Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumours (20 women and 15 men; median age 37 [21-57 years],) were included in this study. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. VHL mutation analysis was performed on DNA isolated from peripheral blood lymphocytes. PCR analysis and direct sequencing of the 3 exons of VHL was performed for all the DNA. If no mutation was detected, Southern blot analysis was performed to detect large rearrangements. Patient no. 14 from family 12 had a missense mutation in the VHL gene (c.245G>C) and presented with pancreatic endocrine tumour, pheochromocytoma, and renal carcinoma. Suggested ACMG evidence codes: The patient's phenotypes are highly specific to VHL disease (PP4).

GroupID/ KindredID: 9YO, 51CE, 4327NCI, 160CA

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Department of Uroglogy, Yokohama database, the Munich, university of Freiburg and Institute of Pathology database, the National Cancer Institute database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 9YO, 51CE, 4327NCI, 160CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

LegacyVariant: p.N78S (c.446A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S111N (c.332G>A)) was taken from the National Cancer Institute database and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 3315NCI and 127CA. It was reported in the paper as c.545G>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

PatientID: 3404

KindredID: 209

Case: Sex Unknown, Age Unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

CaseNotHPOs: N/A

CaseHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9829912

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.L158P (c.473T>C) germline variant of the VHL gene was detected in an individual (ID 5342, Family 252). They presented with renal cell carcinoma. The paper states that this individual is previously reported in PMID 12202531 and/or 9829912.

GroupID: 60

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 2 members of this family were found to harbor the c.482G>A germline variant of the VHL gene. Member 1603 presented with mild renal disease. Member 1601 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0009726; HP:0005584 (Renal neoplasm, Renal cell carcinoma)

GroupHPOFreeText: Mild renal disease (simple renal cyst, multicystic kidney[s], small lesion [less than 10 mm in size] of unknown significance, or small solid tumor without indication for surgical removal [less than 30 mm in size]). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 individuals and 3 families respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family. These previously published individuals could alternatively correspond to family 279.

SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID: 48

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q96* (c.286C>T)

LegacyVariant: c.499C>T

CaseProblemVariantFreeText: N/A

ClinVarID: 428804, https://www.ncbi.nlm.nih.gov/clinvar/variation/428804/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Q96* (c.286C>T)

MultipleGeneVariants: N/A

Patients with ELSTs were identified and included in the International Endolymphatic Sac Tumor Registry. The registry contained 93 patients as of July 2014, and of those, 25 were sporadic, and 68 associated with VHL. Patients with ELSTs and clinically confirmed diagnoses of VHL were included in this study. Statistics of this VHL subgroup are as follows: mean age 30, 62% female, 91% symptomatic, 54% with retinal angioma, 72% with CNS hemangioblastoma, 46% with renal cell carcinoma, 19% with pheochromocytoma, and 12% with pancreatic neuroendocrine tumour. In the data from this study, only endolymphatic sac tumours can be confirmed as a phenotype for this mutation (c.473T>C), which was found in 1 individual from France.

PatientID: 5

KindredID: 5

Case: F, 11Y0M, Korean

DiseaseAssertion: Adrenal Pheochromocytoma

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748 (adrenal pheochromocytoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma (see table 3)

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, NF1, MAX, SDHA/SDHAF2/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

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 kindred #63. A female proband (patient 163) was diagnosed with a CNS hemangioblastoma at 37Y, renal cell carcinoma at 37Y, pheochromocytoma at 17Y, and multiple pancreatic lesions at 37Y. Her brother (patient 164) was diagnosed with CNS hemangioblastoma at 27Y, retinal angioma at 26Y, and pheochromocytoma at 8Y. Her niece of unknown age is asymptomatic. Her mother, who was not genetically confirmed with the mutation due to lack of DNA sample, was diagnosed with multiple pancreatic cysts/tumors at 56Y and pheochromocytoma at 56Y. This kindred was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A variant in the CHEK2 gene (a moderate breast cancer gene) was observed in this case study of a man with 5 different cancers. The man was under investigations of a possible VHL syndrome diagnosis, although this was negative as no variant was detected in him. However, the proband’s maternal aunt had genetic testing done which identified a VHL mutation: c.74C>T(p.Pro25Leu), which was thought to be pathogenic at the time. She was diagnosed with pheochromocytoma at the age of 56Y and breast cancer at 66Y. She was given next-generation sequencing (NGS) for MAX, RET, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and multiplex ligation-dependent probe amplification (MLPA) for VHL, SDHA, MAX, SDHB, SDHC and SDHC. No pathogenic mutation was detected. The mother of the male index case died of non-Hodgkin’s lymphoma at 47Y0M in 1993. His sister was diagnosed with breast cancer at 26Y0M and died at 27Y0M in 1999. Neither his sister nor mother had genetic testing.

GroupID: 5B

DiseaseAssertion: Unknown. Patients were pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 7

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 7 patients with the given mutation were grouped as group 5(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L89P (c.266T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182979 https://www.ncbi.nlm.nih.gov/clinvar/variation/182979/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

GroupID: 10B

DiseaseAssertion: Unknown. Patients were pulled from either the VHL-Registry or NET-Registry and recorded with the given mutation. Symptoms or manifestations are not clear.

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation were grouped as group 10(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F119L (c.357C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625240 https://www.ncbi.nlm.nih.gov/clinvar/variation/625240/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

GroupID: 46

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Japanese

GroupAgeRange: N/A

GroupInfo: 2 individuals from a single family (ID 46).

GroupPresentingHPOs: HP:0001732; HP:0005584 (Abnormality of the pancreas, Renal cell carcinoma)

GroupHPOFreeText: Renal cell carcinoma (2/2) and pancreatic tumor or cyst (unspecified) (1/2).

GroupNotHPOs: HP:0009711; HP:0010797 (Retinal capillary hemangioma, Hemangioblastoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8634692

SupplementalData: N/A

Variant: p.L118P (c.353T>C)

LegacyVariant: c.566T>C

CaseProblemVariantFreeText: N/A

ClinVarID: 428807, https://www.ncbi.nlm.nih.gov/clinvar/variation/428807/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L118P (c.353T>C)

MultipleGeneVariants: N/A

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The L118P (c.353T>C) germline missense mutation was found in a VHL type 1 family presenting with renal cell carcinoma (2/2) and pancreatic tumor or cyst (unspecified) (1/2) (family ID 83). This family was previously reported in PMID 8634692.

PatientID: 16 (tumour 28)

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET

PreviouslyPublished: 7759077, 9681856

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.Q195 (c.583C>T) stop-gain mutation (noted as c.796C>T (p.Q266) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred no.21. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper. ACMG evidence codes: none.

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Not specified

FamilyInfo: Many of the patient’s family members developed lesions in sites suggesting VHL including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and some of the family members have lost their sight because of retinal detachment (probably in the case of retinal haemangiomas). However, the diagnosis of VHL has not been established in the family. One of the patient’s siblings and the patient’s father were also found to have the NM_000551.3:c.194C>T(S65L) mutation after analysis of blood samples, and the patient’s father had an endolymphatic sac tumour at 19Y and a recurrence at 21Y. At 24Y, his father had a hemangioblastoma and had a recurrence at 26Y. His father also had a history of retinal capillary angioma.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

LegacyVariant: p.S65L (c.407C>T)

ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

gnomAD: 0.000, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed. Higher risk of pheochromocytoma was associated with missense mutations that result in substitution of a surface amino acid (p<=0.004) than for patients with missense mutations that disrupt the structural integrity of the VHL gene product (pVHL) or other loss of function mutations (either germline deletions or truncating mutations). This missense mutation (c.461C>T) is within the protein core and was found in a single VHL family with 6 patients. One patient had retinal hemangioblastomas, 2 had cerebellar hemangioblastomas, 3 had renal cell carcinoma, 2 had pheochromocytoma. Only supporting evidence of pathogenicity because of cosegregation of disease with multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

The data of 18 patients with solid renal tumours associated with VHL disease were analyzed. All patients except for Patient 12 came from families with a definite VHL family history (the paper does not provide further details on this.) The patients came from 12 Chinese families and 5 were from the same family. Extrarenal manifestations of VHL disease were detected in 17 patients. Of 18 patients, 15 (including 6 asymptomatic) volunteered for DNA testing as previously described. Patients 1-5 had genetic testing and were found to have the same germline mutation c.223A>G (Asn78Ser). This missense mutation is noted as c.446A>G in the paper due to a difference in the VHL reference sequence notation used. It is unclear if these patients are related. Patients 4 and 5 had family study DNA test as their reason for treatment. Patient 1 was a 34-year-old male with a medical history of asynchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, CNS hemangioblastoma, pancreatic cyst, and epididymal cystadenomas. Patient 2 was a 44-year-old female with a medical history of asynchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, retinal angioma, and pancreatic cysts. Patient 3 was a 43-year-old male a medical history of synchronous bilateral solid renal tumors some which were further characterized as clear cell RCC, multiple renal cysts, retinal angioma, and pancreatic cysts. Patient 4 was a 52-year-old female a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, retinal angioma, and pancreatic cysts. Patient 5 was a 46-year-old female with a medical history of clear cell RCC, multiple renal cysts, and pancreatic cysts.

PatientID: 6

KindredID: 6

Case: 35Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0009711 (hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65L (c.194C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

CAID: N/A

gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L (c.194C>T)

MultipleGeneVariants: N/A

PatientID: (proband)

KindredID: 2

Case: F, Age unknown, Chinese

DiseaseAssertion: pheochromocytoma

FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history as well as a confirmed presence of this same germline mutation in their mother

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: non-syndromic pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: No clinical manifestations of hereditary syndromes, including MEN2A, MEN2B, VHL, and NF1 were found

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: p.R161Q (c.695G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182983 https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was found in a VHL type 1 family of 10 individuals (family ID 1239), using PCR and SSCP sequencing. The mutation of c.351G>T was referred to in the paper by c.564G>T due to a difference in transcript sequence. Seven of 10 individuals were identified with CNS hemangioblastomas and renal cell carcinoma. One identified with retinal hemangioblastomas. This is possibly previously published in PMID 9829911. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This frameshift mutation was found in 3 family members with VHL (Family ID 3575), using PCR and SSCP sequencing. The mutation of c.448delA was referred to in the paper by c.661delA due to a difference in transcript sequence. 2/3 members had retinal angiomas (hemangiomas), 1 had CNS hemangioblastoma and 1 had renal cell carcinoma.

This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation (p.P86S (c.256C>T)) was detected by direct sequencing and MLPA in 2 VHL kindreds. One family had pheochromocytoma, renal cell carcinoma, and retinal angiomas (case no. 182). The other family had hemangioblastomas of the central nervous system (case no. 177). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease, 'PP4' because the patient's phenotypes or family history are highly specific for a disease with single genetic etiology.

PatientID: III-2

KindredID: 1

Case: M, 16Y0M, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo:  2 young male twins were examined with the VHL gene mutation with simultaneously manifesting hemangioblastomas of the right cerebellar hemisphere. Both parents were examined with no VHL mutation, detecting a de novo mutation in the twins. A third sibling, two years older, presented with a cafè au lait skin spot. Grand mother had bilateral high myopia and glaucoma. The medical history of the pedigree shows that member (I-1) had severe hypertension and died at 60 from a stroke, member (I-2) died at 40 from ovarian carcinoma, and member (I-3) died at 54 from clinically diagnosed intracerebral haemorrhage.

CasePresentingHPOs: HP:0006880; HP:0009713 (cerebellar hemangioblastoma, spinal hemangioblastoma)

CaseHPOFreeText: in 1994 patient came complaining of blurred vision thought to be due to his myopia. MRI showed a large cyst and a 4.3 cm mural ovoid nodule in the right cerebellar hemisphere. Another small mural nodule was present in the infero-posterolateral portion of the right cerebellar hemisphere. CT disclosed a round homogeneous, hyperintense nodule at T1 in the spinal cord. Raised intracranial pressure due to the compression of aqueduct from the tumour accounted for hydrocephalus and enlarged lateral and 3rd ventricles.

CaseNotHPOs: HP:0001901 (polycythemia)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N78S (c.233A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.N78S (c.446A>G)

ClinVarID: 93326 https://www.ncbi.nlm.nih.gov/clinvar/variation/93326/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N/A

MultipleGeneVariants: N/A

GroupID: None

DiseaseAssertion: VHL

GroupSize: 6

GroupNumberMales:N/A

GroupNumberFemales:N/A

GroupEthnicity: N/A

GroupAgeRange: ≥12

GroupInfo: The six patients were grouped by mutation.

GroupPresentingHPOs: HP:0001732 (abnormality of the pancreas)

GroupHPOFreeText: N/A

GroupNotHPOs:N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L158P (c.473T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 182980 https://www.ncbi.nlm.nih.gov/clinvar/variation/182980/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L158P (c.473T>C)

MultipleGeneVariants: N/A

PatientID: III-3

KindredID: 1

Case: M, 32Y0M, Mexican

DiseaseAssertion: VHL

FamilyInfo: Family composed of six affected individuals and three diseased subjects (III-2, III-3, III-4) were studied. III-4 (proband) presented with a CNS hemangioblastoma and a retinal hemangioblastoma. The mother (II-1) developed cerebellar, medullar and bilateral retinal HBs; two maternal aunts (II-2 and II-3) were affected by retinal and CNS HBs and unspecified renal tumors, whereas his grandfather (I-2) had unspecified abdominal tumors. All these relatives died in their early 30s. A 35-year-old sister (III-2) demonstrated cerebellar HB, right eye retinal HB and renal cell carcinoma, whereas a 32-year-old brother (III-3) presented with cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma. A mutation-carrier nephew (IV-2) presented only atrophy of the retinal pigment epithelium. All of these family members were found to have the R82P (c.245G>C) germline VHL variant. Eighteen additional healthy relatives were analyzed and tested negative for the mutation.

CohortInfo: Two families and one apparently non-familial case were studied at the Institute of Ophthalmology ‘Conde de Valenciana’ (Mexico City, Mexico).

CasePresentingHPOs: HP:0006880; HP:0009711; HP:0005584; HP:0002666 (Cerebellar hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma, Pheochromocytoma)

CaseHPOFreeText: Cerebellar HB, right eye retinal HB, renal cell carcinoma and pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Family pedigree (Figure 1 (a))

Variant: p.R82P (c.245G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 526675, https://www.ncbi.nlm.nih.gov/clinvar/variation/526675/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: R82P (c.245G>C)

MultipleGeneVariants: N/A

PatientID: VHL-15

KindredID: 15

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

CasePresentingHPOs: HP:0010797; HP:0001732 (Hemangioblastoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma. Clinical classification: A2.

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86S (c.256C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 178692, https://www.ncbi.nlm.nih.gov/clinvar/variation/178692/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P86S (c.256C>T)

MultipleGeneVariants: N/A

This paper analyzed the VHL gene of 21 patients who had clinical a clinical diagnosis of VHL, familial pheochromocytoma, or sporadic pheochromocytoma. 7 patients were from 3 families, while the remaining 14 were unrelated. Mutations were detected by realtime quantitative PCR (RQ-PCR) assays using peripheral venous blood. The mutation (c.533T>A) was found in 1 individual (female, 21Y), without family history, who presented with pheochromocytoma and hypertension. This case was also later presented in PMID: 24735130 (Pai et al, 2014). ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

56 male patients age 12 to 76 years, from 40 families with VHL were examined as part of a larger screening program for VHL. VHL mutations were identified in 16 families. Individual patient phenotype-genotype data was not available, but the mutations found and whether the corresponding patient had epididymal cystadenoma (EC) was reported. A p.Asn78His (c.232A>C) VHL mutation was found in a VHL patient with EC. This mutation was referred to in the paper as c.445A>C due to a difference in transcript sequence.

PatientID: CIV:1

KindredID: C

Case: M, 28Y0M, Chinese

DiseaseAssertion: hemangioblastoma

FamilyInfo: A 4-generation family is given with 3 confirmed members with this mutation. 3 other members had VHL-presenations however had not been tested for the gene.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: diagnosed with hemangioblastoma and died of surgical complications at the age of 28Y

CaseNotHPOs: HP:0002666; HP:0005584; HP:0001737; HP:0009711 (pheochromocytoma, renal cell carcinoma, pancreatic cysts, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80I (c.239G>T) [assumed]

LegacyVariant: p.S80I (c.452G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 625229 https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: No genetic testing was done prior to death, however family history and presentation leads to this assumption

MutationType: missense_variant; transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: None (Child 1)

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Asymptomatic

FamilyInfo: Awaiting testing of the proband’s eight siblings to determine whether or not this is a de novo mutation causing VHL disease. Two of three of the proband’s children have inherited the mutation, they have had no disease manifestations.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G144R (c.430G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 576437, https://www.ncbi.nlm.nih.gov/clinvar/variation/576437/

CAID: N/A

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/3-10188287-G-A?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G144R (c.430G>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 1

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromocytoma

FamilyInfo: The proband was part of a cohort of apparently sporadic cases of pheochromocytoma/ paraganglioma, implying this individual had no family history of VHL disease or pheochromocytoma.

CasePresentingHPOs: HP:0006748 (Adrenal Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002668 (Paraganglioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHB, SDHC, and SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161Q (c.482G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 182983, https://www.ncbi.nlm.nih.gov/clinvar/variation/182983/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q(c.482G>A)

MultipleGeneVariants: N/A

PatientID: None (Cousin 1)

KindredID: G

Case: Sex Unknown, 37Y0M, Hungarian

DiseaseAssertion: Assumed VHL

FamilyInfo: Large VHL family spanning five generations. The index patient presented with pheochromocytoma, renal cell carcinoma as well as spinal cord, cerebellar, and medulla oblongata hemangioblastomas. Her parents showed no clinical, biochemical, or radiological evidence of the disease, but VHL-associated tumors were detected in five other family members (bilateral renal cell carcinomas in one, renal cysts in one, spinal cord, cerebellar, and medulla oblongata hemangioblastomas in three, retinal hemangioblastomas in four, and pheochromocytomas in two family members).

CasePresentingHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: Presented with CNS hemangioblastoma at age 37 and retinal hemangioblastoma at age 18. No VHL diagnosis noted but assumed to have VHL based on genetic, clinical and familial findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 18416845

SupplementalData: N/A

Variant: p.S80I (c.239G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625229, https://www.ncbi.nlm.nih.gov/clinvar/variation/625229/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as S80I and cDNA change was mapped to c.239G>T.

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: 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: 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

PMID: 34192316

Gene: IDUA

Disease: MPS1

Inheritance: AR

InsufficientEvidence: Study used fibroblasts from patients with MPS-1. Protein changes associated with the variants in the fibroblasts are provided, but no other patient details are provided.

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 52, female, Han origin, 2 years 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: Cardiac disease

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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.1210G>T (p.E404X)

Variant1ClinVarID: 552095

Variant1CAID: N/A

Variant2: c.1877G>A (p.W626X)

Variant2ClinVarID: 928997

Variant2CAID: N/A

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 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#: Pt 103 , Age 19 years, Female, DiseaseAssertion: MPS1 Scheie syndrome. FamilyInfo: NA CasePresentingHPOs: NA CaseHPOFreeText: NA CaseNotHPOs: NA CaseNotHPOFreeText: NA

CaseEnzymeAssay: Low leukocyte IDUA enzyme activity CaseUrineGAGs: NA CaseERT: No CaseBMT: No Variant1: IVS7+1G>A This may be the variant c.972+1G>A, though cDNA not mentioned in text. Variant1ClinVarID: 198406 Variant1CAID: Variant2:p.X654R , cDNA not mentioned This variant may result from prev reported c.1960T>C ( ClinVar 960079) or from c.1960T>G ( ClinVar 11920) Variant2ClinVarID: Variant2CAID: AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA

Case#: Pt 102 , Age 37 years, Female, DiseaseAssertion: MPS1 Scheie syndrome. FamilyInfo: NA CasePresentingHPOs: NA CaseHPOFreeText: NA CaseNotHPOs: NA CaseNotHPOFreeText: NA

CaseEnzymeAssay: Low leukocyte IDUA enzyme activity CaseUrineGAGs: NA CaseERT: No CaseBMT: No Variant1: p.Q70X Variant1ClinVarID: 11909 Variant1CAID: CA204563 Variant2:p.D445del Variant2ClinVarID: 840115 Variant2CAID: AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA

Case#: 205 5 yrs male, age at initial diagnosis 1.1 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 1.5 yrs on ERT, then study drug, valanafusp alpha, also called AGT-181 for 12 months

CaseBMT: No PreviouslyPublished Don't know Variant1:l Variant1: c.494-1G>A ClinVarID: 557942 Variant1CAID: Variant2:c.494-1G>A Variant2ClinVarID: 557942 Variant2CAID:

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#: Patient 1 of family A: Enrolled in study at 16 months, male, DiseaseAssertion:MPS1 FamilyInfo:Consanguinity Yes CasePresentingHPOs: Asthma HP:0002099, Sleep apnea HP:0010535, Multiple joint contractures HP:0002828, Kyphosis HP:0002808, Recurrent ear infections HP:0410018, Coarse facial features HP:0000280, Hepatosplenomegaly (HP:0001433), Inguinal hernia HP:0000023 Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), CaseHPOFreeText: nose/throat infections, aggressive, heavy eye brows, large tongue, thick lips , rough skin CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: enzyme values lower than the cut-off values CaseUrineGAGs: NA CaseERT: NA CaseBMT:Nil Variant1:c.1456G>T ,Glu486 Variant1ClinVar ID: 651168 Variant1CAID: Variant2:c.1456G>T ,Glu486 Variant2ClinVarID:651168 Variant2CAID: AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA

Case#: P2 (IDUA-02)

DiseaseAssertion: MPS1

FamilyInfo: None provided

CasePresentingHPOs:No info

CaseHPOFreeText: No info

CaseNotHPOs: No info

CaseNotHPOFreeText: No info

CaseEnzymeAssay: Newborn screening using dried blood spot by stable isotope dilution flow injection MS/MS %IDUA enzyme activity =0.17 microM/hour

CaseUrineGAGs: Confirmatory testing using urinary GAGs (heparan [HS] and dermatan sulfate [DS] by LS-MS/MS method: DS=1.79 mg/L, HS=0.77 mg/L

CaseERT: Started ERT (100 U/kg/Week) withing 15 days of birth

CaseBMT: No info

Variant1:c.46_57del12

Variant1ClinVarID:92643

Variant1CAID:

Variant2: p.Y201X

Variant2ClinVarID:1323100

Variant2CAID:

AdditionalVariants:

ParentalGenotype: No info

PreviouslyPublishedNot stated

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#: 2, Male, 4 years 4 months (diagnosed), 17 years (report), weight at presentation : NA, Height at presentation NA, Born in Uruguay

Disease Assertion: Hurler Scheie ( attenuated phenotype)

FamilyInfo: Parents are not consanguineous

Case Presenting HPOs: HP: 0002808, HP: 0002937, HP: 0000280, HP:0000470, HP:0001376, HP:0034337, HP: 0000768, HP:0000943 (Kyphosis, Hemivertebrae, Coarse face, Short neck, Limitation of joint mobility, claw hands, pectus carinatum, dysostosis multiplex )

CaseHPOFreeText: Bony dysplasia

CaseNotHPOs: HP:0007957 HP:0001249, HP:0001433, ( Corneal opacity , Intellectual disability , visceromegaly)

CaseNotHPOFreeText:

CaseEnzymeAssay: IDUA enzyme in dried blood spot 0.26 nmol/h/L ( 2.20-11.70 )

CaseUrineGAGs: NA CaseERT: N/A

CaseBMT: N/A

Genotyping Method: Sanger Sequencing

Variant1: p.L18P (c.53C>T)

Variant1ClinVarID: 193062

Variant1CAID: NA

Variant2: p.W402X

Variant2ClinVarID: 11908

Variant2CAID: 220498

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#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:int3 -2a>g

Variant1ClinVarID:

Variant1CAID:

Variant2:L238Q

Variant2ClinVarID:265418

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:L238Q

Variant1ClinVarID:265418

Variant1CAID:

Variant2:W402X

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:L238Q

Variant1ClinVarID:265418

Variant1CAID:

Variant2:63delC

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

Case#:Not assigned

DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I

FamilyInfo:No information

CasePresentingHPOs:HP:0100543

CaseHPOFreeText:

CaseNotHPOs:HP:0032557

CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.

CaseEnzymeAssay:No information

CaseUrineGAGs:No information

CaseERT:Yes

CaseBMT:No (exclusion criterion)

Variant1:65delC

Variant1ClinVarID:

Variant1CAID:

Variant2:H240R

Variant2ClinVarID:947028

Variant2CAID:

AdditionalVariants:N/A

ParentalGenotype:Not specified

PreviouslyPublished

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