PMID: 31308404

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9830390

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 11475579

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 17922902

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

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: A79V

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

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: H33Q

Variant1ClinVarID: 2134405

Variant1CAID: CA355945479

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: R89W

Variant1ClinVarID: 580286

Variant1CAID: CA2801156

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: A75T

Variant1ClinVarID: 222993

Variant1CAID: CA356994

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: G51D

Variant1ClinVarID: 193061

Variant1CAID: CA274902

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: Y76C

Variant1ClinVarID: 552686

Variant1CAID: CA2801140

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: Patient 38, male, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Airway obstruction (HP:0001263, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.5 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

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

Case#: Patient 22, male, Han origin, 1 year 8 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

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: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.8 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

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 by parental testing.

PreviouslyPublished N/A

Case#: Patient 18, female, Han origin, 1 year 6 months old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Hepatosplenomegaly, Hernia (HP:0001433, HP:0100790)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.6 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.2T>C (p.Met1Thr)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

Variant2: c.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

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

Case#: Patient 4, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Airway obstruction (HP:0001263, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

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.296+4G>A, it looks like this is a typo and should be c.299+4G>A

Variant1ClinVarID: N/A

Variant1CAID: CA2669476183

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

Case#: Patient 37, male, Han origin, age at diagnosis not available

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 1.5 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.2T>C (p.Met1Thr)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

Variant2: c.2T>C (p.Met1Thr)

Variant2ClinVarID: 639529

Variant2CAID: CA2801095

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

Case#: Patient 17, male, Han origin, 15 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness (HP:0001387)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.1 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

Variant2: c.265C>T (p.R89W)

Variant2ClinVarID: 580286

Variant2CAID: CA2801156

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

Case#: Patient 30, male, Han origin, 37 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Airway obstruction (HP:0001387, HP:0006536)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula, Hepatosplenomegaly, Hernia (HP:0001263, HP:0000256, HP:0011369, HP:0001433, HP:0100790)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 2.2 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.265C>T (p.R89W)

Variant1ClinVarID: 580286

Variant1CAID: CA2801156

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 54, male, Han origin, age of diagnosis not available

DiseaseAssertion: N/A

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.6 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.236C>T (p.A79V)

Variant1ClinVarID: 1458769

Variant1CAID: CA356987

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, 9 years old, Iranian

DiseaseAssertion: MPS1-H/S (Intermediate)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity not detected

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, 10 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.45 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: Unknown

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8, 5 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.04 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 8, female, 4.9 months (age at diagnosis), 8.6 months (age at HSCT), 6.7 - 9.5 months (age at ERT), 4 MRI + neuropsychological observations over the course of 6 years.

DiseaseAssertion: MPS-1H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 28.7 nmol/h/mg (Normal values: 11-43 nmol/h/mg)

CaseUrineGAGs: N/A

CaseERT: Yes

CaseBMT: Yes, transplanted with an unrelated cord blood unit.

Variant1: c.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: c.152G>A (p.G51D)

Variant2ClinVarID: 193061

Variant2CAID: CA274902

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient #4 (see Table 2), male, 2 years old (age at diagnosis), 7 years old (age at report)

DiseaseAssertion: MPS-I

FamilyInfo: Born to a consanguineous marriage.

CasePresentingHPOs: Failure to thrive, short stature, macroglossia, poor eyesight, hearing impairment, scoliosis, developmental delay (HP:0001508, HP:0004322, HP:0000158, HP:0000505, HP:0000365, HP:0002650, HP:0001263)

CaseHPOFreeText: Extra abnormal body and abdominal inflammation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: α-L-iduronidase 6.4 pmol/spot. The activity of this enzyme is below its reference (350–2600 pmol/spot)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient #5 (see Table 2), female, 1 year old (age at diagnosis), 3 years old (age at report)

DiseaseAssertion: MPS-I

FamilyInfo: Born to a consanguineous marriage

CasePresentingHPOs: Coarse facial features, macroglossia, developmental delay, failure to thrive, skeletal dysplasia (HP:0000256, HP:0000158, HP:0001263, HP:0001508, HP:0002652)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: α-L-iduronidase 1.5 pmol/spot. The activity of this enzyme is below its reference (200–2600 pmol/spot)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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: Abnormal

CaseUrineGAGs: Abnormal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.250G>A (p.G84S)

Variant1ClinVarID: 726495

Variant1CAID: CA2801152

Variant2: c.250G>A (p.G84S)

Variant2ClinVarID: 726495

Variant2CAID: CA2801152

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 4, 9 months old (age at report), male, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0100790)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 1.6% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>A (p.Ala75Thr)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>A (p.Ala75Thr)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures (HP:0000280, HP:0001433, HP:0002828)

CaseHPOFreeText: N/A

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.223G>A (p.Ala75Thr)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>A (p.Ala75Thr)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 1, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections, intellectual disability (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0002719, HP:0001249)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.1% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.152G>A (p.Gly51Asp)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: c.152G>A (p.Gly51Asp)

Variant2ClinVarID: 193061

Variant2CAID: CA274902

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 2, 5 months old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, corneal clouding, recurrent infections, intellectual disability (HP:0000280, HP:0007957, HP:0002719, HP:0001249)

CaseHPOFreeText: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.203G>A (p.Trp68Ter)

Variant1ClinVarID: 2734634

Variant1CAID: CA2801137

Variant2: c.203G>A (p.Trp68Ter)

Variant2ClinVarID: 2734634

Variant2CAID: CA2801137

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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.251G>C (p.G84A)

Variant1ClinVarID: 2203494

Variant1CAID: CA355946494

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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.299G>A (p.R100K)

Variant1ClinVarID: 281005

Variant1CAID: CA2801160

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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.223G>A (p.A75T)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

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.250G>A (p.G84S)

Variant1ClinVarID: 726495

Variant1CAID: CA2801152

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, male, 1 year and 6 months (age at presentation)

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint contractures, extensive Mongolian spots (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0100790, HP:0011369)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>A (p.A75T)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>A (p.A75T)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 3, male, 1 year (age at presentation)

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hydrocephalus, intellectual disability, extensive Mongolian spots (HP:0007957, HP:0000256, HP:0000943, HP:0000238, HP:0010864, HP:0011369)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>A (p.A75T)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>a (p.A75T)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 4, female, 2 years and 3 months (age at presentation)

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Coarse facial features, dysostosis multiplex, hepatomegaly, splenomegaly, intellectual disability (HP:0000256, HP:0000943, HP:0002240, HP:0001744, HP:0010864)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.223G>A (p.A75T)

Variant1ClinVarID: 222993

Variant1CAID: CA356994

Variant2: c.223G>A (p.A75T)

Variant2ClinVarID: 222993

Variant2CAID: CA356994

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Family 10, 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.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.178C>T (p.Q60X)

Variant2ClinVarID: 655054

Variant2CAID: CA355946098

AdditionalVariants: N/A

ParentalGenotype: Parental testing conducted, each parent was shown to carry one of the sequence changes found in their affected child.

PreviouslyPublished N/A

Case#: Patient 8, 5 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.04 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 5, 9 years old, Iranian

DiseaseAssertion: MPS1-H/S (Intermediate)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity not detected

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 10, 10 years old, Iranian

DiseaseAssertion: MPS1-S (Attenuated)

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.45 µmol/g.h (Normal ranges: 10-50 µmol/g.h)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.152G>A (p.G51D)

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: Unknown

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No individual patient information available. 11/59 patients studied (18.7%) had this variant. This variant originates from two regions of Iran. 5 patients came from the city of Rasht in the Gilan province, making it a focal point for this variant. 6 patients came from five different provinces in the southwestern regions of Iran.

DiseaseAssertion: MPS1

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.1A>C

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished This variant has previously been reported in studies conducted by Atceken et al. (2016) and Bertola et al. (2011), in patients from Turkey and Spain respectively. However, there has been no report suggestive of a founder effect for this variant.

Case#: Pt 8, age is 8 months (proband can be found in Table 1)

DiseaseAssertion: Hurler syndrome, mucopolysaccharidosis type IH, MPS IH, MPS type I

FamilyInfo: No family information provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: In methods it is stated that an IDUA activity assay was conducted on cartilaginous pellets generated from patient-derived bone marrow stromal cells at 5 weeks. However, results of the IDUA activity assays are not stated.

CaseUrineGAGs: "Significantly higher levels of GAGs in MPS IH compared with HD pellets at.1 week of chondrogenic differentiation, thus indicating that GAG accumulation in MPS IH can be seen during cell condensation and early differentiation stages." Total GAG content for each sample in ug GAG/ug DNA shown in Figure 4 graphs.

CaseERT: Don't know

CaseBMT: Don't know

Variant1: p.G51D

Variant1ClinVarID: 193061

Variant1CAID: CA274902

Variant2: p.G51D

Variant2ClinVarID: 193061

Variant2CAID: CA274902

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental information provided

PreviouslyPublished: No mention of being previously published

Case#: No case information provided

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Exact number not stated but "significantly decreased".

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.2T>C (p.M1?)

Variant1ClinVarID: 639529

Variant1CAID: CA2801095

Variant2: c.2T>C (p.M1?)

Variant2ClinVarID: 639529

Variant2CAID: CA2801095

AdditionalVariants: N/A

ParentalGenotype: Both parents were identified as carriers of the mutation

PreviouslyPublished N/A

Case#: Patient 1, 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.1A>C (p.M1L)

Variant1ClinVarID: 550458

Variant1CAID: CA355945204

Variant2: c.1A>C (p.M1L)

Variant2ClinVarID: 550458

Variant2CAID: CA355945204

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case: P32, Chinese, male, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.646G>A (p.Glu216Lys)

HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)

ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/

CAID: NA

gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1

MultipleGeneVariants

Gene: F8

Variant: p.Arg446Ter - Unregistered Variant

Case1: Female, 4 years old, Japanese

DiseaseAssertion: Thrombocytopenia

FamilyInfo: 4-generation pedigree available

ParentalGenotype: See Figure 1 A for parents in the pedigree

CasePresentingHPOs: HP:0004406, HP:0000979

(Recurrent epistaxis, purpura)

CaseHPOFreeText: Mild bleeding tendency

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed reduced expression levels

PlateletAggregation: Platelet aggregation induced by ADP and collagen was markedly reduced but agglutination induced by ristocetin was within the normal range.

CasePreviousTesting: Direct sequencing analysis around T2231 in exon 14 of the ITGB3 gene. Genomic DNA extracted from the affected and unaffected individuals of the pedigree were amplified by PCR and sequenced (See Figure 2)

Gene: ITGB3

Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)

LegacyVariant: p.Leu718Pro

ClinVar: 50229

CAiD: CA143712

gnomAD: N/A

Case1: Female, 43 years old, Caucasian

DiseaseAssertion: Thrombasthenia

FamilyInfo: Pedigree found in Fig. 2B

ParentalGenotype: See Pedigree Fig 2B

CasePresentingHPOs: HP:0000132 (Menorrhagia)

CaseHPOFreeText: Severe and frequent mucocutaneous hemorrhages, intra-peritoneal bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: 25% decrease of GPIbα and a reduced mean value of side scatter in the patient’s platelets.

PlateletAggregation: Platelet aggregation was markedly reduced in response to ADP, epinephrine, collagen, and arachidonic acid but agglutination induced by ristocetin was normal

CasePreviousTesting: Screening for mutations was carried out by direct sequencing of PCR-amplified overlapping fragments of reversed transcribed αIIb and β3 mRNA.

Gene: ITGB3

Variant: NM_000212.2:c.2231T>C (p.Leu744Pro)

LegacyVariant: (p.Leu718Pro)

ClinVar: 50229

CAiD: CA143712

gnomAD: N/A

Case5: Woman (adult), age not specified, France

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

ProteinExpression: Variant GT; therefore, 50% expression alphaIIbbeta3 (See Table 4)

Platelet Aggregation: N/A

CasePreviousTesting: N/A

Gene: ITGB3

Variant: NM_000212.2:c.2227_2229CTC (p.Leu744del)

LegacyVariant: (p.Leu718del)

ClinVar: 627279

CAiD: CA915940812

gnomAD N/A

PreviouslyPublished: PMID: 29296966

Case#: 1. Patient II-4 43 years

DiseaseAssertion: Hypertrophic cardiomyopathy and left ventricular noncompaction

FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.

ParentalTesting: NR

CasePresentingHPOs: NR

CaseHPOFreeText: The patient had thickened heart muscle, abnormal heartbeats, and extra ridges and deep spaces in the heart muscle.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: ECG, heart monitoring, heart ultrasound, and genetic testing

Genotyping Method: Next- generation sequencing and sanger sequencing

FunctionalAnalysis: computer testing suggested the ACTC1 gene change could weaken the protein

Variant: NM_005159.4:c.62C>T

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

AdditionalInfo: His heart pumping ability was 55%. This article reported changes in his heart muscle cells.

Case#: 2 Patient II-5 46 years old

DiseaseAssertion: HCM and LVNC

FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.

ParentalTesting: NR

CasePresentingHPOs: NR

CaseHPOFreeText: The patient had thickened and enlarged heart muscle, abnormal heartbeats, and deep spaces in his heart muscle. He als had temporary episodes of reduced blood flow to the brain.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart MRI, heart biopsy and genetic testing

Genotyping Method: NGS and sanger sequencing

FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.

Variant: NM_005159.4:c.62C>T

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

AdditionalInfo: His heart pumping ability was 30%. He received a defibrillator and was considered for a heat transplant. He also had a second gene change in TTN.

Case#: 3 Patient II-1 10 years

DiseaseAssertion: left ventricular noncompaction

FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.

ParentalTesting: NR

CasePresentingHPOs: NR

CaseHPOFreeText: The patient had extra ridges and deep spaces in his heart muscle. His ECG also showed changes in his heart's electrical activity.

CaseNotHPOs: NR

CaseNotHPOFreeText: Normal heart muscle thickness and normal heart pumping ability.

CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart biopsy and genetic testing

Genotyping Method: NGS and sanger sequencing

FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.

Variant: NM_005159.4:c.62C>T

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

AdditionalInfo: His heart pumping ability was 63%.He received medication and remained stable during follow up.

Case#: 4 Patient III-2 14 years

DiseaseAssertion: HCM and LVNC

FamilyInfo: Several family members have heart disease. One relative died from cardiac arrest at age 50.

ParentalTesting: NR

CasePresentingHPOs: NR

CaseHPOFreeText: The patient had thickened heart muscle extra ridges and deep spaces in his heart, and episodes of fast or abnormal hearbeats.

CaseNotHPOs: NR

CaseNotHPOFreeText: Heart MRI did not show sign of heart muscle scarring

CasePreviousTesting: ECG, heart monitoring, heart ultrasound, heart biopsy and genetic testing

Genotyping Method: NGS and sanger sequencing

FunctionalAnalysis:computer testing suggested the ACTC1 gene change could weaken the protein.

Variant: NM_005159.4:c.62C>T

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

AdditionalInfo: His heart pumping ability was 60%.He received medication and remained stable during follow up.

Case#: Pedigree I-1; 74-year-old Korean male; admitted for dyspnea (NYHA III), palpitations, and bilateral pitting leg edema over several months

DiseaseAssertion: Idiopathic restrictive cardiomyopathy (RCM) with biatrial enlargement, in a family with MYBPC3-related cardiomyopathy

FamilyInfo: Family history of heart disease with two affected daughters (II-2 and II-4), both heterozygous for the same variant and both diagnosed with HCM. Unaffected granddaughter (III-3) tested negative. Both daughters showed asymmetric septal hypertrophy on TTE (18 mm and 17 mm) with mildly dilated LA; daughter II-2 had grade I diastolic dysfunction and mild exertional chest discomfort. CMR confirmed reverse septal curvature hypertrophy consistent with HCM in both daughters, with no LGE in either.⁠

ParentalTesting: Not performed; the proband is the index case in generation I; his parents were not evaluated. Phase established only through the daughters and granddaughter.

CasePresentingHPOs:HP:0002094; HP:0001962; HP:0001677; HP:0001635; HP:0001639; HP:0001698

CaseHPOFreeText: Exertional dyspnea NYHA class III, palpitations, and bilateral leg pitting edema for several months; dyspnea refractory to heart failure medication, with pulmonary venous congestion. ECG and Holter: atrial fibrillation with rare premature ventricular complexes. TTE: RCM with biatrial enlargement and small pericardial effusion. CMR: normal LV chamber size, borderline diffuse LV hypertrophy, very large atria, extensive transmural LGE in the apical wall and mid-myocardial patchy LGE in the ventricular septum. Coronary angiogram normal; no secondary cause of RCM found.⁠

CaseNotHPOs: HP:0000822; HP:0000819; HP:0001658; HP:0001678

CaseNotHPOFreeText: Coronary angiogram normal, so no obstructive coronary disease. No secondary cause of RCM identified; no inflammatory, infiltrative, or systemic disease found. No AV block; the rhythm disturbance was atrial fibrillation.

CasePreviousTesting: Whole exome sequencing (Agilent SureSelect XT Human All Exon v5, Illumina HiSeq2500, GATK. Sanger sequencing of family members showed only the MYBPC3 variant tracked with disease; the other four (KALRN c.1702C>T, KCNH2 c.442C>T, SKI c.30T>G, TTN c.54293T>C) did not correlate with phenotype.⁠

Genotyping Method: WES in the proband, with annotation via dbNSFP and Ensembl VEP; Sanger sequencing confirmed the MYBPC3 frameshift in the proband (I-1), daughters II-2 and II-4, and its absence in granddaughter III-3 (Fig. 3B).⁠

FunctionalAnalysis: None performed. CMR showed extensive LGE in the apical LV, and the authors propose that advanced myocardial fibrosis in end-stage HCM can provoke myocardial atrophy, explaining the relatively normal LV chamber size with a predominantly restrictive phenotype hypothesis.⁠

Variant: MYBPC3 NM_000256.3:c.3313_3314insGG (p.Ala1105Glyfs*85); heterozygous frameshift insertion; absent from gnomAD and the Korean Reference Genome Database.

ClinVar: 1473634

CAID: Not reported.

Gene:MYBPC3

HGNC: HGNC: 7551

PMID: 33803538

gnomAD: Absent per the authors' check of gnomAD as of 8 November 2020, and absent from KRGDB.

AdditionalInfo: Authors conclude the MYBPC3 frameshift is the pathogenic variant, with the same allele producing RCM in the proband and HCM in both daughters; an example of pleiotropy and variable expressivity within one family. The frameshift has previously been reported in Korean HCM. Poor-prognosis features in RCM cited by the authors: male sex, age over 70, high NYHA class, and LA dimension >60 mm.

Case#: P16, 17 year old male

DiseaseAssertion: left ventricular noncompaction cardiomyopathy

FamilyInfo: His mother, sister, and grandfather on his mothers side also had LVNC

ParentalTesting: NR

CasePresentingHPOs: NR

CaseHPOFreeText: The patient had an abnormal structure in the left side of his heart. His heart ultrasound showed extra muscle ridges and deep spaces in the heart muscle.

CaseNotHPOs: NR

CaseNotHPOFreeText: The study did not report fainting, heart rhythm problems, blood clots, or heart failure for this patient.

CasePreviousTesting: Heart ultrasound, ECG, heart MRI, blood tests, and genetic testing.

Genotyping Method: Next generation sequencing followed by Sanger sequencing to confirm this gene change

FunctionalAnalysis: NR

Variant: NM_005159.5:c.329>T

Clinvar: 2137647

CAID: CA391631478

gnomAD: Exact frequency not provided

AdditionalInfo: The patient's heart pumping ability was 70 %on ultrasound. Researchers classified his ACTC1 variant as a variant of uncertain significance meaning they were not sure whether it causes diseases.

PMID: 34109129

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 23298237

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: N/A

OVID: 613950722

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 18209888

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 25371412

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 16600797

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID:10749302

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 27527340 Gene: VHL StandardizedReferenceSequence: NM_000551.3

PMID: 31317677

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 23797736

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 19958924

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 11036115

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 21384277

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 11106358

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 16360474

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 34036514

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 17001110

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 19399650

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 11990703

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 33222672

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 23407287

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9663592

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 15709172

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 29616089

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 32432044

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Case#: Family 2, III-10 47 year old female

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Multiple family members had DCM. The disease followed an autosomal dominant inheritance pattern.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText:Female aged 47 with DCM. Her left ventricular end diastolic diameter was 57mm and her ejection fraction was 40%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation.

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The E194X mutation reduced the ability of KLF13 to activate ACTC1 and MYH7 and bind their promoters. It also disrupted cooperation with GATA4.

Variant: KLF13 c.580G>T

Clinvar: NR

CAID: NR

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The mutation was found in affected family members and was absent from 418 unrelated healthy controls.

PMID: 32974018

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 9681858

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 25715769

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 19096585

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 16572651

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 19288063

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 29124493

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 33471715

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 10942118

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 21673464

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 25683602

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 34937752

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 20952280

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: N/A

OVID: 613520271

Reference: Sirinvaravong S., Boonsaen T. & Wannachalee T. (2016). Pancreatic serous cystadenocarcinoma in von hippel-lindau disease. Endocrine Reviews, 37(2 Supplement 1), no pagination. https://doi.org/10.1210/endo-meetings.2016.TB.9.SAT-076

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PMID: 10612832

Gene: VHL

StandardizedReferenceSequence: NM_000551.3