27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 23 was found with an exon 3 deletion of the VHL gene: 4/4 members had CNS hemangioblastoma and 1/4 had retinal capillary hemangioma. ACMG PVS1 PP4

GroupID: 394

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor a germline large rearrangement of the VHL gene. Member 9248 presented with moderate renal disease (RCC). Member 9313 and 2222 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:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). 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, where 12 individuals with this mutation are reported. It is unclear which of the previously reported individuals correspond to which of the currently reported families/individuals (i.e. families 40, 90, 174, 237, 264, 284, 307 or 394).

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

Variant: Rearrangement

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: rearrangement_region

CivicName: Rearrangement

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.K159delinsI* (c.475_476insTTT) germline variant of the VHL gene was detected in a family (ID 43). Member 3207 had no renal involvement. Members 3206 and 3203 presented with mild renal disease. Member 3189 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 12202531 and/or 9829912.

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.N67_V74del (c.197_221del) germline variant of the VHL gene was detected in a family (ID 287). Member 6396 presented with mild renal disease. Member 6611 presented with severe renal disease (RCC). The paper states that this family is previously reported in PMID 9829912, where 1 patient with this mutation is reported but relation to this patient is unclear. The variant is reported as c.197_220del which was mapped to c.198_221del.

PatientID: None

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: His brother and grandfather had the same VHL mutation. His mother also had this mutation and presented with pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, and spinal hemangioblastoma.

CohortInfo:Three patients with endolymphatic sac tumors were studied.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>A

LegacyVariant: N/A

CaseProblemVariantFreeText: The paper describes the mutation as "C-to-A transversion at position −1 on the exon 3 splice acceptor sequence in the VHL gene"

ClinVar: 43603 https://www.ncbi.nlm.nih.gov/clinvar/variation/43603/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: Splice Site (c.464-1G>A)

MultipleGeneVariants: N/A

GroupID: 43

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0030393; HP:0001737; HP:0030405 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Pancreatic endocrine tumor)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (2), Retinal capillary hemangioma (4), Hemangioblastoma/brain/cerebellum (3), Endolymphatic sac tumor (2), Pancreatic cysts (3), Pancreatic endocrine tumor (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, partial deletion

MultipleGeneVariants: Germline, ENST197804, partial deletion

PMID: 10533077

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

ArticleReferenceSequence: Not specified – only protein change was documented by the author, nucleotide variant was found under reference sequence NM_000551.3

GenotypingMethod: PCR amplification of entire VHL coding sequence and promoter region, including exon-intron boundaries. Amplification was performed in a Gene Amp PCR System 9700. When mutations were detected in DNA from tumor samples, we searched for the same mutation in the corresponding PB DNA in order to identify germline mutations. LOH analysis and methylation specific PCR were also performed.

SamplingMethod: formalin-fixed paraffin-embedded tissue, uninvolved normal tissue, peripheral blood

PatientID: 30

KindredID: 64

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584; HP:0030405 (renal cell carcinoma, pancreatic endocrine tumour)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q73* (c.217C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223164 https://www.ncbi.nlm.nih.gov/clinvar/variation/223164/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

CivicName: Q73* (c.217C>T)

MultipleGeneVariants: N/A

PatientID: VCB.14T

KindredID: 6

Case: Sex Unknown, 34Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002668; HP:0002666 (paraganglioma, pheochromocytoma)

CaseHPOFreeText: Presented with bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: 25545346 (see table S1 and S10)

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: SDHA, Germline, c.619A>C (p.Arg207=); SDHA, Germline, c.1969G>A (p.Val657Ile); KIF1B, Germline, c.2192A>G (p.Asn777Ser); MDH2, Somatic, c.26C>T (p.Ala9Val)

Mutational analysis for 16 patients with clinically diagnosed VHL disease, revealed 12 germline mutations. This missense mutation was found in a 43-year-old VHL type 1 patient with renal cell carcinoma, pancreatic cysts, an endolymphatic sac tumor, and an epididymal /ovarian cystadenoma (proband no. 5) and no family history. HPO terms: renal cell carcinoma, multiple pancreatic cysts, epididymal cysts, endolymphatic sac tumors.

PMID: 31383958

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 12

KindredID: 1 (group ID 5)

Case: M, 40Y0M (deceased), Chinese

DiseaseAssertion: assumed VHL

CohortInfo: Clinical characteristics of 258 patients from 80 unrelated Chinese families were reported in this study. Grouped by the 21 mutations found, 2 families with 21 members total were described, and phenotypic information was given for this group.

FamilyInfo: In family 1, 17 members were described. The first generation describes 5 members with the VHL mutation, each passing on the gene to further generations. Patient 12’s mother and brother had this familial mutation. His two daughters had not been yet tested at the time of the study. See Fig 4 for family pedigree; Table 3 for details.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: He had RCC at 40Y

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W88R (c.262T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496053 https://www.ncbi.nlm.nih.gov/clinvar/variation/496053/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: W88R (c.262T>C)

MultipleGeneVariants: N/A

PatientID: 208

KindredID: 79

Case: M, 49Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband's mother and sister had a CNS hemangioblastoma at ages 40 and 50, respectively. His nephew presented with a CNS hemangioblastoma (age 15), a retinal angioma (age 27), and renal cell carcinoma (age 25). His daughter had a retinal angioma at age 14, and a CNS hemangioblastoma at age 24. No genetic testing information was available for family members.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0002666; HP:0005584 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Pheochromocytoma, Renal cell carcinoma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 29. At age 46, they presented with renal cell carcinoma and a pheochromocytoma. At age 49 they presented with multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0009711; (Retinal Capillary Hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Kindred #79 was published in Wang et al., 2014 (PMID: 24581539). This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2216, https://www.ncbi.nlm.nih.gov/clinvar/variation/2216/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 186

KindredID: 72

Case: F, 39Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 72, has multiple family members with the same mutation. Her father (patient 73) had a CNS hemangioblastoma at 65, renal cell carcinioma at 54, and multiple pancreatic cysts/tumors at 67. Her sister 2 (second sister) had multiple pancreatic cysts/tumors at 36, and a CNS hemangioblastoma at 39. Her sister 3 had multiple pancreatic cysts/tumors at 32, and a retinal angioma at 34. The proband's sister 1 had a CNS hemangioblastoma at 22, but passed away before they could be diagnosed/ confirmed with the mutation.

CasePresentingHPOs: HP:0010797; HP:0005584; HP:0001732; HP:0001737; HP:0002666 (Hemangioblastoma, Renal cell carcinoma, Abnormality of the pancreas, Pancreatic cysts, Pheochromocytoma)

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at 37, and a pheochromocytoma at 39.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218; https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954; https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 1

Case: M, Age Unknown, German

DiseaseAssertion: Asymptomatic

FamilyInfo: The patient's father (patient 8) was had both mutations and presented with pheochromocytoma. The patient's brother (patient 10) did not carry the mutation and was unaffected. The patient's maternal grandfather (patient 3) presented with pheochromocytoma and carried both mutations. The patient's materal grandmother (patient 4) was unaffected and did not carry either mutation. The patient's great aunt (patient 2) presented with pheochromocytoma and had both mutations. Her husband (patient 1) was unaffected and did not carry either mutation. They had four children; one died and presented with pheochromocytoma, two (patient 5 and 7) had both mutations and presented with pheochromocytoma, and one child (patient 6) was unaffected and carried neither mutation. Patient 7 had a child (patient 9) who also carried both mutations and presented with pheochromocytoma. See Figure 3 for family pedigree.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P81S (c.241C>T)

LegacyVariant: P81S (c.454C>T)

CaseProblemVariantFreeText: N/A

ClinVar: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: CA020148 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.241C%3ET

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S (c.241C>T) and L188V (c.562C>G)

MultipleGeneVariants: Germline, VHL, c.562C>G (p.Leu188Val)

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 (L188fs (c.563delT)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 141CA. It was reported in the paper as c.776delT 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.

PatientID: III-1

KindredID: 3

Case: M, Age Unknown (deceased), Chinese

DiseaseAssertion: CNS Hemangioblastoma

FamilyInfo: The transition mutation was found and confirmed in 1 patient (II-3) and 2 carriers (III-7, IV-2). 5 members, including III-1, had hemangioblastomas of the CNS, but had all passed away before genetic testing. Could be assumed and deduced the genetics due to pedigree showing future linear relations of this mutation.

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L116V (c.346C>G) [assumed]

LegacyVariant: p.L116V (c.559C>G) [assumed]

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753642 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.346C%3EG

gnomAD: N/A

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

MutationType: missense_variant;transversion

CivicName: L116V (c.346C>G)

MultipleGeneVariants: N/A

A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this synonymous mutation (p.P154= (c.462A>C)) was found in a VHL patient with retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided.

GroupID: None

KindredID: 17

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: American Admixed /Latino

GroupAgeRange: N/A

GroupInfo: 10 members of a South American family expressed this mutation.

GroupPresentingHPOs: HP:0010797, HP:0009711, HP:0005584 (hemangioblastoma, retinal capillary hemangioma, renal cell carcinoma)

GroupHPOFreeText: All 10 family members had a central nervous system hemangioblastoma. One also had a retinal angioma. Five had renal carcinoma. One patient per family with renal tumour <3 cm under follow up detected by imaging.

GroupNotHPOs: HP:0002894, HP:0002666 (neoplasm of the pancreas, pheochromocytoma )

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Partial Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: Deletion

CivicName: Partial Deletion and P61=( c.183C>G)

MultipleGeneVariants: Germline, VHL, c.183C>G (Pro61Pro)

PatientID: 22

KindredID: 3816

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)

CaseHPOFreeText: He presented with one pathologic pancreatic endocrine tumour.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114R (c.340G>C)

LegacyVariant: p.G114R (c.553G>C)

CaseProblemVariantFreeText: N/A

ClinVar: 223193 https://www.ncbi.nlm.nih.gov/clinvar/variation/223193/

CAID: CA357101 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340G%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

PatientID: 11

KindredID: 11

Case: 31Y0M, sex unknown, ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; 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.F76del (c.226delTTC)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA357012 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.224_226del

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.226_228delTTC)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 6Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: No history - the only noteworthy point in her medical history being her conception through in vitro fertilization, however no noted concerns. This mutation was not present in either parent, indicating a de novo.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: patient presented with a prolonged history of general malaise, headaches and abdominal pain. She was noted to have malignant hypertension. Subsequent imaging of the abdomen demonstrated a left adrenal mass (diagnosis of phaeochromocytoma confirmed by serial raised urinary metanephrines). Sympathetic blockade was established prior to definitive surgical treatment, resulting in complete resolution of the patient’s symptoms and hypertension.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90H (c.268A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750708 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.268A%3EC

gnomAD: N/A

VariantEvidence: Neurofibromatosis type (NF) 1 was excluded on clinical grounds as she had none of the cutaneous features. Mutational analysis of the RET proto-oncogene was normal, making MEN2 unlikely. Sequencing of exons 1–3 of the VHL gene revealed a novel single base pair substitution (A268C).

MutationType: missense_variant;transversion

CivicName: N90H (c.268A>C)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation. c.182_185del was found in a VHL patient with retinal angiomas diagnosed at 31Y, and hemangioblastomas of the cerebellum at 30Y.

PatientID: 4

KindredID: F02

Case: F, Age Unknown, Taiwanese

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 2 members of this family (F02) had a complete deletion of the VHL gene. One of these patients (3) presented with clinical features of VHL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of 53.3kb resulted in deletion of Exon 1 in the VHL gene.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, deletion

Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This nonsense mutation was found in a patient with retinal hemangioblastoma, cerebellar hemangioblastoma, and pancreatic cysts (patient no. F3). Patient has family history of paragangliomas, epididymial cysts, and clear cell renal carcinoma. Paper gives variant by protein sequence: L135*. NM_000551.3:c.404T>A and NM_000551.3:c.404T>G both could result in this protein change. Unclear which is correct to the given patient.

ArticleReferenceSequence: Not specified – Assumption: variants assumed to have been documented by the author under reference sequence NM_000551.3

GenotypingMethod: PCR, direct automated sequencing wild-type and mutated VHL sequences were compared manually.

SamplingMethod: peripheral blood leukocytes

PatientID: I.1

KindredID: 3

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion:Asymptomatic

FamilyInfo: The patient had a son who he passed this mutation to. The son (II.1) presented with hemangioblastoma and pancreatic cysts and had an additional de novo exon 1-3 deletion. Refer to figure 1, pedigree C for family information.

CohortInfo: Patients were registrants from the European-American Pheochromocytoma-Paraganglioma and German von Hippel-Lindau Disease Registries.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD/SDHC

PreviouslyPublished: May have been previously published in 11106358 and/or 7563486.

SupplementalData: Yes, File 1 for methods.

Variant: p.P81S(c.241C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2233 https://www.ncbi.nlm.nih.gov/clinvar/variation/2233/

CAID: N/A

gnomAD: 0.0002179 https://gnomad.broadinstitute.org/variant/3-10183772-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: P81S(c.241C>T)

MultipleGeneVariants: N/A

GroupID: 13

Case: Sex unknown, Age unknown, German

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114Vfs*45 (c.339delA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA645509026 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.339delA

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: G114Vfs*45 (c.339delA)

MultipleGeneVariants: N/A

GroupID: 23

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Unknown. 1 registrant from France was found with this variant; no family info was mentioned

CasePresentingHPOs: HP:0030393 (Endolymphatic sac tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: 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: 6 (Sister)

KindredID: 1

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 9 members of this family were found to harbor the c.193T>G germline variant of the VHL gene. ID 35 was asymptomatic. IDs 1 (proband), 28, 2, 17 and 19 all presented with pheochromocytoma. ID 5 presented with CNS hemangioblastoma, retinal angioma and renal cyst OR tumor (not specified). ID 21 presented with retinal angioma and pheochromocytoma.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient presented with a Pheochromocytoma at age 9.

CaseNotHPOs: HP:0009711; HP:0005584; HP:0001732; HP:0000077; HP:0010797 (Retinal capillary hemangioma, Renal cell carcinoma, Abnormality of the pancreas, Abnormality of the kidney, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table 1.

Variant: p.S65A (c.193T>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223160, https://www.ncbi.nlm.nih.gov/clinvar/variation/223160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65A (c.193T>G)

MultipleGeneVariants: N/A

Case#: Attali_LY04 (assumed male, from France)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: 3 ; FIX:Ag: 41)

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#: 40

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.892C>T

LegacyVariant:

ClinVar: No

CAID: CA255370

gnomAD:

Case#: 4

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.160G>C

LegacyVariant:

ClinVar: No

CAID: CA414435755

gnomAD:

Case#: 24

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.1193G>A

LegacyVariant:

ClinVar: No

CAID: CA414446384

gnomAD:

Case#: 29

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.1279G>A

LegacyVariant:

ClinVar: No

CAID: CA414447040

gnomAD:

Case#: 11

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.677G>A

LegacyVariant:

ClinVar: No

CAID: CA121128

gnomAD:

Case#: 39

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.892C>T

LegacyVariant:

ClinVar: No

CAID: CA255370

gnomAD:

Case#: 32

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.1306G>A

LegacyVariant:

ClinVar: No

CAID: CA414447233

gnomAD:

Case#: 23

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.1193G>A

LegacyVariant:

ClinVar: No

CAID: CA414446384

gnomAD:

Case#: B17 - B27

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C Chr = 31, FVIII:AG = 90, inverse assay discrepancy present (OSA<CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.1636C>T

LegacyVariant:

ClinVar: No

CAID: CA255112

gnomAD:

PMID: 24452774

Gene: F8

HGNCID: 3546

Case#: A9-A11

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 13, FVIII:AG = 28, assay discrepancy present (OSA>CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.1648C>T

LegacyVariant:

ClinVar: No

CAID: CA255113

gnomAD:

Case#: B74

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C Chr = 19, FVIII:AG = 17, inverse assay discrepancy present (OSA<CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.5325G>C, NM_000132.4:c.5325G>T

LegacyVariant:

ClinVar: No

CAID: CA255160, CA414910668

gnomAD:

Case#: A12

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 28, FVIII:AG = 54, assay discrepancy present (OSA>CSA)

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers

Gene: F8

Variant: NM_000132.4:c.2045T>C

LegacyVariant:

ClinVar: No

CAID: CA414909247

gnomAD:

Case#: S27, Iranian

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125, HP:0005261

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed

Gene: F8

Variant: NM_000132.3:c.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: S8, Iranian

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Family history of HA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125, HP:0005261

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed

Gene: F8

Variant: NA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: S16, Iranian

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125, HP:0005261

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed

Gene: F8

Variant: NA

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

PMID: 29388273

Gene: F9

HGNC: 3551

Case#: 97, male, 66 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6517A>G

LegacyVariant:

ClinVar: No

CAID: CA414907348

gnomAD:

Case#: 108, male, 36 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 3.3%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6870G>T

LegacyVariant:

ClinVar: No

CAID: CA414903147

gnomAD:

Case#: 40, male, 32 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 24.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.871G>A

LegacyVariant:

ClinVar: No

CAID: CA414918134

gnomAD:

Case#: 117, male, 8 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5219+1G>A

LegacyVariant:

ClinVar: 993734

CAID: CA414913420

gnomAD:

Case#: 152, male, 27 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 3.6%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.2777delC

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 123, male, 7 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6273+1G>T

LegacyVariant:

ClinVar: No

CAID: CA414902680

gnomAD:

Case#: 175, male, 32 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.4%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.del exons5_6

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 183, male, 38 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.del exons15_26

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 101, male, 7 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 3%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6611T>C

LegacyVariant:

ClinVar: No

CAID: CA414906072

gnomAD:

Case#: 73, male, 67 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 6%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5422C>T

LegacyVariant:

ClinVar: 10278

CAID: CA255166

gnomAD:

Case#: 164, male, 43 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.4339delG

LegacyVariant:

ClinVar: No

CAID: CA873341376

gnomAD:

Case#: 24, male, 8 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6666G>A

LegacyVariant:

ClinVar: No

CAID: CA414905572

gnomAD:

Case#: 142, male, 22 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.7%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.599_601delAAG

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 10, male, 9 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 2.1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1596G>A

LegacyVariant:

ClinVar: No

CAID: CA414912044

gnomAD:

Case#: 42, male, 24 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.901C>T

LegacyVariant:

ClinVar: No

CAID: CA414917990

gnomAD:

Case#: 166, male, 12 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.4379delA

LegacyVariant:

ClinVar: No

CAID: CA255151

gnomAD:

Case#: 26, male, 13 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6976C>T

LegacyVariant:

ClinVar: 10085

CAID: CA255007

gnomAD:

Case#: 36, male, 10 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.387G>C

LegacyVariant:

ClinVar: No

CAID: CA414919866

gnomAD:

Case#: 139, male, 17 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.dup exons7_22

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 115, male, 37 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1271+1G>A

LegacyVariant:

ClinVar: 811704

CAID: CA414915622

gnomAD:

Case#: 13, male, 24 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1861C>T

LegacyVariant:

ClinVar: No

CAID: CA414910596

gnomAD:

Case#: 16, male, 22 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.2404C>T

LegacyVariant:

ClinVar: No

CAID: CA414901774

gnomAD:

Case#: 161, male, 8 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 88, male, 29 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.6406G>A

LegacyVariant:

ClinVar: No

CAID: CA414899430

gnomAD:

Case#: 80, male, 52 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 10.9%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5707G>A

LegacyVariant:

ClinVar: No

CAID: CA414907751

gnomAD:

Case#: 56, male, 12 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 29%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1834C>T

LegacyVariant:

ClinVar: 10236

CAID: CA255129

gnomAD:

Case#: 69, male, 11 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5321A>T

LegacyVariant:

ClinVar: No

CAID: CA414910719

gnomAD:

Case#: 34, male, 25 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.382T>C

LegacyVariant:

ClinVar: 811825

CAID: CA414919878

gnomAD:

Case#: 75, male, 14 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 16.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.5545T>A

LegacyVariant:

ClinVar: No

CAID: CA414908552

gnomAD:

Case#: 179, male, 11 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.del exon14

LegacyVariant:

ClinVar: No

CAID: No

gnomAD:

Case#: 146, male, 13 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.209_212delTTGT

LegacyVariant:

ClinVar: No

CAID: CA255050

gnomAD:

Case#: 61, male, 7 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.2066T>C

LegacyVariant:

ClinVar: No

CAID: CA414909145

gnomAD:

Case#: 132, male, 28 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 2.7%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.4379dupA

LegacyVariant:

ClinVar: No

CAID: CA645292749

gnomAD:

Case#: 7, male, 8 years old, Chinese

DiseaseAssertion: Hemophilia A, severe

FamilyInfo: NA

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C < 1%, Inhibitor present

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1063C>T

LegacyVariant:

ClinVar: 10139

CAID: CA255031

gnomAD:

Case#: 45, male, 75 years old, Chinese

DiseaseAssertion: Hemophilia A, mild

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 6.5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.1172G>A

LegacyVariant:

ClinVar: 10111

CAID: CA120918

gnomAD:

Case#: 157, male, 30 years old, Chinese

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: Noted Family History

ParentalTesting: Maternity confirmed

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: FVIII:C = 1.2%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA

Gene: F8

Variant: NM_000132.3:c.3637delA

LegacyVariant:

ClinVar: No

CAID: CA255146

gnomAD:

Case#: 21

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Moderate

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.1538G>T (p.Gly494Val)

ClinVar: NA

CAID: CA414912397

gnomAD: Not reported

Case#: 11

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.5374-1G>C

ClinVar: NA

CAID: CA414909191

gnomAD: NA

Case#: 29

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.6515C>T (p.Pro2153Leu)

ClinVar: NA

CAID: CA414907354

gnomAD: Not reported

Case#: 13

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.556G>A

ClinVar: NA

CAID: CA414919461

gnomAD: Not reported

PMID: 18184865

Gene: F8

HGNCID: 3546

Case#: 31

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Moderate

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.7006A>T (p.Ile2317Phe)

ClinVar: NA

CAID: CA414896884

gnomAD: Not reported

Case#: 2

DiseaseAssertion: Hemophilia A

FamilyInfo: Sporadic

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Severe

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.1682del (p.Asp561ValfsTer2)

ClinVar: NA

CAID: CA1139532041

gnomAD: Not reported

Case#: 24

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Mild

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.5159C>T (p.Ala1701Val)

ClinVar: NA

CAID: CA414913679

gnomAD: Not reported

Case#: 12

DiseaseAssertion: Hemophilia A

FamilyInfo: Positive

ParentalTesting: NA

CasePresentingHPOs: NA

CaseHPOFreeText: Mild

CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit

Gene: F8

Variant: NM_000132.3:c.248C>G (p.Pro83Arg)

ClinVar: NA

CAID: CA10568618

gnomAD: MAF for Pro83Arg in the Ashkenazi Jewish population 0.0001335<br>https://gnomad.broadinstitute.org/variant/X-154227771-G-C?dataset=gnomad_r2_1

Case#: 004-2009

DiseaseAssertion: Hemophilia A, moderate

FamilyInfo: NA

ParentalTesting: NA

CasePresentingHPOs: HP:0003125

CaseHPOFreeText: 1% < FVIII:C < 5%

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification

Gene: F8

Variant: NM_000132.3:c.1899G>T

LegacyVariant:

ClinVar: No

CAID: CA414910251

gnomAD: