumors or cysts (undefined) (22Y).
CaseNotHPOs: HP:0005584; HP:0000077; HP:0002666 (Renal cell carcinoma, Abnormality of the kidney, Pheochromocytoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)
SupplementalData: Supplementary Table 1.
Variant: p.R167W (c.499C>T)
LegacyVariant: c.712C>T
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
PatientID: 8 (Mother)
KindredID: 3
Case: F, 43Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: 3 members of this family were genetically confirmed to be carriers of a germline partial deletion of exon 2 of the VHL gene. ID 2 presented with retinal angioma and pancreatic abnormality. ID 1 was asymptomatic. ID 16 presented with a retinal angioma (33Y), CNS hemangioblastoma at (32Y) and died at age 42. ID 16 was stated as having the germline variant but this was inferred from family/personal history and was not genetically confirmed.
CasePresentingHPOs: HP:0010797 (Hemangioblastoma)
CaseHPOFreeText: The patient presented with CNS hemangioblastoma (26Y and 40Y).
CaseNotHPOs: HP:0005584; HP:0001732; HP:0000077; HP:0002666; HP:0009711 (Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Pheochromocytoma, Retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary Table 1.
Variant: Exon 2 Partial Deletion
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Null (Partial deletion of Exon 2)
MultipleGeneVariants: N/A
WM03 VHL VHL 0.74
PatientID: WM03
KindredID: 9
Case: Sex Unknown, 3Y0M, Ethnicity Unknown
DiseaseAssertion: pheochromocytoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: MAX, RET, SDHA, SDHB, SDHC, SDHD, TMEM127
PreviouslyPublished: N/A
SupplementalData: Yes
Variant: Unspecified Exon 1 mutation
LegacyVariant: Unspecified Exon 1 mutation - no other information given
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: N/A
CivicName: N/A
MultipleGeneVariants: N/A
PatientID: 74
KindredID: 74
Case: Sex Unknown, 31Y0M, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Single benign PCC.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Patient information pulled from Supplemental Table 1a.
Variant: Complete Deletion (c.1-?_642+?del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: Carbonic anhydrase 9 (CA9) mRNA level of 34.31 was detected. Membrane CA9 immunostaining was observed.
MutationType: deletion
CivicName: Deletion
MultipleGeneVariants: N/A
PatientID: 47
KindredID: 47
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0002666 (Pheochromocytoma)
CaseHPOFreeText: Bilateral pheochromocytoma.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Patient information pulled from Supplemental Table 1b.
Variant: p.Y156S (c.467A>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351756049
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: Y156S (c.467A>C)
MultipleGeneVariants: N/A
171044N—N—YNYYYc.227_229delTCTExon 1p.Phe76delFrameshift
PatientID: 17
KindredID: 10
Case: Sex Unknown, 44Y0M, Brazilian (Latino/Admixed American)
DiseaseAssertion: VHL
FamilyInfo: None.
CasePresentingHPOs: HP:0001737; HP:0010797; HP:0005584; HP:0009711 (pancreatic cyst, hemangioblastoma, renal cell carcinoma, retinal capillary hemangioma)
CaseHPOFreeText: The patient at 44Y was confirmed with VHL. They developed pancreatic cyst, hemangioblastoma, renal cell carcinoma, and retinal capillary hemangioma
CaseNotHPOs: HP:0002668, HP:0002666; HP:0030405; HP:0000107 (paraganglioma, pheochromocytoma, pancreatic endocrine tumor, renal cyst)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.F76del (c.227_229delTCT)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: F76del (c.227_229del)
MultipleGeneVariants: N/A
Genomic DNA was extracted from peripheral blood, saliva, and fresh frozen tumor samples using conventional methods. Whole exome sequencing of the proband’s germline DNA was prepared using NimbleGen 44Mb SeqCap EZ Exome Kit v2, sequenced on a HiSeq 2000, and analyzed using filtering parameters previously reported (16), with the exception that synonymous variants of PHEO susceptibility genes were not excluded. Sanger sequencing of VHL from germline and tumor genomic DNA of affected and unaffected relatives was conducted as published (16). RNA was isolated from peripheral leukocytes and fresh frozen PHEO using TRIzol, according to the manufacturer’s guidelines. cDNA was generated as we previously reported (17). Sanger sequencing of leukocyte and tumor VHL cDNA was performed by amplification of VHL transcripts using primers spanning exon 1 and exon 2 (downstream of the c.414 variant) or exon 1 and exon 3 (primer sequences available upon request).
ArticleReferenceSequence: NM_000551.3 (Standard)
GenotypingMethod: Sanger sequencing.
SamplingMethod: peripheral blood.
Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease
PMID: 30946460
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
13 (17%) had large deletions,
PatientID: 78
KindredID: 78
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL (asymptomatic)
FamilyInfo: N/A
CasePresentingHPOs: None
CaseHPOFreeText: N/A
CaseNotHPOs:HP:0010797; HP:0006770; HP:0100634; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.
Variant: Deletion of 3p25.3
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: deletion
CivicName: Deletion
MultipleGeneVariants: N/A
Genetic screening and management The patient was investigated to determine if there was a genetic cause for her phaeochromocytoma. Neurofibromatosis type 1 was excluded on clinical grounds as she had none of the cutaneous features. Mutational analysis of the RET proto-oncogene was normal, making MEN2 unlikely. Sequencing of exons 1–3 of the VHL gene revealed a novel single base pair substitution (A268C). This replaces asparagine with histidine at codon 90 of VHL (N90H) and was not present in either parent. Another mutation at the same amino acid residue (N90I) has previously been reported in an individual with vHL disease,1 and in vitro studies indicate that this alters vHL function. Therefore, N90H is highly likely to be pathogenic.
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: Sequencing of exons 1–3 of the VHL gene revealed a novel single base pair substitution (A268C). Unclear of exact methods.
SamplingMethod: Unclear - investigated conducted to determine if there was a genetic cause.
PMID: 7977367
Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline p.76delF (c.227_229delTTC) mutation, stated in the paper as c.437_439delF due to an older transcript. It was seen in two families: [pedigree No] 17 and 20, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.
GroupID/ KindredID: VHL 56
DiseaseAssertion: assumed VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: German
GroupAgeRange: N/A
GroupInfo: 2 patients with the given mutation belonging to VHL family 56
GroupPresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)
GroupHPOFreeText: both (2) patients have retinal angioma and hemangioblastomas
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Q195* (c.583C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: p.Q195* (c.796C>T)
ClinVarID: 428794 https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/
CAID: CA70052558 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.583C%3ET
gnomAD: N/A
VariantEvidence: allele-specific oligonucleotide (ASO) probes and hybridization conditions confirmed
MutationType: missense_variant; transition
CivicName: Q195* (c.583C>T)
MultipleGeneVariants: N/A
481C>T Arg161X Germline mutation
PatientID: 51
KindredID: 51
Case: Age, sex, ethnicity unknown
DiseaseAssertion: hemangioblastoma
FamilyInfo: N/A
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R161* (c.481C>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: R161* (c.481C>T)
MultipleGeneVariants: N/A
A female patient presented with VHL disease at age 16, when a symptomatic left adrenal pheochromocytoma was diagnosed and removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. Molecular genetic testing revealed the mutation VHL c.500 G > A (p. R167Q).In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized
PatientID: 3
KindredID: 3
Case: F, 28Y0M, German
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0006748, HP:0006880, HP:0009713, HP:0030405, HP:0010302 (Adrenal pheochromocytoma, cerebellar hemangioblastoma, spinal hemangioblastoma, pancreatic endocrine tumour, spinal cord tumor)
CaseHPOFreeText: At age 16 she presented with a left adrenal pheochromocytoma which was removed laparoscopically. At age 28, a cystic cerebellar hemangioblastoma was removed. In 2010, she was admitted to the Freiburg Preventive Medicine Center. Baseline MRI detected multiple intraspinal hemangioblastomas associated with tumor cysts. Abdominal MRI also showed a 5.6 × 5.4 cm solid tumor in the pancreatic tail that was richly vascularized. Three of eleven lymph nodes showed metastases.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVar: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
Pancreatic involvement in von Hippel-Lindau disease: report of two cases and review of the literature
PMID: 16952288
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: VII-3
KindredID: 1
Case: F, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL (Asymptomatic)
FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666; HP:0002668 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma, Paraganglioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)
SupplementalData: N/A
Variant: p.Y112H (c.334T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y112H (c.334T>C)
MultipleGeneVariants: N/A
PatientID: III-6
KindredID: 1
Case: M, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.
CasePresentingHPOs: HP:0002666; HP:0002668; HP:0009711 (Pheochromocytoma, Paraganglioma, Retinal capillary hemangioma)
CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient). Deceased.
CaseNotHPOs: HP:0005584 (Renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)
SupplementalData: N/A
Variant: p.Y112H (c.334T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2222, https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y112H (c.334T>C)
MultipleGeneVariants: N/A
GroupID: 1
DiseaseAssertion: VHL
GroupSize:14
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 14 members of this family presented with the c.499C>T germline variant of the VHL gene. Members 296, 419, 295 and 414 had no renal involvement. Members 427, 318, 403 and 406 had unknown renal involvement. Members 402, 322, 403 and 1 had mild renal disease (RCC). Members 401 and 404 had moderate renal disease (RCC). 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.
GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)
GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 15 individuals and 3 families 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 reported individuals/families could alternatively correspond to family 23 or 50.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
PatientID: 9799
KindredID: 416
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: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.S43_E47del (c.123_137del)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA039321, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.123_137del
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion; deletion
CivicName: S43_E47del (c.123_137del)
MultipleGeneVariants: N/A
GroupID: 87
DiseaseAssertion: VHL
GroupSize: 3
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: French
GroupAgeRange: N/A
GroupInfo: 3 members of this family were found to harbor the c.466T>G germline variant of the VHL gene. Member 4587 presented with severe renal disease (RCC). Members 4588 and 5177 had unknown renal involvement. 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.
GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)
GroupHPOFreeText: 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).
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: 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.
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.Y156D (c.466T>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351756043, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.466T%3EG
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: Y156D (c.466T>G)
MultipleGeneVariants: N/A
PatientID: 2178
KindredID: 113
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: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.
Variant: p.V87A (c.260T>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA351750654, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.260T%3EC
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: V87A (c.260T>C)
MultipleGeneVariants: N/A
Genomic DNA was extracted from peripheral blood leukocytes using DNA isolation kit for mammalian blood (Roche Diagnostics GmbH). Mutation analysis of splice sites and exons 1, 2, and 3 of the VHL gene was performed by using direct sequencing of DNA samples amplified by PCR. PCR amplifications were carried out using modified oligonucleotide primers (24), which covered the exon–intron boundaries. Sequence analysis was performed by direct cycle sequencing using the SequiTherm Excel II DNA Sequencing Kit-LC (Epicentre Technologies, Madison, WI, USA) and an automated Li-COR IR2 sequencer (Li-COR Inc., Lincoln, NE, USA) or by direct cycle sequencing using the Big Dye Terminator Cycle Sequencing kit v3.1 (Applied Biosystems, Foster City, CA, USA), and run on an automated sequencer 310 Genetic Analyzer from Applied Biosystems.In cases when direct sequencing failed to show VHL gene mutations, DNA samples were analyzed for germline deletion of the VHL gene. A nonsequence-specific real-time detection of PCR products was performed by using the DNA binding dye SYBR Green I, as described by Ponchel et al.
ArticleReferenceSequence: Not specified- Assumption: Nucleotide change is not specified in the paper, only protein coding change is. cDNA variant was inferred based on protein coding change, and reported based on VHL reference sequence NM_000551.3
GenotypingMethod: DNA samples amplified by PCR underwent direct sequencing using SequiTherm Excel II DNA Sequencing Kit-LC (Epicentre Technologies, Madison, WI, USA) and an automated Li-COR IR2 sequencer (Li-COR Inc., Lincoln, NE, USA) or by direct cycle sequencing using the Big Dye Terminator Cycle Sequencing kit v3.1 (Applied Biosystems, Foster City, CA, USA), and run on an automated sequencer 310 Genetic Analyzer from Applied Biosystems. In cases where direct sequencing failed to detect any VHL mutations, patients also underwent nonsequence-specific real-time detection of PCR products using the DNA binding dye SYBR Green I.
SamplingMethod: peripheral blood
More than It Meets the Eye! Vision Loss as a Presenting Symptom of von Hippel-Lindau Disease
PMID: 33531956
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
D121Y (32)
301 were enrolled in a prospective clinical protocol to evaluate the natural history of vHL-associated pancreatic lesions (NCT00062166). Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study. Individual patient phenotype was not described, but overall of the 60 patients, 57 had RCC, 41 had CNS hemangioblastomas, 28 had retinal hemangioblastoma, 23 had pheochromocytoma. 36/69 patients were female and the mean age was 50.5 years old. All patients underwent genetic testing using Sanger sequencing and Southern Blotting. One patient was listed with this missense mutation, c.361G>T.
c.269A > T p.Asn90Ile (group 8)
GroupID: 8
DiseaseAssertion: assumed VHL
GroupSize: 15
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Chinese
GroupAgeRange: 36.9Y +/- 15.6Y
GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 15 members total were described, and phenotypic information was given for this group.
GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0002666 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, pheochromocytoma)
GroupHPOFreeText: 10 of the 15 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/15 had retinal capillary hemangiomas at 23Y and 30Y, renal cell carcinoma in 4 members (at a mean age of 41.5Y), pancreatic cysts in 5 members (with a mean age of onset of 41.4Y), and 1 member with pheochromocytoma at 38Y
GroupNotHPOs: HP:0009715 (papillary cystadenoma of the epididymis)
GroupNotHPOFreeText: No patients were given with papillary cystadenoma of the epididymis
GroupPreviousTesting: N/A
PreviouslyPublished: 29330336; 28388566
SupplementalData: N/A
Variant: p.N90I (c.269A>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223172 https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: N90I (c.269A>T)
MultipleGeneVariants: N/A
c.263G > C p.Trp88Ser
GroupID: 6B
DiseaseAssertion: assumed VHL
GroupSize: 9
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: Chinese
GroupAgeRange: 33.8Y +/- 17.6Y
GroupInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 3 families with 13 members total were described. it is unclear how many distinct families are reported in group 6B. 9 individuals were described. Phenotypic information was given for this mutation.
GroupPresentingHPOs: HP:0010797; HP:0009711; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)
GroupHPOFreeText: 7 of the 9 members presented with CNS hemangioblastoma (mean age of 29.9Y), 2/9 had retinal angiomas at 25Y and 35Y, 1 had renal cell carcinoma (at 30Y), pancreatic cysts in 2 members (with an age of onset of 30 and 31Y), and 1 member with a genital system tumor (epididymis or broad ligament) at 24Y
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: No patients were given with pheochromocytoma
GroupPreviousTesting: N/A
PreviouslyPublished: 29330336; 28388566
SupplementalData: N/A
Variant: p.W88S (c.263G>C)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2220, https://www.ncbi.nlm.nih.gov/clinvar/variation/2220/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: W88S (c.263G>C)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
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 (L135* (c.404T>A)) was taken from the National Cancer Institute database, and the Bristol Myers Squibb database. It had an unknown number of members belonging to Family ID 3710NCI, reported in Table 3, as being found in VHL families without pheochromocytoma, and with renal cell carcinoma. Additionally, it was reported in table 5, specified as families without detailed clinical information, under family ID 8BMS. It was reported in the paper as c.617T>A due to a difference in transcript reference.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
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 (Y112* (c.336C>A)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family IDs 3759NCI and 3760NCI. It was reported in the paper as c.549C>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMID: 7728151.
The patient was heterozygous for the novel c.163 G > T (p.55GluX) amber nonsense mutation
PatientID: 1
KindredID: 1 (A)
Case: M, 15Y0M, Hungarian
DiseaseAssertion: VHL
FamilyInfo: Both parents were healthy with no display of any mutations in the VHL gene, indicating a de novo mutation.
CasePresentingHPOs: HP:0006770; HP:0009711 (clear cell renal cell carcinoma, retinal capillary hemangioma)
CaseHPOFreeText: Patient developed bilateral retinal angioma (retinal capillary hemangioma) and had serious retinal detachment.
CaseNotHPOs: HP:0010797; HP:0002666 (hemangioblastoma, pheochromocytoma)
CaseNotHPOFreeText: MRI of the craniospinal axis could not detect any alterations. No deviation from normal values was observed in the laboratory test.
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.E55* (c.163G>T)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVar: N/A
CAID: CA351748495 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.163G%3ET
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: E55* (c.163G>T)
MultipleGeneVariants: N/A
Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.
PMID: 8592333
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
2. Materials and methods2.1. PatientThe 32-year-old male patient was admitted to Xiangya Hospital in 2006 and presented with progressive back and neck pain, and numbness and weakness of both legs which had continued for 1 month followed by fecal and urinary retention for 5 days. The MRI (1.5 Tesla) of the brain and entire spinal cord showed multiple lesions in the cerebellum, brain stem, and spinal cord, which were obviously enhanced and highly suggestive of hemangioblastomas (Fig. 1a–e). Subsequent evaluation, by MRI, of the abdomen revealed a solid kidney tumor (Fig. 1f). He underwent surgical resection for hemangioblastomas of T10 and T12 of the spinal cord, which appeared bright red at surgery. The pathological examination of the tissues showed many small blood vessels, most of which were a capillary plexus. Vascular endothelial cells were flat and distributed within a large number of stromal cells. Some of the vascular endothelial cells formed solid masses and cords. Between the capillary plexus, various forms of stromal cells were found, including nest-like or sheet arrangements with hyperchromatic nuclei, rich cytoplasm, rich lipid vacuoles and rare or no mitoses. Some foam cells and adipose-like cells were also found. Immunohistochemistry of the biopsied tissues from the lesions in the spinal cord were negative on immunostaining (–) for glial fibrillary acidic protein (GFAP), CD68, cytokinin (CK)-pan and epithelial membrane antigen (EMA), but stained positive (+) for factor 8 related antigen (F8RAg). Vascular endothelial cells were F8RAg(+) but stromal cells were F8RAg(–). Vascular endothelial cells and stromal cells were all immunonegative for GFAP, EMA, CK-pan, and CD68 (Fig. 1g, h). The patients’ symptoms resolved after surgery. At 5-year follow-up his condition did not recur or deteriorate, but active surveillance was continued.12Download : Download high-res image (1MB)Download : Download full-size imageFig. 1. Main clinical manifestations of von Hippel-Lindau (VHL) disease. (a) Sagittal T1-weighted MRI of the thoracic spinal cord showing two brightly enhancing nodular lesions with clear boundaries at T10 and T12 (arrows). (b) Sagittal T1-weighted MRI of the cervical spinal cord showing two brightly enhancing nodular lesions with clear boundaries at C5 and C6 (arrows). (c) Sagittal T1-weighted MRI of the cervical spinal cord showing a brightly enhancing nodular lesion with a clear boundary at C2 (arrow). (d) Sagittal T1-weighted MRI of the cranial–cervical region showing three brightly enhancing round lesions with clear boundaries at the posterior of the medulla oblongata, superior spinal cord and basilar part of the pons (arrows). (e) Axial T1-weighted MRI of the brain showing two brightly enhancing nodular lesions with clear boundaries at the posterior of the medulla oblongata and the right cerebellar hemisphere (arrows). (f) Sagittal T1-weighted MRI of the kidney showing the small (1.2 cm × 0.6 cm) enhancing nodular lesion (arrow). (g) Histopathological examination of the lesions at T10 and T12 in the spinal cord of the patient with VHL (hematoxylin and eosin stain, ×400). (h) Immunohistochemistry of the biopsied tissue from the lesions at T10 and T12 in the spinal cord of the patient with VHL (factor 8 related antigen stain, ×400).After genetic counseling, all family members of the patient (his parents, sister, son, sister’s son, brother, and brother’s son) were recruited into this study. His 66-year-old father and 63-year-old mother were both in good health without clinical symptoms of VHL. They did not undergo a whole-body examination, but all other family members underwent clinical examination, including ophthalmoscopy, MRI of the CNS, and ultrasonography of the abdomen, to exclude the disease. Informed consent was obtained from all individuals before their participation in the study.
PatientID: 1
KindredID: 1
Case: M, 39Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: No family history. All 7 of his other family members (his parents, sister, son, sister’s son, brother, and brother’s son) were sequenced and no mutation were found. Additionally, all were healthy members. Suggestive of de novo due to no abnormal changes in the VHL gene of either parent.
CasePresentingHPOs: HP:0010797; HP:0009713; HP:0006880; HP:0009726 (hemangioblastoma, spinal hemangioblastoma, cerebellar hemangioblastoma, renal neoplasm)
CaseHPOFreeText: At 32Y this patient presented with progressive back and neck pain and numbness. Patient developed multiple CNS hemangioblastomas (multiple lesions in the cerebellum, brain stem, and spinal cord). Subsequent evaluation of the abdomen revealed a solid kidney tumor (visceral tumor).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.F76del (c.227_229delTCT)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA357012 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.227_229delTCT
gnomAD: N/A
VariantEvidence: N/A
MutationType: inframe_deletion
CivicName: F76del (c.227_229delTCT)
MultipleGeneVariants: N/A
p.*214G
17 patients with genetic variants in SDHB, VHL, EPAS1, or RET with pheochromocytoma were identified retroactively for this study. 5 pathogenic germline variants were confirmed in patients with clinical criteria of von Hippel Lindau syndrome. Next generation sequencing (NGS) re-confirmed these germline mutations. One of which was a p.*214G (c.640T>G) mutation in patient 6, a 46Y male with pheochromocytoma. No further manifestation details were provided, nor family information.
Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 571insAC) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.358_359insAC (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 14 had p.Arg120fs ( c.358insAC) mutation. 2 members were affected with renal cell carcinoma. Other demographics of the members were not described.
Von Hippel-Lindau with early onset of hemangioblastoma and multiple drop-metastases like spinal lesions
PMID: 30278534
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: ccRCC-132
KindredID: 132
Case: M, 59Y0M, Ethnicity Unknown
DiseaseAssertion: Clear Cell Renal Cell Carcinoma
FamilyInfo: N/A
CohortInfo: 240 ccRCC specimens.
CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)
CaseHPOFreeText:He was diagnosed with ccRCC at age 54.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Supplementary table 1.
Variant: c.464-1G>T
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: 223221 https://www.ncbi.nlm.nih.gov/clinvar/variation/223221/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.464-1G>T)
MultipleGeneVariants: N/A
VHL mutation c. 232A>T; p. Asn78Tyr in this patient. The same point mutation of VHL was identified in three family members including one sister
PatientID: N/A (proband's sister)
KindredID: 2
Case: F, 40Y0M, Ethnicity Unknown
DiseaseAssertion: assumed VHL
FamilyInfo: The same point mutation of VHL (c. 232A>T; p.Asn78Tyr) was identified in three family members including one sister, one brother and one nephew. Her sister was found with adrenal pheochromocytoma, cerebellar hemangioblastoma, and her brother and nephew refused for further examinations for VHL-related lesions. Her mother died of stroke at early of 50 years.
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)
CaseHPOFreeText: patient died of the hemorrhagic stroke at age of 40 years.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.N78Y (c.232A>T)
LegacyVariant: N/A
ClinVar: 223167 https://www.ncbi.nlm.nih.gov/clinvar/variation/223167/
CAID: CA357056 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.232A%3ET
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: N78Y (c.232A>T)
MultipleGeneVariants: N/A
PatientID: None
KindredID: 12
Case: F, 20Y0M, Chinese
DiseaseAssertion: asymptomatic
FamilyInfo: Patient 12's 20 year old niece (this patient) was identified as a carrier of the same mutation as patient 12. Patient 12 was noted to not have a family history of VHL or other lesions associated with VHL disease.
CasePresentingHPOs: N/A
CaseHPOFreeText: The 20-year-old niece of patient 12 was identified as a carrier of the same mutation by genetic screening (no evidence of VHL disease.)
CaseNotHPOs:None
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.P86L (c.257C>T)
LegacyVariant: c.470C>T
CaseProblemVariant Free Text: N/A
ClinVar: 182977, https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/
CAID: CA020186
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_transition
CivicName: P86L (c.257C>T)
MultipleGeneVariants: N/A
1 (25)
GroupID: 29b
Case: Sex Unknown, Age Unknown, Ethnicity Unknown
DiseaseAssertion: VHL CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.
CasePresentingHPOs: N/A
CaseHPOFreeText: This was 1 of 4 patients discussed with this mutation. The individual did NOT have retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.
CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes - Supplementary Table S1
Variant: p.R107G (c.319C>G)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 43599 https://www.ncbi.nlm.nih.gov/clinvar/variation/43599/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: R107G (c.319C>G)
MultipleGeneVariants: N/A
c.220del p.Val74Leufs*85
216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There were 2 patients reported with the p.V74Sfs*85 (c.220del) mutation. Both members presented with retinal hemangiomas, while no other clinical manifestations were discussed. Additionally, no family information was provided.
PMID: 20567917
PatientID: 2
KindredID: 2
Case: F, 29Y0M, Brazilian
DiseaseAssertion: VHL
FamilyInfo: VHL type 1. Genetic testing has been performed in her parents and brother with negative results. Her only child has not undergone predictive testing yet.
CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0000107; HP:0001737; HP:0001407 (endolymphatic sac tumor; retinal capillary hemangioma; hemangioblastoma; renal cysts; pancreatic cysts; hepatic cysts)
CaseHPOFreeText: endolymphatic sac tumor diagnosed at 11Y, retinal angiomas at 16Y; hemangioblastoma, renal, pancreatic, and hepatic cysts at 29Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: Yes
Variant: p.Q73* (c.217C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: stop_gained
CivicName: Q73* (c.217C>T)
MultipleGeneVariants: N/A
The tests revealed that the same missense mutation in the VHL gene [c.500G>A (p.Arg167Gln)] was found in the patient and his two sons,
PatientID: III-7
KindredID: 3
Case: M, Age Unknown, Chinese
DiseaseAssertion: Asymptomatic
FamilyInfo: The patient's father, the proband (II-4) carried the VHL mutation and presented with clear cell renal cell carcinoma, pancreatic cysts, spinal hemangioblastoma, and renal cysts. The patient's brother (III-6) carried the mutation but was asymptomatic. The patient's grandmother (I-2) died as a result of pancreatic cancer. His paternal aunt (II-1) underwent surgery for a brain tumor and had pancreatic and renal cysts. Another paternal aunt (II-2) underwent surgery for breast cancer. See Figure 3 for family pedigree.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: Abdominal ultrasound examination of the patient revealed no abnormality.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216 https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: CA020454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.500G%3EA
gnomAD: 0.000003977 https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients
PMID: 23404858
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
All family members underwent clinical, laboratory, imaging, and genetic evaluation.
PatientID: IV-28 [written in Table 2 as IV-24 - typo]
KindredID: 1
Case: F, 33Y0M, Iranian
DiseaseAssertion: assumed VHL
FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient who proved to be symptomatic. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.
CasePresentingHPOs: HP:0011732; HP:0006880; HP:0010302 (abnormality of adrenal morphology, cerebellar hemangioblastoma, spinal cord tumor)
CaseHPOFreeText: Originally thought to be an asymptomatic carrier, however after follow-up was found to be symptomatic: brain MRI revealed multiple tutors, including a frontal mass (cerebellar tumor) with multiple spinal lesions, and an abdominal CT showed a 1.6x1.7 right adrenal mass. Additionally, this patient was pregnant at the time, to which was terminated at the 38th week of gestation with a caesarian section. She has two other children already.
CaseNotHPOs: HP:0000077 (abnormality of the kidney)
CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167Q (c.500G>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/
CAID: N/A
gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R167Q (c.500G>A)
MultipleGeneVariants: N/A
Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A
PMID: 8863170
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
Family 1+1C.292T > A, p.Tyr98AsnNo135373937––
PatientID: None
KindredID: 1
Case: Sex Unknown, 39Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: Positive. Patient's mother did not undergo genetic testing but had a hemangioblastoma at age 50 and a pancreatic cyst or tumour at age 62. The patient's sister also had this mutation but was asymptomatic. Another one of the patient's sisters presented with hemangioblastoma (age 40), renal cell carcinoma (age 43), and pancreatic cysts or tumours (age 43). This patient died before diagnosis. The proband's brother also died before diagnosis and presented with hemangioblastoma and retinal angioma at age 27.
CasePresentingHPOs: HP:0010797, HP:0005584, HP:0001732, HP:0009711 (hemangioblastoma, renal cell carcinoma, abnormality of the pancreas, retinal capillary hemangioma)
CaseHPOFreeText: The patient presented with hemangioblastoma at age 35. At age 37 she presented with retinal angioma and pancreatic cysts or tumours. At age 39 she presented with renal cell carcinoma.
CaseNotHPOs: HP:0002666, HP:0009715 (pheochromocytoma, Papillary cystadenoma of the epididymis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 29330336
SupplementalData: N/A
Variant: p.Y98N (c.292T>A)
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: CA351750883 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.292T%3EA
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant; transversion
CivicName: Y98N (c.292T>A)
MultipleGeneVariants: N/A
Somatic mutations in VHL germline deletion kindred correlate with mild phenotype
PMID: 14755727
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%.
PatientID: 19
KindredID: C
Case: Sex Unknown, 30Y0M, Mexican (Latino/Admixed American)
DiseaseAssertion: assumed VHL
FamilyInfo: At least 13 members in this family presented with the mutation. 5 were asymptomatic (ages 9, 12, 13, 17, and 29Y). Other family manifestations include: cerebellar, spinal, retinal HBs, pancreatic, hepatic, suprarenal and kidney cysts, epididymal cystadenoma, and RCC. Fig 1 displays family pedigree.
CasePresentingHPOs: HP:0009713 (spinal hemangioblastoma)
CaseHPOFreeText: Patient had 2 spinal HBs. They however appeared absent of clinical manifestations of VHL disease prior to clinical and imaging scrutiny.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 20064270 (Here, the family cohort is given with a reportedly different variant of: p.G34Rfs*98 (c.99_100insA). Unclear of why this is or which most correctly corresponds to the family).
SupplementalData: N/A
Variant: p.T100Nfs*32 (c.298dupA)
LegacyVariant: c.1012_1013insA
CaseProblemVariantFreeText: The ‘1012_1013insA’ mutation is out-of-frame, leading to a modification of 31 amino acids downstream and a premature stop codon at nucleotides 5441-5443 (amino acid residue 131).
ClinVarID: N/A
CAID: CA2573129737 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.298dupA
gnomAD: N/A
VariantEvidence: The modified amino acids are located in a domain common to all pVHL isoforms, the highly conserved cctbinding domain of the protein, involved in the formation of the pVHL elongin complex that is crucial for tumor suppression. Furthermore, the mutant protein is prematurely truncated and lacks the C-terminal half of exon 2 and exon 3 completely, which includes the nuclear export signal and the elongin C binding site of pVHL. Thus, this truncated protein would affect the two functional isoforms of pVHL: the major isoform pVHL30 and pVHL19, but not isoform 2, which lacks exon 2 but is not functional
MutationType: plus_1_frameshift_variant; duplication
CivicName: T100Nfs*32 (c.298dupA)
MultipleGeneVariants: N/A
2,3Deletion
PatientID: I:1
KindredID: 1
Case: M, 50Y0M, Chinese
DiseaseAssertion: VHL
FamilyInfo: the patient’s son was observed to be affected with CNS hemangioblastoma diagnosed at 37Y, retinal capillary hemangioma at 31Y, and epididymal/ovarian cystadenoma at 16Y
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: patient had hemangioblastomas at 50Y
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: exon 2,3 deletion
CaseProblemVariantFreeText: N/A
LegacyVariant: N/A
ClinVarID: N/A
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: exon_loss_variant
CivicName: exon 2-3 deletion
MultipleGeneVariants: N/A
MODERATED POSTER SESSION - 4: MP4-01: VHL with adrenal pheochromocytoma needs multidisciplinary approach – a case report
PMID: N/A
OVID: 620924735
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
PatientID: Carrier 12 (sister to proband 7)
KindredID: 3
Case: M, Age Unknown, Chinese
DiseaseAssertion: Asymptomatic
FamilyInfo: Father, mother and sister (all relative to proband 7) had this variant. Both father and sister were asymptomatic. Proband and mother presented with unilateral PCC.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.P138Afs*6 (c.410dup)
LegacyVariant: 623insTTTGTtG
CaseProblemVariantFreeText: N/A
ClinVarID: N/A
CAID: CA432421860, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.410dup
gnomAD: N/A
VariantEvidence: The VHL NM_000551.3 reference sequence surrounding nucleotide 410 is a TTTGTG sequence, where the 4th T is at position 410, which converts to nucleotide 623 in the legacy reference sequence (AF010238.1). Therefore it is assumed that the authors reported their insertion variant in the legacy nomenclature and this was mapped to p.Pro138Alafs*6 (c.410dup) in NM_000551.3.
MutationType: insertion; plus_1_frameshift_variant
CivicName: P138fs (c.410dup)
MultipleGeneVariants: N/A
PMID: 30853203
The 10 year old female patient presented with sustained hypertension, headaches, and vomiting for several weeks. She had no signs of hypertensive retinopathy or papilledema. However, in the right eye, a small, white-yellowish nodular lesion in the retinal periphery was found. Luoresceinangiography showed early and late leakage and marked hyperfluorescence compatible with retinal hemangioblastoma. A heterozygous mutation 488T>A (Leu163His) in exon 3 of the VHL gene was identified (methods unspecified). Subsequently, bilateral pheochromocytomas were found. After surgical resection of the pheochromocytomas the patient was asymptomatic. No family history was mentioned.
Germline mutations of the VHL gene in seven Chinese families with von Hippel-Lindau disease
PMID: 21972040
Gene: VHL
StandardizedReferenceSequence: NM_000551.3
One of his two children (III/3) also developed the disease.
PatientID: III/3
KindredID: 2
Case: F, Age Unknown, Italian
DiseaseAssertion: VHL
FamilyInfo: Case II/3 (patient III/3's father) had retina angioma with renal carcinoma. Case II/2 (her uncle) also had the mutation and presented with renal carcinoma, central nervous system haemangioblastoma, pheochromacytoma and pancreatic cysts. Case I/1 (her grandfather) also had the mutation and presented with haemangioblastom. Pedigree: see Figure 2.
CasePresentingHPOs: N/A
CaseHPOFreeText: This patient has developed VHL disease as mentioned in the paper, however, specific clinical presentations of the disease are not outlined.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: R167W (8702C->T)
ClinVar: 2218 https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: CA020450 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.499C%3ET
gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
Total cellular RNA was extracted from peripheral blood cells (PBLs) from each patient following the clinical trial, using a Nucleo Spin RNA kit (Macherey-Nagel, Düren, Germany). One microgram of total RNA was reverse-transcribed in a final volume of 20 μl with the First Strand cDNA Synthesis Kit (Roche, Mannheim, Germany) using random primers. The SYBR Green PCR system (BioRad, Hercules, CA, USA) was used to perform real-time PCR with an iQ5 system (Biorad, Spain)
ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3
GenotypingMethod: polymerase chain reaction (PCR)
SamplingMethod: peripheral blood using Nucleo Spin RNA kit (Macherey-Nagel, Düren, Germany)