Case:Female, 35.

DiseaseAssertion:Hypertrophic cardiomyopathy (HCM) with left ventricular noncompaction (LVNC) and conduction abnormalities.

Familyinfo:The patient's father had hypertrophic cardiomyopathy and carried a heterozygous MYBPC3 p.(Pro1066Arg) variant. The patient's mother was also heterozygous for the MYBPC3 variant. The patient had one sister who did not have reported cardiac abnormalities and was heterozygous for the MYBPC3 variant. The family was initially considered non-consanguineous. Genetic analysis identified a 26 Mb region of homozygosity, suggesting distant parental relatedness.

ParentalTesting:Both parents were tested. The father and mother were heterozygous for MYBPC3 c.3197C>G (p.Pro1066Arg). The affected daughter inherited the variant from both parents and was homozygous.

CasePresentingHPOs:HP:0031992, HP:0001685, HP:0005157, HP:0031295, HP:0001667, HP:0001670, HP:0001712, HP:0005144, HP: 0031195, HP:0030682, HP:0005135, HP: 0006682, HP: 0004763

CaseHPOFreeText:The patient developed severe cardiac manifestations associated with homozygous MYBPC3 p.(Pro1066Arg). Cardiac MRI showed ventricular hypertrophy, myocardial fibrosis, and features of left ventricular noncompaction. At follow-up, imaging showed asymmetric ventricular wall thickness, with a maximum diastolic thickness of 20 mm in the mid-lateral segment. She also had apical hypokinesia and left atrial enlargement. Electrocardiography and Holter monitoring showed premature ventricular complexes and a 20-beat episode of nonsustained ventricular tachycardia.

CaseNotHPOs:No specific negative HPO findings were established for the affected daughter in the reported HPO table.

CaseNOTHPOFreeText:not reported

CasePreviousTesting:Cardiac MRI, echocardiography, electrocardiography, and 24-hour Holter monitoring were performed. Genetic evaluation was also conducted to identify the MYBPC3 and MYH7 variants.

GenotypingMethod:Whole-exome sequencing (WES) trio analysis was performed using DNA from the affected daughter and both parents. Family segregation analysis was performed by Sanger sequencing using an Applied Biosystems 3130 sequencer.

FunctionalAnalysis:No direct functional analysis of the MYBPC3 variant was reported.

Variant:NM_000256.3 (MYBPC3): c.3197C>G; p.(Pro1066Arg).

ClinVar: 1171602

CAID:not reported

gnomAD:not reported

AdditionalInfo:The patient was homozygous for the MYBPC3 p.(Pro1066Arg) variant. Both parents carried the variant in the heterozygous state. A 26 Mb region of homozygosity was identified on chromosome 11, supporting the possibility of distant parental relatedness. The variant was initially classified as a variant of uncertain significance and was subsequently reclassified as likely pathogenic following family segregation analysis.

Case:Female, born at 34 weeks of gestation, 5 years old at the first detailed examination, 8 years old during a later clinical description.

DiseaseAssertion:Arthrogryposis multiplex congenita (AMC). Cardiomyopathy not reported.

Familyinfo:The patient was the first child of unrelated parents. Her mother and one maternal aunt were born with bilateral clubfeet and later developed scoliosis. The mother also had a history of cleft palate. Neither the mother nor the patient had a reported history of cardiac problems.

ParentalTesting:The patient's mother carried the same heterozygous ACTC1 c.325G>A (p.Glu109Lys) variant. The variant was therefore inherited from the mother.

CasePresentingHPOs:Bilateral clubfeet, scoliosis, cleft palate, neck webbing, camptodactyly, joint contractures.

CaseHPOFreeText:The patient was born by cesarean section at 34 weeks of gestation. Bilateral clubfeet, cleft palate, neck webbing, and spinal deformity were noted. At age 5, she had severe scoliosis measuring 120 degrees and severe short stature. At age 8, mild camptodactyly of both hands and mild contractures of the neck, left hip, both knees, and feet were observed. She had no significant mobility or cognitive difficulties and was independent in self-care activities.

CaseNotHPOs:No reported cardiac problems, no significant cognitive difficulties, no significant mobility difficulties.

CaseNOTHPOFreeText:The patient had no reported cardiac phenotype despite carrying an ACTC1 variant. Her mother also had no history of cardiac problems.

CasePreviousTesting:Genome sequencing was performed to identify genetic variants associated with the patient's clinical presentation.

GenotypingMethod:Genome sequencing. Plasmid sequencing was also verified by Sanger sequencing for the experimental functional studies.

FunctionalAnalysis:In vitro functional studies were performed using MC3T3-E1 preosteoblastic cells. The p.Glu109Lys variant caused decreased ACTC1 protein levels and impaired actin filament assembly. Immunofluorescence and Western blotting were used to evaluate protein expression and actin filament organization.

Variant:NM_005159.5 (ACTC1): c.325G>A; p.Glu109Lys.

ClinVar:not reported

CAID:not reported

gnomAD:not found

AdditionalInfo:The variant was inherited from the patient's mother, who also had bilateral clubfeet, scoliosis, and a history of cleft palate. The authors classified the variant as likely pathogenic using ACMG criteria (PM1, PM2, PP1, PP2, PP3). The functional studies demonstrated reduced ACTC1 protein levels and impaired actin filament assembly.

Case:Male, born at 39 weeks of gestation, evaluated during infancy-age 6.

DiseaseAssertion:Arthrogryposis multiplex congenita (AMC). The patient also had Shone's complex with coarctation of the aorta. Cardiomyopathy not reported.

Familyinfo:The patient was the first child of unrelated parents. No family history of arthrogryposis multiplex congenita was reported.

ParentalTesting:The ACTC1 c.650A>C (p.Lys217Thr) variant was identified as de novo. Neither parent was reported to carry the variant.

CasePresentingHPOs:Limited range of motion in wrists, Limited range of motion in fingers, Limited range of motion in thumbs, Hip contractures, Knee contractures, Bilateral clubfeet, Clenched hands, Hypotonia, Lower extremity weakness,

CaseHPOFreeText:The patient was born at 39 weeks of gestation. At birth, he had limited range of motion in the wrists, fingers, thumbs, hips, and knees, along with bilateral clubfeet. Echocardiography revealed Shone's complex, including coarctation of the aorta, which required surgical repair. At age 1, he had clenched hands with deep single palmar creases, overlapping toes, and hypoplastic fifth toenails. He also had truncal hypotonia, mild lower extremity weakness, and delayed gross motor milestones. At age 3, moderate wrist contractures, thumb-in-palm deformities, and mild bilateral hip contractures were observed. He began walking independently at age 4. At age 5, he underwent additional heart surgery and pacemaker insertion.

CaseNotHPOs:Scoliosis: not identified on spine X-rays, cognitive difficulties: not reported

CaseNOTHPOFreeText:The patient did not have reported cognitive difficulties. Spine X-rays did not reveal scoliosis.

CasePreviousTesting:Genome sequencing was performed to identify genetic variants associated with the patient's clinical presentation. Echocardiography was used to identify Shone's complex and coarctation of the aorta.

GenotypingMethod:Genome sequencing. Plasmid sequences used for the functional experiments were verified by Sanger sequencing.

FunctionalAnalysis:In vitro functional studies were performed using MC3T3-E1 preosteoblastic cells. The p.Lys217Thr variant did not demonstrate a clear effect on ACTC1 protein expression or localization compared with wild-type ACTC1. The authors reported no apparent reduction in protein levels or impaired actin filament organization.

Variant:NM_005159.5 (ACTC1): c.650A>C; p.Lys217Thr.

ClinVar:not reported

CAID:not reported

gnomAD:not reported

AdditionalInfo:The variant was identified as de novo and classified as likely pathogenic using ACMG criteria (PS2, PM1, PM2, PP2, PP3). Although functional testing did not demonstrate a clear effect on ACTC1 protein expression or localization, the authors considered the variant likely pathogenic based on the genetic and clinical evidence.

Case:Female, 21.

DiseaseAssertion:Left ventricular noncompaction cardiomyopathy (LVNC).

Familyinfo:The patient's father had hypertrophic cardiomyopathy. Her paternal grandfather and paternal uncle also reportedly had cardiac disease, although detailed clinical information was unavailable. The patient's mother had microscopic hematuria and was diagnosed with thin basement membrane nephropathy. The maternal grandmother also had a history of kidney disease.

ParentalTesting:The mother was tested and did not carry the ACTC1 c.922T>C variant. The father could not be tested because the patient had no contact with him. The authors presumed paternal inheritance of the ACTC1 variant based on the family history, but paternal inheritance was not genetically confirmed.

CasePresentingHPOs:Left ventricular noncompaction cardiomyopathy, Abnormal cardiac morphology, Cardiac hypertrophy, Hematuria

CaseHPOFreeText:The patient had microscopic hematuria beginning at age 6. At the same age, routine school screening identified cardiac dysfunction, and echocardiography revealed a myocardial densification defect. At age 21, echocardiography showed a noncompacted-to-compacted myocardial ratio greater than 2:1, consistent with LVNC. Electrocardiography showed sinus rhythm with ST-T wave flattening in leads V4–V6, indicative of cardiac hypertrophy. The patient remained without cardiac symptoms and had a normal ejection fraction. Her BNP level increased to 204 pg/mL. She had normal renal function, with a serum creatinine level of 0.58 mg/dL, and no proteinuria.

CaseNotHPOs:Hearing impairment: not reported, Ophthalmological abnormalities: not reported, Cardiac symptoms: not reported

CaseNOTHPOFreeText:The patient remained asymptomatic despite the cardiac findings. No hearing impairment or ophthalmological abnormalities were identified.

CasePreviousTesting:Echocardiography identified LVNC during childhood. Further cardiac evaluation included electrocardiography and follow-up BNP measurements. Renal evaluation included serum creatinine testing, urinalysis, abdominal ultrasonography, and genetic evaluation for hereditary kidney disease.

GenotypingMethod:Whole exome sequencing was performed using DNA extracted from the patient's blood sample. Sanger sequencing was used to confirm both identified variants. The mother's DNA was also analyzed to determine inheritance.

FunctionalAnalysis:No direct functional studies were performed on the ACTC1 variant. The authors used AlphaFold3 protein structure prediction to examine the effect of the amino acid substitution. The variant was located near the ATP-binding site, suggesting a possible effect on ACTC1 function and ATP binding.

Variant:NM_005159.5 (ACTC1): c.922T>C; p.(Tyr308His).

ClinVar:accession: VCV000948806.7.

CAID:not reported

gnomAD:not reported

AdditionalInfo:The patient carried two separate heterozygous variants associated with different conditions. The COL4A4 c.2510G>C (p.Gly837Ala) variant was associated with autosomal dominant Alport syndrome, while the ACTC1 c.922T>C (p.Tyr308His) variant was identified as a candidate associated with LVNC. The ACTC1 variant was classified as a variant of uncertain significance (VUS) by the authors using ACMG criteria (PM2, PP3, PP4). The authors noted that there were no functional studies confirming its effect on ACTC1 protein function.

Patient7: Male, 3.8mo at ERT start, 3.3yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 40mg/kg/wk, patient had 10 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481 + 102_2646 + 31del)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Patient1: Italian

CasePresentingHPOs:

HPOsFreeText: non-classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C

GroupID: 237

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 a germline large rearrangement of the VHL gene. Member 7398 had no renal involvement. Member 645 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: 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

PatientID: 9760

KindredID: 415

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: 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]).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: 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

PatientID: 251

KindredID: 96

Case: F, 44Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 250) presented with a CNS hemangioblastoma at 23, retinal angioma at 17, and multiple pancreatic cysts/tumors at 19. His mother (patient 251) presented with a CNS hemangioblastoma at age 43, retinal angioma at 35, renal cell carcinoma/multiple pancreatic cysts/tumors at 44.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001737; HP:0001732; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma)

CaseHPOFreeText: The patient's mother presented with a CNS hemangioblastoma at age 43, retinal angioma at 35, renal cell carcinoma/multiple pancreatic cysts/tumors at 44.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 277

KindredID: 108

Case: M, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28. Their father who passed away before diagnosis presented with a CNS hemangioblastoma at 48.

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0005584 (Hemangioblastoma, Retinal capillary hemangioma, Renal cell carcinoma)

CaseHPOFreeText: The proband, patient 277, presented with a CNS hemangioblastoma at age 16, retinal angioma a 20, and renal cell carcinoma at 28.

CaseNotHPOs: HP:0002666; HP:0001737; HP:0001732 (Pheochromocytoma, Pancreatic cysts, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 253

KindredID: 98

Case: F, 27Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 253, presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 27. Their father (patient 254) was asymptomatic at the time of assessment. Their grandmother (patient 255) presented with renal cell carcinoma at 60 and multiple pancreatic cysts/tumors at 27, but passed away before diagnosis/ before the mutation could be confirmed.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 27.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

PatientID: 290

KindredID: 114

Case: M, 41Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001732; HP:0001737; HP:0005584; HP:0009711 (Hemangioblastoma, Abnormality of the pancreas, Pancreatic cysts, Renal cell carcinoma, Retinal capillary hemangioma)

CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 38, and at age 41 presented with a retinal angioma, renal cell carcinoma, and multiple pancreatic cysts/tumors.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 291

KindredID: 115

Case: M, 31Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: The proband, patient 291, presented with a CNS hemangioblastoma at 27, and at 31 presented with renal cell carcinoma, multiple pancreatic cysts/tumors, and pheochromocytoma.

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

PatientID: 259

KindredID: 100

Case: F, 28Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24. The proband's son, patient 260, was asymptomatic at the time of analysis.

CasePresentingHPOs: N/A

CasePresentingHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0005584; HP:0010797 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

CaseHPOFreeText: The proband, patient 259, presented with a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 28, and a retinal angioma at age 24.

CaseNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 1-2 Deletion (c.1-?_463+?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 1-2 Deletion

MultipleGeneVariants: N/A

PatientID: 280

KindredID: 110

Case: M, 22Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22. Their father presented with a CNS hemangioblastoma at age 25, and retinal angioma at age 29.

CasePresentingHPOs: HP:0010797; HP:0001737; HP:0001732; HP:0009711 (Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Retinal capillary hemangioma)

CaseHPOFreeText: The proband, patient 280, presented with a CNS hemangioblastoma at age 16, a retinal angioma at age 15, and multiple pancreatic cysts/tumors at age 22.

CaseNotHPOs: HP:0002666; HP:0005584 (Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: Exons 1, 2, and 3 of the VHL gene and their immediately flanking sequences were amplified by use of polymerase chain reaction (PCR). Amplicons were denatured at 94°C and renatured at 25°C for heteroduplex analysis. Denaturing acetonitrile gradient profiles and melting temperatures were established by the Wavemaker 3.0 software prediction. Equal amounts (50 ng) of PCR product were mixed with reference human wild-type genomic DNA and after denaturation-renaturation, were screened for heteroduplexes by dHPLC

SamplingMethod: peripheral blood

PatientID: 23

KindredID: KS

Case: M, 27Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001737 (Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: CNS hemangioblastoma and multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 30

KindredID: PM

Case: M, 49Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0001737 (Hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: CNS hemangioblastoma and multi-cystic pancreatic lesions.

CaseNotHPOs: HP:0030393; HP:0009711; HP:0002666; HP:0005584 (Endolymphatic sac tumor, Retinal capillary hemangioma, Pheochromocytoma, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: This variant is noted as a full-length deletion involving genes BRK1 and FANCD2.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A

SamplingMethod: N/A

PatientID: III-6

KindredID: Family A

Case: M, 31Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. His aunts II-2 and II-3 both had confirmed VHL and CNS hemangioblastoma. His dad (II-3) has confirmed VHL gene and pancreatic and renal cysts. His cousins (2 boys 1 girl: III-3; III-5; III-3) were all found with the confirmed VHL gene mutation; III-3 and III-5 with retinal hemangioblastoma and CNS/spinal hemangioblastomas and III-4 with pancreatic and ovarian cysts. Patient’s son and nephew IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

CasePresentingHPOs: HP:0005584; HP:001079 (renal cell carcinoma, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioblastoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 deletion

MultipleGeneVariants: N/A

PatientID: IV-1

KindredID: Family A

Case: M, Age unknown, Ethnicity unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Patient’s great-grandfather (I-1), now deceased, and great-aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. His great-aunt II-2 and great-uncle II-3 both had confirmed VHL and (II-2) CNS hemangioblastoma; (II-3) with pancreatic and renal cysts. His dad (III-3) has confirmed VHL gene retinal and CNS hemangioblastoma, his aunt (III-4) had confirmed VHL and pancreatic and ovarian cysts. His uncle III-5 was found with the confirmed VHL gene mutation and retinal hemangioblastoma and CNS/spinal hemangioblastomas. III-6 with renal cell carcinoma and hemangioblastoma. Patient’s cousin IV-3, was confirmed with the VHL gene mutation although no other manifestations.

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 deletion

MultipleGeneVariants: N/A

PatientID: III-4

KindredID: Family A

Case: F, 38Y0M, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s grandfather (I-1), now deceased, and aunt (II-1) had CNS/spinal hemangioblastoma and the confirmed VHL gene mutation. Her mom II-2 had confirmed VHL and CNS hemangioblastoma; and her cousin (III-6) has renal cell carcinoma and CNS/spinal hemangioblastoma and also the confirmed VHL gene mutation. Her uncle (II-3) has confirmed VHL gene and pancreatic and renal cysts. Her brother and sister (III-3; III-5) both were found with the confirmed VHL gene mutation; with retinal hemangioblastoma and CNS/spinal hemangioblastomas. IV-1 and IV-3, were confirmed with the VHL gene mutation although no other manifestations.

CasePresentingHPOs:HP:0001737; HP:0000138 (pancreatic cyst; ovarian cyst)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584; HP:0002666; HP:0009711; HP:0010797 (renal cell carcinoma, pheochromocytoma, retinal capillary hemangioblastoma, CNS hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exon 3 (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: Mutation analysis of exons 1, 2 and 3 of the VHL gene was performed using direct sequencing of the PCR-amplified DNA.

SamplingMethod: peripheral blood

PatientID: None

KindredID: VHL25

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had no LOH found in the BAC array CGH data. No variants were found in the tumor tissue.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: VHL24

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: A total of 190 patients recruited by the COMETE network over 15 years were included in the study.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: The patient had one benign pheochromocytoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had no LOH found in the BAC array CGH data. Somatic VHL variant c.250G>C was found in the tumor tissue.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 122

KindredID: 122

Case: Sex Unknown, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711; HP:0001732 (Hemangioblastoma, Retinal capillary hemangioma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, retinal hemangioblastoma and pancreatic cyst or tumor.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (8.2kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 8.2kb

MultipleGeneVariants: N/A

PatientID: 65

KindredID: 65

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

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

CaseHPOFreeText: CNS hemangioblastoma and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete deletion)

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.3

GenotypingMethod: Polymerase chain reaction (PCR) amplification, denaturating high-performance liquid chromatography (DHPLC), and direct sequence analysis were used to analyze the entire coding sequence and intron-exon boundaries.

SamplingMethod: peripheral blood

PatientID: 254

KindredID: 254

Case: Sex Unknown, 32Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

CasePresentingHPOs: HP:0009711; HP:0001732 (Retinal capillary hemangioma, Abnormality of the pancreas)

CaseHPOFreeText: Retinal hemangioblastoma and pancreatic cyst or tumor.

CaseNotHPOs: HP:0010797; HP:0002666; HP:0000107; HP:0006770 (Hemangioblastoma, Pheochromocytoma, Renal cyst, Clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant; deletion

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 121

KindredID: 121

Case: Sex Unknown, 14Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (11kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Partial deletion of 11kb

MultipleGeneVariants: N/A

PatientID: 204

KindredID: 204

Case: Sex Unknown, 45Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history is positive but no details provided.

CasePresentingHPOs: HP:0010797; HP:0000107; HP:0001732 (Hemangioblastoma, Renal cyst, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma, renal cyst and pancreatic cyst or tumor.

CaseNotHPOs: HP:0006770; HP:0002666; HP:0009711 (Clear cell renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete deletion)

MultipleGeneVariants: N/A

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

GenotypingMethod: The different exons and intron-exon boundaries of SDHD, SDHB, SDHC, and VHL genes were amplified by polymerase chain reaction (PCR). Screening for mutations was performed by single strand conformation polymorphism (SSCP), and heteroduplex analysis, as previously described [10] or by denaturing high performance liquid chromatography (dHPLC) analysis, using the WAVE 3500 HT system

SamplingMethod: whole blood

PatientID: 16

KindredID: F01

Case: F, Age Unknown, Taiwanese

DiseaseAssertion: VHL

FamilyInfo: A total of 10 members of this family (F01) had a complete deletion of the VHL gene. Four of these patients (16, 18, 21, 33) presented with clinical features of VHL.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: Brain hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19288063

SupplementalData: Figure 1

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of 142.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 31

KindredID: F01

Case: M, Age Unknown, Taiwanese

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 10 members of this family (F01) had a complete deletion of the VHL gene. Four of these patients (16, 18, 21, 33) presented with clinical features of VHL.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19288063

SupplementalData: Figure 1

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of 142.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

Supplementary Data: Table 2

Case B: proband, Female

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, LMNA)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case K:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) VCL Variant:

Variant: NM_014000.2(VCL):c.688C>T (p.Arg230Cys)

ClinVar: 45620, https://www.ncbi.nlm.nih.gov/clinvar/variation/45620/

gnomAD: 0.00008137, https://gnomad.broadinstitute.org/variant/10-75834566-C-T

Supplementary Data: Table 2

Case A: proband, female

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, LMNA)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case L:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case N:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, MYBPC3)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case H: proband, Female

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case F: proband, Female

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case J: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case D: proband, female

DiseaseAssertion: Hypertrophic cardiomyopathy

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) DSC2 Variant:

Variant: NM_004949.4(DSC2):c.2194T>G (p.Leu732Val)

ClinVar: 36005, https://www.ncbi.nlm.nih.gov/clinvar/variation/36005/

gnomAD: 0.001181, https://gnomad.broadinstitute.org/variant/18-28650748-A-C

(2) DSG2 Variant:

Variant: NM_001943.4(DSG2):c.1174G>A (p.Val392Ile)

ClinVar: 36009, https://www.ncbi.nlm.nih.gov/clinvar/variation/36009/

gnomAD: 0.002137, https://gnomad.broadinstitute.org/variant/18-29111109-G-A

(3) DSP Variant:

Variant: NM_001008844.2(DSP):c.1778A>G (p.Asn593Ser)

ClinVar: 44867, https://www.ncbi.nlm.nih.gov/clinvar/variation/44867/

gnomAD: 0.0005695, https://gnomad.broadinstitute.org/variant/6-7571692-A-G

Supplementary Data: Table 2

Case 3:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

Variant - paternal: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case 2:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: WES, Cytoscan HD SNP array (performed on proband, 3 additional carriers, and parents)

Variant - maternal: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case M:

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, MYBPC3)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case C: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7, CSRP3, DES, LMNA, MYBPC3, TNNT2, TNNI3)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case E: proband, male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

MultipleGeneVariants:

(1) PRDM16 Variant:

Variant: NM_022114.3(PRDM16):c.2666C>T (p.Pro889Leu)

ClinVar: 487607, https://www.ncbi.nlm.nih.gov/clinvar/variation/487607/

gnomAD: 0.0001771, https://gnomad.broadinstitute.org/variant/1-3331186-C-T

Supplementary Data: Table 2

Case G: proband, Male

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, partial testing (MYH7)

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Data: Table 2

Case I: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

CasePreviousTesting: 12-lead electrocardiogram (ECG), echocardiography, exercise test and 24-hour (or 48-hour) Holter monitoring, cardiac MRI, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplemental table 2

CaseGenotypingMethod: genomic DNA isolated from peripheral blood, initially analyzed via Sanger Sequencing then by next-generation sequencing using targeted gene panels, variant pathogenicity assed using in silico prediction tools, Haplotype analysis was performed using 16 microsatellite markers around MYH7 (DNA from the 14 probands was analysed, and DNA samples of 6 family members carrying the mutation were used to verify the phase and reconstruct the haplotype Supplementary Data: Table 1)

Variant: NM_000257.2(MYH7):c.5754C>R (p.Asn1918Lys)

ClinVar: 66082, https://www.ncbi.nlm.nih.gov/clinvar/variation/66082/

gnomAD: n/a

Supplementary Material 4

Case M-31: Japanese

DiseaseAssertion: idiopathic cardiomyopathy (HCM and DCM)

CasePreviousTesting: Clinical evaluation, chest radiography, electrocardiography, echocardiography, cardiac catheterization, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1)

CaseGenotypingMethod: 8 sarcomeric genes amplified from genomic DNA via PCR then screened using bidirectional direct sequencing

Variant: NM_000257.3(MYH7):c.4721G>A (p.Arg1574Gln)

ClinVar: 228912, https://www.ncbi.nlm.nih.gov/clinvar/variation/228912/

gnomAD: 0.00001989, https://gnomad.broadinstitute.org/variant/14-23885445-C-T

Supplementary Data: S2 Table

Case 156: Spanish, 82yo, Female

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePreviousTesting: Full Testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data table S1

CaseGenotypingMethod: genomic DNA obtained from blood or saliva, Next-gen sequencing panels of 55 or 78 genes

Variant: NM_000257.3(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Case: Patient 19, female, 33yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0008959, HP:0009053, HP:0008997, HP:0008994, HP:0002650, HP:0003458 (foot drop, Distal upper limb muscle weakness, Distal lower limb muscle weakness, Proximal muscle weakness in upper limbs, Proximal muscle weakness in lower limbs, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: respiratory involvement - restrictive from 25yo, normal CK levels, minicores present on muscle biopsy

CaseNotHPOs: no cardiac involvement

FamilyInfo: family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Case: 6, femaly, 16yo, congenital onset of symptoms

CasePresentingHPOs: HP:0003327, HP:0008959, HP:0009053, HP:0002650 (axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, scoliosis)

HPOsFreeText: normal CK

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: family history, pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4807G>C (p.Ala1603Pro)

ClinVar: 190407, https://www.ncbi.nlm.nih.gov/clinvar/variation/190407/

gnomAD: absent

Case: Patient 4, male, 22yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0008959, HP:0009053, HP:0001701, HP:0030682 (foot drop, axial muscle weakness, distal upper limb muscle weakness, distal lower limb muscle weakness, pericarditis, left ventricular noncompaction)

CaseNotHPOs: HP:0003306 (rigid spine)

HPOsFreeText: restrictive respiratory involvement from age 16, CK = 711U/l, minicores present on muscle biopsy, hypertrophy of gastrocnemii

FamilyInfo: no family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below; variants in SEPN1 and LMNA rules out

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Case: Patient 13, female, 59yo, symptom onset in adulthood

CasePresentingHPOs: HP:0003701, HP:0003306, HP:0003458 (proximal muscle weakness, rigid spine, EMG: myopathic abnormalities)

HPOsFreeText: normal CK levels, cores present on muscle biopsy

CaseNotHPOs: no respiratory or cardiac involvement

FamilyInfo: family history

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant: NM_000257.4(MYH7):c.4315G>C (p.Ala1439Pro)

ClinVar: 190404, https://www.ncbi.nlm.nih.gov/clinvar/variation/190404/

gnomAD: absent

Case: Patient 8, male, 35yo, symptom onset in childhood

CasePresentingHPOs: HP:0009027, HP:0003327, HP:0002460, HP:0002650, HP:0003458 (foot drop, axial muscle weakness, distal muscle weakness, scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: CK = 720U/l, neurogenic EMG, cores present on muscle biopsy

CaseNotHPOs:

NotHPOsFreeText: no respiratory or cardiac involvement

FamilyInfo: pedigree in Figure 1

DiseaseEntity: no assertion

InheritancePattern: no assertion

CasePreviousTesting: see below

CaseGenotypingMethod: 9 cases underwent targeted Sanger sequencing of MYH7, 12 cases underwent Motorplex analysis (NGS of 93 myopathy-related genes - PMID:25214167), all MYH7 variants confirmed via Sanger sequencing, segregation analysis performed on available family members, which cases received which sequencing technique is not specified

Variant 1: NM_000257.4(MYH7):c.4844_4846AGA[2] (p.Lys1617del)

ClinVar: 190401, https://www.ncbi.nlm.nih.gov/clinvar/variation/190401/

gnomAD: absent

Variant 2: NM_000257.4(MYH7):c.4855G>A(p.Glu1619Lys)

ClinVar: 181268, https://www.ncbi.nlm.nih.gov/clinvar/variation/181268/

gnomAD: absent

Case: Patient UK1-IV:1, female, 31yo, Caucasian, Irish ancestry

CasePresentingHPOs: HP:0040083, HP:0002650, HP:0001508, HP:0011471, HP:0002093, HP:0002877, HP:0001620 (toe-walking, scoliosis, poor weight gain, Feeding problem necessitating gastrostomy tube feeding, respiratory impairment, nocturnal hypoventilation, high-pitched voice)

HPOsFreeText: scoliosis required spinal fusion surgery, required nocturnal BiPAP ventilation in adolescence, reduced muscle bulk

Muscle biopsy showed variability in myofiber size, uniformity of type I myofibers on ATPase, moth-eaten appearance of myofibers

CaseNotHPOs:

FamilyInfo: non-consanguineous family

CasePreviousTesting: 32 Illumina genes

CaseGenotypingMethod: NGS (Illumina gene panel) or 32 genes previously associated with congenital myopathies, Sanger sequencing to confirm recessive inheritance

InheritancePattern: autosomal recessive

DiseaseEntity:

Variant 1: NM_000257.3:c.4699C>T (p.Gln1657Ter), maternal

CAID: CA389037829, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389037829

gnomAD: n/a

Variant 2: NM_000257.4(MYH7):c.4664A>G (p.Glu1555Gly), paternal

ClinVar: 181261, https://www.ncbi.nlm.nih.gov/clinvar/variation/181261/

gnomAD: n/a

Supplementary Data: Table S3

Case 56:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

CaseHPOFreeText: >7yo, able to hold breath, non compacted segment = distinct 2-layered appearance of trabeculated and compacted myocardium, NC/C ratio > 2.3:1

CasePreviousTesting: Cardiac MRI using 17-segment model of LV segmentation, ECG, transthoracic echocardiography, full testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), additional testing listed in supplementary data tables S1 and S2.

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.4717G>A (p.Glu1573Lys)

ClinVar: 222729, https://www.ncbi.nlm.nih.gov/clinvar/variation/222729/

gnomAD: 0.00005967, https://gnomad.broadinstitute.org/variant/14-23885449-C-T

MultipleGeneVariants:

(1) TMPO Variant:

Variant: NM_003276.2(TMPO):c.821G>A (p.Arg274Lys)

ClinVar: 44673, https://www.ncbi.nlm.nih.gov/clinvar/variation/44673/

gnomAD: 0.002714, https://gnomad.broadinstitute.org/variant/12-98926856-G-A

Case#: D26, female, 54 years

DiseaseAssertion: FDCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: DNA extraction, whole exome sequencing, pyrosequencing, RNA extraction, q-RT-PCR, SDS-PAGE electrophoresis, western blotting and immunofluorescence microscopy

CaseGenotypingMethod: N/A

Variant: NM_000257.4(MYH7):c.4828G>C (p.Glu1610Gln)

ClinVar: 181267 https://www.ncbi.nlm.nih.gov/clinvar/variation/181267/

CAID: N/A

gnomAD: absent

CaseVIII: Brazil, Caucasian

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: Family history of HCM, 1 other relative without phenotypes

CasePresentingHPOs: HP:0001712, HP:0001639, HP:0011103 (Left ventricular hypertrophy, Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Cosegregation confirmed for MYH7

CasePreviousTesting: Only MYH7, MYBPC3, and TNNT2 were tested.

CaseGenotypingMethod: DNA was extracted from peripheral blood and the above genes were subject to PCR amplification and directly sequenced. The resulting sequences were compared with the reference and filtered for pathogenicity.

Variant: NM_000257.3:c.4402G>A (p.Glu1468Lys)

ClinVar: 235033 https://www.ncbi.nlm.nih.gov/clinvar/variation/235033/

gnomAD: Not in gnomAD

Multiple Gene Variants

MYBPC3 Variant

Variant: NM_000256.3:c.2686G>A (p.Val896Met)

ClinVar: 42652 https://www.ncbi.nlm.nih.gov/clinvar/variation/42652/

gnomAD: European (Finnish) 0.02794, Overall 0.006194 https://gnomad.broadinstitute.org/variant/11-47357479-C-T

CaseHCM014: 43 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0100749, HP:0001712, HP:0031295 (Chest pain, Left ventricular hypertrophy)

HPOsFreeText: Maximal LV thickness 27 mm

CaseNotHPOs: HP:0005110, HP:0001297, HP:0004756 (Atrial fibrillation, Stroke, Ventricular tachycardia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: The gene panel included 10 sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1, MYH6), 9 genes encoding Z-disk components and Ca2+ homeostasis factors (LDB3, CSRP3, TCAP, VCL, ACTN2, MYOZ2, NEXN, JPH2, PLN), and 4 genes involved in HCM phenocopies (GLA, LAMP2, PRKAG2, TTR), All probands had left ventricular wall thickness >= 15 mm and no other diseases that can cause secondary hypertrophy

CaseGenotypingMethod: The coding region, flanking sequences, and untranslated regions of each gene were enriched by LC-PCR, amplified, and sequenced on the Illumina MiSeq or MiniSeq platform. Identified variants were then filtered for pathogenicity and confirmed by Sanger sequencing.

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00004657, http://gnomad.broadinstitute.org/variant/14-23884860-C-T

DiseaseAssertion: None

VariantPreviousTesting: Some combination of ACTC1, ACTN2, CSRP3, LAMP2, MYBPC3, MYH7, NEXN, PLN, TNNC1, TNNI3, TNNT2, TPM1, ABCC9, CTF1, DES, EMD, LDB3, LMNA, MYH6, RBM20, SGCD, TAZ, TCAP, TTN, VCL, CAV3, GLA, MYL2, MYL3, MYOZ2, PRKAG2, TTR, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TMEM43, CASQ2 and RYR2 were tested via NGS.

VariantGenotypingMethod: Next-generation sequencing panels were used to sequence and read the genetic information of probands for variants within exons and in +/- 10 nucleotides within the flanking introns of the genes provided above. These variants were then interpreted and filtered for pathogenicity.

Variant: NM_000257.4(MYH7):c.4668C>A (p.Gly1556=)

ClinVar: 626810 https://www.ncbi.nlm.nih.gov/clinvar/variation/626810/

gnomAD: 0.0009022, http://gnomad.broadinstitute.org/variant/14-23885498-G-T

Supplementary Data table 1

Variant noted to be present in 3 individuals

Variant: NM_000257.3(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642, https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

gnomAD: 0.00002125, https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Case#: Consequence 16 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

CAID: n/a

gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Case#: Consequence 2 Table 1 in Data Supplement (1 case)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

CAID: n/a

gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

PatientID: 43

KindredID: F01

Case: M, Age Unknown, Unknown Ethnicity

DiseaseAssertion: VHL

FamilyInfo: A total of 12 members of this family (F01) had a complete deletion of the VHL gene. Five of these patients (16, 18, 21, 33, 43) presented with clinical features of VHL. This family was previously published except for patients 43 and 48 which were newly diagnosed with VHL disease in the current study.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17537157

SupplementalData: Figure 2.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of ~250.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

PatientID: 21

KindredID: F01

Case: F, Age Unknown, Unknown Ethnicity

DiseaseAssertion: VHL

FamilyInfo: A total of 12 members of this family (F01) had a complete deletion of the VHL gene. Five of these patients (16, 18, 21, 33, 43) presented with clinical features of VHL. This family was previously published except for patients 43 and 48 which were newly diagnosed with VHL disease in the current study.

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 17537157

SupplementalData: Figure 2.

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Deletion of ~250.9kb resulted in deletion of the VHL gene.

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

GroupID: 9

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:0002666; HP:0009711; HP:0010797; HP:0009713; HP:0030424; HP:0001737 (Renal cell carcinoma, Renal cyst, Pheochromocytoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Epididymal cyst, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (2), Renal cyst (2), Pheochromocytoma (1), Retinal capillary hemangioma (2), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (2), Epididymal cyst (1), Pancreatic cysts (2)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-2 Deletion (c.1-?_463+?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 1-2 Deletion

MultipleGeneVariants: N/A

GroupID: 45

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:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Pancreatic cysts/single cyst (1), Epididymal cyst (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, HSPC300, partial deletion

MultipleGeneVariants: Germline, ENST197804, deletion

MultipleGeneVariants: Germline, IRAK2, deletion

MultipleGeneVariants: Germline, TATDN2, partial deletion

GroupID: 26

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:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Pancreatic cysts (1), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

GroupID: 51

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:0010797; HP:0030393; HP:0030424 (Renal cell carcinoma, Hemangioblastoma, Endolymphatic sac tumor, Epididymal cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Hemangioblastoma/brain/cerebellum (1), Endolymphatic sac tumor (1), Epididymal cysts (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, deletion

MultipleGeneVariants: Germline, FANCD2, deletion

GroupID: 4

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:0002666; HP:0009711; HP:0001737 (Renal cell carcinoma, Pheochromocytoma, Retinal capillary hemangioma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Pheochromocytoma (1), Retinal capillary hemangioma (1), Pancreatic cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

GroupID: 20

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: 0 GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

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

GroupPresentingHPOs: HP:0005584; HP:0009711; HP:0010797; HP:0009713 (Renal cell carcinoma, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (2)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: None

KindredID: 4

Case: F, 60Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

CohortInfo: The National Cancer Institute has a frozen tumour bank of ccRCC tumours that have been removed from VHL patients. We selected six patients, three males and three females, with at least five tumours from a single surgery from one kidney.

CasePresentingHPOs: HP:0006770 (clear cell renal cell carcinoma)

CaseHPOFreeText: The patient presented with ccRCC at age 60.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.W117C(c.351G>X)

LegacyVariant:N/A

CaseProblemVariantFreeText: This protein change corresponds to both c.351G>C or c.351G>T.

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:W117C(c.351G>X)

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A

SamplingMethod: peripheral blood

PatientID: Proband

KindredID: 13

Case: M, 44Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Son and brother presented with the same VHL variant. Son is asymptomatic. Brother presented with CNS hemangioblastoma at 29Y, retinal hemangioblastoma at 52Y, bilateral RCC at 43Y, multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 43Y and bilateral renal cysts at 43Y. Nephew presented with CNS hemangioblastoma at 22Y, retinal hemangioblastoma at 18Y, bilateral RCC at 29Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 18Y but was not genetically confirmed.

CohortInfo: Thirteen unrelated patients with germline VHL mutations who were diagnosed with VHL disease were evaluated.

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

CaseHPOFreeText: CNS hemangioblastoma at 32Y, retinal hemangioblastoma at 44Y, bilateral RCC at 44Y and multiple pancreatic lesions (pancreatic cyst or tumor, unspecified) at 41Y. Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0000107; HP:0002666 (Renal cyst, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 2-3 Deletion (c.341-?_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 2-3 Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: Direct sequencing uaing an ABI PRISM 3730xl DNA Analyzer (Applied Biosystems, Foster City, CA, USA) using the BigDye Terminator v.3.1 Cycle Sequencing Kit (Applied Biosystems). and multiplex ligation-dependent probe amplification.

SamplingMethod: peripheral blood

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

GenotypingMethod: DNA sequencing and gene dosage analysis

SamplingMethod: Not stated

GroupID: 4

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: N/A

CaseHPOFreeText: This individual patient did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: Exon 2-3 deletion

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 deletion

MultipleGeneVariants: N/A

GroupID: 2a

DiseaseAssertion: VHL

GroupSize: 10

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 10/15 patients with a VHL gene deletion had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: VHL gene deletion

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Complete Deletion)

MultipleGeneVariants: N/A

GroupID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

CohortInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

CasePresentingHPOs: N/A

CaseHPOFreeText: This individual patient did NOT have retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: HP:0009711 (retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: Exon 1-2 deletion

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: MLPA complete VHL gene sequencing.

SamplingMethod: peripheral blood

PatientID: 15

KindredID: 15

Case: 34Y0M, Sex Unknown, Argentinian

DiseaseAssertion: VHL

FamilyInfo: Positive family history

CasePresentingHPOs: HP:0006770; HP:0001737; HP:0000107; HP:0030393 (clear cell renal cell carcinoma; pancreatic cysts; renal cyst; endolymphatic sac tumor)

CaseHPOFreeText: Aged 34Y at diagnosis (genetic testing); fulfils type 1 VHL clinical diagnosis. ccRCC, pancreatic cysts, renal cysts, and endolymphatic sac tumors were all diagnosed at 34Y (See Table 1 & 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: exon 3 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

ArticleReferenceSequence: NM_000551.2

GenotypingMethod: PCR and multiple ligation-dependent probe amplification (MLPA) analysis; re-PCR and resequencing with alliquot of stored DNA was additionally done.

SamplingMethod: peripheral blood leukocytes

PatientID: 14

KindredID: 14

Case: M, 51Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database) [Refer to table 2].

SupplementalData: N/A

Variant: Exon 3 deletion (c.464-?_642+?del)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 deletion

MultipleGeneVariants: N/A

PatientID: None (sister)

KindredID: 10

Case: F, 38Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Patient had a positive family history: Her father was died of RCC (no mutation availible), and her older sister who presented with spinal HB and multiple cysts in pancreas and both kidneys, harbored the same exon deletion

CasePresentingHPOs: HP:0010797; HP:0005584 (hemangioblastoma, renal cell carcinoma)

CaseHPOFreeText: presented with medullary HB at the age of 37 and multiple RCC in both kidneys at the age of 38

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: N/A

GroupID: 37

Case: Sex unknown, Age unknown, French

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: Exon 2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2 Deletion

MultipleGeneVariants: N/A

GroupID: 36

Case: Sex unknown, Age unknown, Dutch (The Netherlands)

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: Exon 1 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: MLPA. Those cases that were found in the MLPA assay to have deletions affecting VHL exon 1 but not FANCD2, were further characterized by means of a user-designed multiplex-PCR analysis in order to establish the retention of HSPC300 band ENST197804. The presence of. VHL point mutations were evaluated in apparently sporadic ccRRCs by PCR amplification and sequencing, and loss of heterozygosity (LOH) was analyzed by commercial multiplex ligation-dependent probe amplification (MLPA).

SamplingMethod: peripheral blood, tissue resection

PatientID: None

KindredID: 36

Case: M, 31Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: Positive for familial antecedents. No known familial tumors.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0001737 (Cerebellar hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300, ENST197804 and FANCD2 (unclear if partial or complete) gene deletions. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, HSPC300, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, FANCD2, Deletion

PatientID: None (Proband)

KindredID: 53

Case: F, 18Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: Positive for familial antecedents. Family history of clear cell renal cell carcinoma.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0009711 (Cerebellar hemangioblastoma, Pancreatic cysts, Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300 (Figure 2 appears to indicate an exon 2-3 deletion of this gene since it spans the same left-most distance as the mutation in patient 108 which is stated to be an exon 2-3 deletion) and ENST197804 deletion. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, HSPC300, Exon 2-3 Deletion MultipleGeneVariants: Germline, ENST197804, Deletion

GroupID: 2

DiseaseAssertion: VHL

Group size: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

Group Info: Retrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and retinal haemangioblastomas. All patients were categorized in two genotypic categories: missense mutations and truncating mutations.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: The patient presented with retinal capillary hemangioma.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1

Variant: Exon 1-2 deletion

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: cDNA level information: c.(?_1)_463+?del

MutationType: exon_loss_deletion

CivicName: Exon 1-2 deletion

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A - Genetic testing done previously (PMID: 21673464)

SamplingMethod: N/A

PatientID: None

KindredID: 1

Case: F, 22Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL, it was concluded that it was a de novo mutation.

CasePresentingHPOs: HP:0009711; HP:0001737; HP:0009713; HP:0006880; HP:0002094; HP:0001962; HP:0011703; HP:0031664; HP:0001635; HP:0002375; HP:0001653; HP:0002666; HP:0006770 (Retinal capillary hemangioma, Pancreatic cysts, Spinal hemangioblastoma, Cerebellar hemangioblastoma, Dyspnea, Palpitations, Sinus tachycardia, Systolic heart murmur, Congestive heart failure, Hypokinesia, Mitral regurgitation, Pheochromocytoma, Clear cell renal cell carcinoma)

CaseHPOFreeText: 22-year-old woman who was diagnosed in childhood with type IIb VHL, with known multiple retinal angiomas, pancreatic cysts, and spinal and cerebellar hemangioblastomas. She was admitted to our hospital complaining of progressive dyspnea and palpitations. Physical examination revealed a systolic murmur at the mitral focus with irradiation to the axilla and pulmonary rales. Electrocardiography revealed no remarkable findings, except for sinus tachycardia. Chest X-ray showed signs of pulmonary interstitial edema. The patient was admitted to the Department of Cardiology with the diagnosis of acute decompensated heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed ejection fraction due to generalized hypokinesia and a mild mitral regurgitation. During admission, the patient had several episodes of paroxysmal dyspnea. Cardiac MRI was performed in order to complete the cardiomyopathy study, and confirmed the echocardiographic findings as well as revealed an incidental finding of a great left renal mass. Abdominal MRI was performed, which showed the presence of two cystic masses located at the left hypochondrium confirming the diagnosis of pheochromocytoma and clear cell renal carcinoma on histology.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A