PatientID: N/A

KindredID: 12

Case: M, Age Unknown, Indian

DiseaseAssertion: VHL

FamilyInfo: Family history not mentioned. Patient’s variant reported as germline.

CasePresentingHPOs: HP:0002666; HP:0010797; HP:0001737; HP:0005584 (Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Renal cell carcinoma)

CaseHPOFreeText: Patient had CNS-HB, RCC, Unilateral PH, PCy (see table 1). Previously published 2018 paper (PMID:29124493) reports patient as an Indian 39Y male

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29124493

SupplementalData:  N/A

Variant: p.F76del (c.227_229del)

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: Variant reported as c.224_226del and was mapped to c.227_229del.

MutationType: inframe_deletion

CivicName: F76del (c.227_229del)

MultipleGeneVariants: N/A

PatientID: 38

KindredID: 5960

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Another member of his family (patient 39) has the same VHL mutation and presents with one pathologic pancreatic endocrine tumour.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with one radiologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167Q (c.500G>A)

LegacyVariant: p.R167Q (c.713G>A)

CaseProblemVariantFreeText: N/A

ClinVar: 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

PatientID: 36

KindredID: 6015

Case: F, 27Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: She presented with three pathologic pancreatic endocrine tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.R167W (c.712C>T)

CaseProblemVariantFreeText: N/A

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

Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This mutation was found in a 30-year-old VHL patient with hemangioblastomas of the central nervous system, retinal angiomas, renal cell carcinoma, and pancreatic cysts (proband no. 16). HPO terms: hemangioblastoma, retinal hemangioblastoma, renal cell carcinoma, multiple pancreatic cysts.

PatientID: 16

KindredID: C

Case: Sex Unknown, 54Y0M, 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:0000107 (renal cyst)

CaseHPOFreeText: Patient had renal cysts. 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

PatientID: 40/41

KindredID: 40/41

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Multiple benign PCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Patient information pulled from Supplemental Table 1a.

Variant: p.L178P (c.533T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428795, https://www.ncbi.nlm.nih.gov/clinvar/variation/428795/

CAID: N/A

gnomAD: N/A

VariantEvidence: Patient data is extracted from two rows assumed to be referring to the same patient (i.e. tumor samples 40 and 41 in Supplementary Table 1a). Carbonic anhydrase 9 (CA9) mRNA level of 795.70 (PCC) and 815.38 (PCC) were detected. Membrane CA9 immunostaining was observed in both PCC samples.

MutationType: missense_variant;transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This familial mutation was confirmed in family #48. Only the male proband (patient 128) was genetically confirmed with the mutation. He was diagnosed with CNS hemangioblastoma at 32Y, RCC at 38Y, pheochromocytoma at 40Y and multiple pancreatic lesions at 38Y. His father (patient 129) was diagnosed with RCC at 58Y and his daughter (patient 130) was diagnosed with CNS hemangioblastoma at 13Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

Tissue specimens of apparent sporadic pheochromocytoma were retrieved from the archives of the Department of Pathology of the Erasmus MC (Rotterdam), the Radboud University Nijmegen Medical Center, and the University Hospital Zurich (Switzerland). Mutation analysis was performed for 136 VHL cases and six germline VHL mutations were found. Mutation analysis was performed using SSCP analysis and BigDye® Terminator V3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA). 136 VHL cases and six germline VHL mutations were found. A c.639T>G mutation (stated as c.852T>G in the paper which used the Latif sequence as reference) was found in one 49Y female patient (patient ID 25B) with benign adrenal pheochromocytoma. No other phenotypes, patient demographics, or family history was described.

PatientID: 26

KindredID: N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: The authors evaluated 64 VHL patients (32 women and 32 men) with renal involvement of whom 54/64 had undergone renal surgery or a radiofrequency thermal ablation procedure for RCC. In 10/64 VHL patients, at least one or more RCC were diagnosed, however at the time of diagnosis an indication for treatment was not yet present. For all patients several CT/MRI scans existed for retrospective description of tumour growth kinetics.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: This is a tumor resolution study (VHL patients were investigated based on the presence of renal tumors.) No other phenotypic information is available.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S6 describes 3 patients with small insertions, including this patient.

Variant: p.R69Afs*63 (c.204dup)

LegacyVariant: c.417insG

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189244

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant, duplication

CivicName: R69Afs*63 (c.204_205insG)

MultipleGeneVariants: N/A

PatientID: 53

KindredID: 53

Case: Sex Unknown, 37Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history noted but details not specified.

CasePresentingHPOs: HP:0009711; HP:0002666 (Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0001732; HP:0010797; HP:0000107 (Clear cell renal cell carcinoma, Abnormality of the pancreas, Hemangioblastoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

Variant: p.V170G (c.509T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756196, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.509T%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170G (c.509T>G)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: paraganglioma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668 (paraganglioma)

CaseHPOFreeText: Paraganglioma of the head and neck region (HNPGL): Left carotid body; nonsecreting paraganglioma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.T152I (c.455C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351754382 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.455C%3ET

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: T152I (c.455C>T)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Bilateral Pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: no other endocrine tumours

CasePreviousTesting: SDHB, SDHD, SDHC, RET

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y156C (c.467A>G)

LegacyVariant: N/A

ClinVar: 43600 https://www.ncbi.nlm.nih.gov/clinvar/variation/43600/

CAID: CA020394 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA020394

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y156C(c.467A>G)

MultipleGeneVariants: N/A

PatientID: 14

KindredID: 14

Case: F, 56Y0M, 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.Y112H (c.334T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2222 https://www.ncbi.nlm.nih.gov/clinvar/variation/2222/

CAID: CA020277 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.334T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 18Y0M, Ethnicity Unknown

DiseaseAssertion: Cerebellar Hemangioblastoma

FamilyInfo: N/A

CohortInfo: The cohort included a series of 20 capillary haemangioblastomas of the central nervous system for mutations of the VHL gene.

CasePresentingHPOs: HP:0006880 (cerebellar hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S183Cfs*19(c.548delC)

LegacyVariant: p.S183Cfs*19(c.761delC)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA658795184 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.548delC

gnomAD: N/A

VariantEvidence: Refer to Table 1 for abnormal SSCP or heteroduplex patterns.

MutationType: minus_1_frameshift_variant

CivicName: S183fs (c.548delC)

MultipleGeneVariants: N/A

Case#: 21

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1136G>A

LegacyVariant:

ClinVar: No

CAID: CA255394

gnomAD:

Case#: 15

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 3.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.881G>A

LegacyVariant:

ClinVar: No

CAID: CA255368

gnomAD:

Case#: 14

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 10%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.835G>A

LegacyVariant:

ClinVar: No

CAID: CA277507

gnomAD:

Case#: 44

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.253-2A>G

LegacyVariant:

ClinVar: No

CAID: CA414436483

gnomAD:

Case#: 20

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C = 6%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1136G>A

LegacyVariant:

ClinVar: No

CAID: CA255394

gnomAD:

Case#: 7

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.344A>G

LegacyVariant:

ClinVar: No

CAID: CA414437636

gnomAD:

Case#: 28

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.1274T>C

LegacyVariant:

ClinVar: No

CAID: CA414447009

gnomAD:

Case#: 35

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.223C>T

LegacyVariant:

ClinVar: No

CAID: CA340993

gnomAD:

Case#: 36

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0011858

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing

Gene: F9

Variant: NM_000133.3:c.535G>T

LegacyVariant:

ClinVar: No

CAID: CA414440319

gnomAD:

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0001929

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)

ClinVar: Absent

CAID: CA414434483

gnomAD: Absent/Not Reported

Case#: N/A

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0001929

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.50T>A (p.Ile17Asn)

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case#: Belvini_Proband_4 (male, Italian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.59T>C (p.Leu20Ser)

ClinVar: Absent

CAID: CA414434363

gnomAD: Absent/Not Reported

Case#: Belvini_Proband_14 (male, Italian)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant:

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: 14

DiseaseAssertion: Hemophilia B, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.59T>C

LegacyVariant:

ClinVar: No

CAID: CA414434363

gnomAD:

Case#: 3

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.881G>A

LegacyVariant:

ClinVar: No

CAID: CA255368

gnomAD:

Case#: 9

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 5.1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.172G>C

LegacyVariant:

ClinVar: No

CAID: CA414435830

gnomAD:

Case#: 12

DiseaseAssertion: NA

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Na

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.434G>A

LegacyVariant:

ClinVar: No

CAID: CA414438950

gnomAD:

Case#: 22

DiseaseAssertion: Hemophilia B, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 19.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.571C>T

LegacyVariant:

ClinVar: No

CAID: CA255340

gnomAD:

Case#: 13

DiseaseAssertion: Hemophilia B, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: FIX:C = 3.7%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing

Gene: F9

Variant: NM_000133.3:c.374G>A

LegacyVariant:

ClinVar: No

CAID: CA414437883

gnomAD:

Case#: Green_London_3 & Green_London_4 (assumed male)

DiseaseAssertion: Severe Hemophillia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (London 3: FIX:C:1, FIX:Ag: 48) (London 4: FIX:C:1, FIX:Ag: 45)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: HB348 (assumed male, Caucasian, 28 y/o)

DiseaseAssertion: No disease assertion made

FamilyInfo: Of the 30 families, germline or so- matic origins were found in 9 mothers, 5 maternal grandmothers, and 16 maternal grandfathers. For the 29 incomplete families, origins were found in 14 mothers, 5 maternal grandmothers, and 10 maternal grandfathers. Comparing the two family types shows no significant difference (P=0.29), suggesting that no major bias occurs in the analyses because of the inclusion of incomplete families

ParentalTesting: N/A

CasePresentingHPOs: N/A

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Patient C (assumed male)

DiseaseAssertion: Severe, Sporadic Hemophilia B

FamilyInfo: Patient C's mother and two sisters were also heterozygous; and the third sister was homozygous for cleavage and is a non-carrier

ParentalTesting: Mother was heterozygous for the variant

CasePresentingHPOs: HP:0011858

CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1; FIX:Ag:65)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

LegacyVariant: c.6365 G>A (p.Arg-4Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: IG38 (Italian, assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 20)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.16364C>T (p.Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Pezeshkpoor_Patient_N (male, 68 y/o, from Switzerland)

DiseaseAssertion: Hemophilia B

FamilyInfo: The daughter of the patient has the mutation, while the brother of the patient does not.

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: mechanical aoritc valve replacement, low FIX:C levels

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: IG1, Italy

DiseaseAssertion: Hemophilia A, severe (Table 1)

FamilyInfo: Table 1 - female relative(s) tested

ParentalTesting: No

CasePresentingHPOs: HP:0003125

(Reduced factor VIII activity)

CaseHPOFreeText: FVIII:C <1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Entire FVIII coding region, flanking splicing sites and promoter sequence were amplified. Mutational analyses included DHPLC followed by sequencing.

Gene: F8

Variant: NM_000132.3:c.98G>A p.(Trp33Ter)

LegacyVariant: c.207G>A p.(Trp14Ter) [based on Antonarakis, 1998; PMID: 9450896]

ClinVar: No

CAID: CA414920533

gnomAD: Not reported

Case#: N/A

DiseaseAssertion: Hemophilia B (severity not specified)

FamilyInfo: Not provided

ParentalTesting: Not provided

CasePresentingHPOs: Not provided

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.68T>C (p.Leu23Pro)

ClinVar: Absent

CAID: CA414434403

gnomAD: Absent/NotReported

Case#: Family HB90

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C:4 (post therapy values but clinically severe by criteria of Eyster et al. (1980)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

AdditionalCaseInfo: Previously reported by Giannelli et al. (1990)

Case#: B21 (assumed male, Indian origin)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: reduced factor IX activity (FIX:C: 1.3%)

CaseHPOsFreeText: HP:0011858

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Saad_Probands 86-92 (assumed male; from UK)

DiseaseAssertion: Saad_Probands 86-87: no disease assertion made ; Saad_Probands 88, 90, 91: Moderate Hemophilia B ; Saad_Probands 89, 92: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (Proband_88 FIX:C:1 ; FIX:Ag:48, Proband_ 89 FIX:C: <1, Proband_90: FIX:C: 1 ; FIX:Ag:45, Proband_91: FIX:C: 2, Proband_92: FIX:C:<1)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: HB-KHF-25 (Male, Korean)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Among the 33 patients, 13 had a family history (39%), while the rest of the patients did not (sporadic, 61%). 27 patients (82%) had the severe form of the disease, while 6 patients (18%) had the moderate form

ParentalTesting: N/A

CasePresentingHPOs: HP:0003645, HP:0011858

CaseHPOsFreeText: Prolonged partial thromboplastin time, reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: aPTT and one-stage clotting assay at labs where patients were ascertained: FIX-deficient plasma (STA®-Deficient IX; Diagnostica Stago, Asnieres-sur-Seine, France; reference range, 60–150%) at Samsung Medical Center or HemosIL™ (Instrumentation Laboratory, Milan, Italy; reference range, 50–145%) at the Korea Hemophilia Foundation.

Gene: F9

Variant: NM_000133.4:c.128G>T (p.Arg43Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: Odnoczko_Case (male, 74 y/o, in Poland)

DiseaseAssertion: Severe Hemophilia B (only in patients who receive vitamin K antagnoists (VKAs). The authors believe that during VKA therapy, the FIX activity is much lower than that of other vitamin K-dependent clotting factors for cases with this variant.

FamilyInfo: Family history of bleeding diathesis was negative

ParentalTesting:

CasePresentingHPOs: HP:0012233, HP:0031364, HP:0001892

CaseHPOsFreeText: left thigh & buttock hematoma, ecchymosis on extremeties with no mucosal bleeding, bleeding diathesis

CasePreviousTesting: local labaratory blood tests revealed anemia (hemoglobin concentration 8 g/dl; ref. range 14–18 g/dl), prolongation of prothrombin time (PT) with International Normalized Ratio (INR) within the therapeutic range (between 2.0 and 3.0). The proband's activated partial thromboplastin time (APTT) was significantly (>2-folds) prolonged and FIX activity markedly decreased

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Mutation found in 4 patients, and in 4 families

DiseaseAssertion: Severe in 2 cases, moderate in the other 2 cases

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858, HP:0003645, HP:0001892

CaseHPOsFreeText: reduced factor IX activity, activated partial thromboplastin time (APTT), normal FVIII clotting activity and bleeding tendency

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Patient HB401 (Hispanic; Male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX Coagulant Activity: 1%

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.50T>A (p.Ile17Asn)

LegacyVariant: c.79T>A (p.Ile-30Asn)

ClinVar: Absent

CAID: CA414434315

gnomAD: Absent/Not Reported

Case#: Patient 63 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = 3 (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Patient 66 (Spanish origin; assumed male)

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Factor IX: C = 30% (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4(F9):c.19A>T (p.Ile7Phe)

LegacyVariant: c.48A>T (p.Ile-40Phe)

ClinVar: 367997

CAID: CA10529708

gnomAD: Filtering AF: 0.0007752 (no homozygotes)

Case#: Patient 72 (Spanish origin; assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Not available

ParentalTesting: Not available

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: FIX:C = <1 (reduced factor IX activity)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: P4 (female)

DiseaseAssertion: Carrier

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0003125, HP:0001928

CaseHPOFreeText: Low FVIII levels (FVIII:Ag showed a moderate reduction (29.8% ± 1.7, p < 0.01) compared to the WT; FVIII:C undetectable), abnormal blood coagulation

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection and in silico analysis were also performed.

Gene: F8

Variant: NM_000132.4:c.1730C>A

CAID: CA414911649

gnomAD: Absent/Not Reported

Case#: 37HBT150 (Turkish; assumed male)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: Not provided

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: Reduced factor IX activity (FIX:C: 1.3)

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>T (p.Arg43Leu)

LegacyVariant: c.6365 G>T (p.Arg-4Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: HB-125 (assumed male, India)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C <1%)

CaseNotHPOs: None

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case#: Heit_Proband_HB535 (assumed male, AmerIndian from Peru)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

LegacyVariant: c.6364C>T (Arg-4Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Absent/Not Reported

Case#: Mülling_Proband_1 (55 y/o, male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858, HP:0100584, HP:0002094

CaseHPOsFreeText: Reduced factor IX activity (FIX activity: 3%), infective endocarditis, dyspnea

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.110C>T (p.Ala37Val)

ClinVar: Absent

CAID: CA414435437

gnomAD: 0.00002186 in European (non-Finnish) population (highest frequency of variant found in this population)

AdditionalCaseInfo: Patient developed severe bleeding under therapy with phenprocoumon, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors

Case#: Ghanem_Paris 2 (assumed male, from Paris) & Ghanem_ Caen 2 (assumed male, from Caen)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (Paris 2: FIX:C: <1, FIX:Ag: 28, Caen 2: FIX:C: <1

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.127C>T (p.Arg43Trp)

ClinVar: 811505

CAID: CA414435537

gnomAD: Highest AF (South Asian population): 0.0004904

Case#: Calgary 15

DiseaseAssertion: Hemophilia B (severity not provided)

FamilyInfo: None

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (does not specify severity for probands) "patients from these kindreds have various disease severity, with plasma factor IX activity from < 0.01 U/mL to 0.30 U/mL." "FIX antigen was not available from patients from 6 kindreds, reduced in seven, normal in six, and not available from six."

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

LegacyVariant: c.6365 G>A (p.Arg-4Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case: Gustafson_II:3

CasePresentingHPOsFreeText: Retrospective review of ophthalmic examination notes was performed in three affected family members (II:2, II:4, and II:6). Information about eye examination, including best corrected visual acuity (BCVA) and dilated fundus examination, kinetic perimetry, and spectral-domain optical coherence tomography (SD-OCT) scans through the fovea were obtained in all three affected patients (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany and Cirrus HD OCT, Carl Zeiss Meditech Inc., Dublin, CA, USA). Full-field electroretinogram (ERG) testing was performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards [ 4 ] in the two sisters (II:2 and II:4) but was not performed in the second cousin (II:6).

CasePreviousTesting: WES

CaseGenotypingMethod: Whole exomes of three affected (II:2, II:4 and II:6) and to unaffected family members (I:6, II:3) were sequenced using Agilent Sure Select V1 probes (Agilent Technologies, Inc., Santa Clara, CA, USA) and Illumina HiSeq 2500 (Illumina, San Diego, CA, USA). Whole genomes of family members II:2, II:3, II:4, II:6, and I:6 were sequenced at more than 30X depth using Illumina HiSeq X (Illumina,). Segregation of substitution mutations and small deletions were tested by dideoxy sequencing

Variant: c.226C>T (p.Arg76*)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Ashkenazi Jewish

PreviouslyPublished:

VariantEvidence:

Case: Gustafson_II:1, female, 60 years old

CasePresentingHPOsFreeText: Retrospective review of ophthalmic examination notes was performed in three affected family members (II:2, II:4, and II:6). Information about eye examination, including best corrected visual acuity (BCVA) and dilated fundus examination, kinetic perimetry, and spectral-domain optical coherence tomography (SD-OCT) scans through the fovea were obtained in all three affected patients (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany and Cirrus HD OCT, Carl Zeiss Meditech Inc., Dublin, CA, USA). Full-field electroretinogram (ERG) testing was performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards [ 4 ] in the two sisters (II:2 and II:4) but was not performed in the second cousin (II:6)

CasePreviousTesting: WES

CaseGenotypingMethod: Whole exomes of three affected (II:2, II:4 and II:6) and to unaffected family members (I:6, II:3) were sequenced using Agilent Sure Select V1 probes (Agilent Technologies, Inc., Santa Clara, CA, USA) and Illumina HiSeq 2500 (Illumina, San Diego, CA, USA). Whole genomes of family members II:2, II:3, II:4, II:6, and I:6 were sequenced at more than 30X depth using Illumina HiSeq X (Illumina,). Segregation of substitution mutations and small deletions were tested by dideoxy sequencing

Variant: c.226C>T (p.Arg76*)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Ashkenazi Jewish

PreviouslyPublished:

VariantEvidence:

Case: Shamieh_FamilyC_II:3; CIC01225

CasePresentingHPOsFreeText: Rod-cone dystrophy, Each subject underwent an ophthalmic exami- nation with clinical assessment as previously described. The three affected individuals with KIZ variants in this study were all diagnosed with RCD in their late teens on the basis of night blindness followed by changes in mid- peripheral visual fields and undetectable responses in a full-field electroretinogram by approximately 35 years of age.

CasePreviousTesting: No mention of previous testing

CaseGenotypingMethod: screening of coding and flanking exonic regions of KIZ by direct Sanger sequencing

Variant: compound heterozygous for the c.52G>T (p.Glu18) and c.119_122delAACT (p.Lys40Ilefs14) variants.

ClinVarID: or CAID: c.52G>T (CA151550) , c.119_122delAACT (CA151553)

gnomAD: allele frequency = 0.00009237 for the c.119_122delAACT variant, c.52G>T variant is absent from gnomAD v2.1.1

AddCaseInfo: Cosegregation analysis revealed that the father was heterozygous for the nonsense mutation and the mother was heterozygous for the frameshift deletion

Case#: P10-GR, F, Age of Report: 63 y.o., Ethnicity: Greece.

CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000613 (Photophobia), HP:0200070 (Peripheral retinal atrophy/diffuse outer retinal atrophy), HP:0025010 (Foveal atrophy), HP:0500087 (Peripapillary atrophy), HP:0030329 (Retinal thinning), HP:0008619 (Bilateral sensorineural hearing impairment/bilateral hearing impairment/moderate SNHL)

CaseHPOFreeText: P10-GR is a 63 year-old female with adulthood-onset RP. She is the third offspring of a non-consanguineous marriage with no family history of RP or hearing loss (Fig.1g).

She reported night blindness since the age of 25 years with subsequent visual field constriction around the age of 35 and recent onset of photophobia. Her BCVA was 0.16 D in the right eye and 0.125 D in the left eye and she was pseudophakic. Fundoscopy revealed the presence of diffuse outer retinal atrophy with intraretinal pigment migration in the mid- and far-periphery along with foveal and peripapillary atrophy and vessel attenuation. FAF imaging showed areas of hypo-autofluorescence in the periphery, around the optic disc and in the fovea corresponding to the areas of retinal atrophy. SD-OCT showed retinal thinning with atrophy of outer retinal layers and foveal RPE loss (Fig. 2f, Table 2). The patient reported bilateral hearing impairment since the age of 58 years. Audiometry confirmed the presence of moderate SNHL with a flat audiogram and a PTA of 50 dB (Fig. 3).

CaseNotHPOs: N/A..

CaseNotHPOFreeText: N/A.

CasePreviousTesting: N/A.

CaseMethod1: N/A

CaseMethod2: N/A.

CaseGenotypingMethod: WES.

Variant: Variant 1: NM_021831.6:c.883G>A (p.Asp295Asn). Variant 2: NM_021831.6:c.316A>G (p.Met106Val ).

ClinVar: Variant 1: 242932. Variant 2: N/A.

CAID: Variant 1: CA10584033. Variant 2: CA346170014.

gnomAD: Variant 1: Frequency: 0.000005530. Link: https://gnomad.broadinstitute.org/variant/chr2-27055228-G-A?dataset=gnomad_r4. Variant 2: Frequency: 6.800e-7. Link: https://gnomad.broadinstitute.org/variant/chr2-27053502-A-G?dataset=gnomad_r4.

VariantEvidence: N/A.

CaseAddInfo: Molecular analysis identified two compound heterozygous variants in AGBL5: c.883G>A, p.(Asp295Asn) and c.316A>G, p.(Met106Val), that were shown to be in trans, since the unaffected daughter of the patient only carries the c.883G>A, p.(Asp295Asn) (Fig. 1g, Table 1).

CasePMIDs: N/A.

Case: Jauregui_Case3

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.226C>T (p.R76X)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Male. Caucasian, 21 years old

PreviouslyPublished:

VariantEvidence:

Case: Jauregui_Case2

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.226C>T (p.R76X)

ClinVarID: or CAID: CA151548

gnomAD: allele freq. of 0.001173 in the Latino population

AddCaseInfo: Male. Caucasian, 60 years old

PreviouslyPublished:

VariantEvidence:

Case: Jauregui_Case1

CasePresentingHPOsFreeText: The data presented in this study, including images and genetic testing results, is not identifiable to individual patients. A retro- spective review of patients with a clinical diagnosis of RP by an inherited retinal disease specialist (SHT) at the Department of Ophthalmology at Columbia University was conducted. The clinical diagnosis was based on pre- senting symptoms, family history, fundus examination, and subsequently supported by clinical imaging, full-field electroretinography (ffERG), and/or genetic testing. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best-corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW- AF, 488 nm excitation), and spectral domain optical coherence tomography (SD-OCT). The inclusion criteria for this study were the diagnosis of RP and genetic characterization of the disease, while the exclusion criteria precluded monocular patients or those without SD-OCT or SW-AF imaging

CasePreviousTesting: not mentioned

CaseGenotypingMethod: not mentioned

Variant: c.119_122delAACT (p.K40IfsX14)

ClinVarID: or CAID: CA151553

gnomAD: allele freq. of 0.00009237 in the European (non-finnish) population

AddCaseInfo: Male. Caucasian, 56 years old

PreviouslyPublished:

VariantEvidence:

Case: Lin_FamilyB_II:1

CasePresentingHPOsFreeText: Ophthalmic examination notes were retrospectively reviewed in patients. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT) scans through the fovea, and short-wavelength fundus autofluorescence (SW-AF, 488 nm), were obtained in all four affected patients with Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Full-field electroretinogram (ERG) testing was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients in this study exhibited chorioretinal phenotypes characteristic of RP (Figure 1). All patients initially presented with night blindness followed by progressive constriction of their visual field. ERG recordings were collected from three patients (A-II:2, B-II:1, and D-II:5) (Figure 3). For A-II:2 at 60 years of age and D-II:5 at age 37 years of age, ERG rod responses of the right eyes were almost undetectable.

CasePreviousTesting: WES

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either whole exome sequencing (WES, A-II:2, B-II:1, and D-II:5)

Variant: c.119_122delAACT (p.Lys40llefsTer14)

ClinVarID: or CAID: CA151553

gnomAD: allele frequency of 0.00009237 in the European (non-Finnish) population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Case: Lin_FamilyD_II:5

CasePresentingHPOsFreeText: Ophthalmic examination notes were retrospectively reviewed in patients. Best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus examination, spectral-domain optical coherence tomography (SD-OCT) scans through the fovea, and short-wavelength fundus autofluorescence (SW-AF, 488 nm), were obtained in all four affected patients with Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Full-field electroretinogram (ERG) testing was performed according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. The patients in this study exhibited chorioretinal phenotypes characteristic of RP (Figure 1). All patients initially presented with night blindness followed by progressive constriction of their visual field. ERG recordings were collected from three patients (A-II:2, B-II:1, and D-II:5) (Figure 3). For A-II:2 at 60 years of age and D-II:5 at age 37 years of age, ERG rod responses of the right eyes were almost undetectable.

CasePreviousTesting: WES

CaseGenotypingMethod: Genetic testing was performed in all four patients in this study, using either whole exome sequencing (WES, A-II:2, B-II:1, and D-II:5)

Variant: c.226C>T (p.Arg76Ter)

ClinVarID: or CAID: CA151548

gnomAD: allele frequency of 0.001173 in the Latino population

AddCaseInfo:

PreviouslyPublished:

VariantEvidence:

Family#: RP19

PresentingHPOs: HP:0007642, HP:0030824 (Congenital stationary night blindness, Mizuo-Nakamura phenomenon)

PresentingHPOsFreeText: Diffuse gray discoloration of the fundus, scotopic ERG showed a significantly reduced rod response (in selected individuals analyzed)

FamilyNotHPOsFreeText: During fundoscopy of the individuals IV-3 and V-1, no bone spicule deposits were observed in the fundus.

CountryOrigin: Pakistan, central region of Punjab province

Family#PreviousTesting: None

Family#Method1: Homozygosity mapping

Family#Method2: Sequencing

Family#GenotypingMethod: Linkage: Six affected family members were analyzed by whole-genome SNP analysis, which showed homozygosity for a 15.2 Mb region on chromosome 13q34. Using fluorescently labeled microsatellite markers to analyze all available family members, the critical region was refined to a 5-Mb region between D13S1315 (position 109.1 Mb) at the centromeric side and 13qter (position 114.1 Mb). All eight affected individuals were homozygous for this chromosomal interval (Figure 1). A maximum two-point LOD score of 5.1 for marker D13S1295 at theta 0 was determined.

All seven coding exons and flanking intronic sequences of GRK1 were sequenced in affected family members IV-1, V-5, and V-11. The segregation of a novel mutation in the family and the frequency of the identified mutation in the Pakistani population were determined by StuI RFLP analysis.

Affected: 8

Unaffected: 14

PublishedLOD: Maximum two-point LOD score of 5.1 for marker D13S1295 at theta 0.

ProbandLabel: RP19, IV-1

Variant: NM_002929.3(GRK1):c.614C>A (p.Ser205Ter) (homozygous)

ClinVar: 870430

CAID: CA388824706

gnomAD: Not in gnomAD

FamilyAddInfo: All parents, as well as several unaffected siblings, were heterozygous carriers of the variant. Eight unaffected individuals were homozygous for the wild-type sequence. In two branches of the family, (IV6/IV7, IV8/IV9, and their children) the parents are first cousins.

Case#: RP19, IV-1

CaseHPOs: HP:0007642, HP:0030824 (Congenital stationary night blindness, Mizuo-Nakamura phenomenon)

CaseHPOsFreeText: Diffuse gray discoloration of the fundus, scotopic ERG showed a significantly reduced rod response (in selected individuals analyzed)

CaseNotHPOsFreeText: During fundoscopy of the individuals IV-3 and V-1, no bone spicule deposits were observed in the fundus.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: All seven coding exons and flanking intronic sequences of GRK1 were sequenced in affected family members IV-1, V-5, and V-11.

Variant: NM_002929.3(GRK1):c.614C>A (p.Ser205Ter) (homozygous)

ClinVar: 870430

CAID: CA388824706

gnomAD: Not in gnomAD

Case#: Uttarilli Patient 6, male, 4yo at presentation

DiseaseAssertion: MPS1, Hurler-Scheie

FamilyInfo: non-consanguineous

CasePresentingHPOs: HP:0007957, HP:0000280, HP:0000943, HP:0002240, HP:0001744

CaseHPOFreeText: IDUA enzyme activity=0 (reference = 11–26 nmol/h/mg)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of all exons of IDUA and IDS genes and bidirectional sequencing

PreviouslyPublished:

Variant: [c.223G>A] [p.Ala75Thr]; [c.895G>T] [p.Glu299*]

CAID: CA356994; CA355962511

SupplementalData: n/a

Case#: Patient 25, male, 7 months (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomyopathy, dysostosis multiplex, global developmental delay, hepatomegaly, inguinal hernia, skeletal abnormalities, splenomegaly, recurrent respiratory infections (HP:0007957, HP:0000256, HP:0001638, HP:0000943, HP:0001263, HP:0002240, HP:0000023, HP:0002652, HP:0001744, HP:0002205)

CaseHPOFreeText: Global dyskinesia

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: N/A

PreviouslyPublished N/A

Case#: Patient 20, male, 8 years (age at presentation).

DiseaseAssertion: MPS1-H/S

FamilyInfo: Consanguinity in the family not present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, cardiomyopathy, dystosis multiplex (HP:0007957, HP:0000256, HP:0001638, HP:0000943)

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.1469T>C (p.L490P)

Variant2ClinVarID: 11919

Variant2CAID: CA220503

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 12, female, 6 months (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, intellectual disability, recurrent respiratory infections, splenomegaly, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0010864, HP:0002205, HP:0001744, 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.783delC (p.His262Thrfs*55)

Variant1ClinVarID: 956890

Variant1CAID: CA2802083

Variant2: c.783delC (p.His262Thrfs*55)

Variant2ClinVarID: 956890

Variant2CAID: CA2802083

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 26, male, 1 year (age at presentation).

DiseaseAssertion: MPS1-H

FamilyInfo: Consanguinity in the family not present for this patient.

CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, intellectual disabilities, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0010864, 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: N/A

PreviouslyPublished N/A

Case#: Patient 47, female, Han origin, 4 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0001387, HP:0001433, HP:0006536)

CaseHPOFreeText: Cardiac disease

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

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: IDUA activity 0.9 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: N/A

Variant1ClinVarID: N/A

Variant1CAID: N/A

Variant2: c.1898C>T (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355961718

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 57, female, Han origin, 2 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/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 1.5 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.1262T>C (p.L421P)

Variant1ClinVarID: 1328979

Variant1CAID: CA355963724

Variant2: c.1898C>T (p.S633L)

Variant2ClinVarID: 556406

Variant2CAID: CA355966010

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 27, female, Han origin, 9 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/S

CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Hernia (HP:0001263, HP:0000256, HP:0100790)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 3.4 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.98A>C (p.H33P)

Variant1ClinVarID: N/A

Variant1CAID: CA355945475

Variant2: c.1402+2T>G

Variant2ClinVarID: 553131

Variant2CAID: CA355964392

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 21, female, Han origin, 10 years old (age at diagnosis)

DiseaseAssertion: MPS1-S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly, Mongolian macula (HP:0001263, HP:0000256, HP:0011369)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 0.2 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.1898C>T (p.S633L)

Variant1ClinVarID: 556406

Variant1CAID: CA355966010

Variant2: c.536C>G (p.T179R)

Variant2ClinVarID: 556358

Variant2CAID: CA355961718

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 36, female, Han origin, 5 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 1.5 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.159C>A (p.C53X)

Variant1ClinVarID: 1458768

Variant1CAID: N/A

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 in trans by parental testing.

PreviouslyPublished N/A

Case#: Patient 43, male, Han origin, 5 years old (age at diagnosis)

DiseaseAssertion: MPS1-H/S

FamilyInfo: N/A

CasePresentingHPOs: Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Global Developmental Delay, Macrocephaly (HP:0001263, HP:0000256)

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.300-3C>G

Variant1ClinVarID: 551563

Variant1CAID: CA549265042

Variant2: c.530dupT (p.Glu178ArgfsTer5) (Paper refers to the variant as c.531dupT, there is a typo in the article where all duplication variants are one base pair off)

Variant2ClinVarID: N/A

Variant2CAID: CA2586973520

AdditionalVariants: c.1037T>G (p.L346R)

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 10, born in 2010 (paper published in 2017), 6 months (age at first 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: 60 ng/mol (26 weight matched enzyme reference assay)

CaseUrineGAGs: 0.29 DS/CS

CaseERT: Yes

CaseBMT: Yes, Cord

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

Case#: Patient 14, born in 1998 (paper published in 2017), 19 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding, cataract (HP:0007957, HP:0000518)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy (HP:0000488)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 31.4 ng/mol (60.7 weight matched enzyme reference assay)

CaseUrineGAGs: 0.60 DS/CS

CaseERT: No

CaseBMT: Yes, MUD

Variant1: c.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

Variant2: c.979G>C (p.A327P)

Variant2ClinVarID: 167190

Variant2CAID: CA234128

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 24, born in 2009 (paper published in 2017), 8 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Cataract, retinopathy (HP:0000518, HP:0000488)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 48.88 ng/mol (48.75 weight matched enzyme reference assay)

CaseUrineGAGs: 0.28 DS/CS

CaseERT: Yes

CaseBMT: Yes, MUD

Variant1: c.1205G>A (p.W402X)

Variant1ClinVarID: 11908

Variant1CAID: CA220498

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

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A