PMID: 42569619

Gene: MYBPC3

HGNC ID: 7551

Case1: 42 year old Male

DiseaseAssertion: History of acromegaly

FamilyInfo: N/A

ParentalTesting: No parental testing done

CasePresentingHPOs: “elevated levels of growth hormone, and IGF-1”

CaseHPOFreeText: Genetic analysis revealed a heterozygous nonsense variant in MYBPC3

CaseNotHPOs: N/A

CaseNotHPOFreeText: Cardiac MRI revealed normal dimensions of thoracic aorta, no evidence of stenosis or aneurysms

CasePreviousTesting: An oral glucose tolerance test was performed, growth hormone failed to suppress below 0.88

Genotyping Method: Echocardiography used to confirm enlarged left atrium, increased septal thickness, mild mitral and tricuspid regurgitation

Variant: NM_000256.3 c.3408C>G MANE select

ClinVar: 851340

CAID: CA380313523

gnomAD: chr11-47332896

https://www.ncbi.nlm.nih.gov/clinvar/variation/851340/?term=%22c.3408C%3EG%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

PMID:30565988

Gene:TNNT2

HGNC ID:11949

Case#:A 65-year-old woman with severe hypertrophic cardiomyopathy

DiseaseAssertion:Severe hypertrophic cardiomyopathy

FamilyInfo:no information reported

ParentalTesting:no parental testing reported

CasePresentingHPOs:HP:0001639

CaseHPOFreeText: gene panel testing that identified a single variant

CaseNotHPOs: not found

CaseNotHPOFreeText: not found

CasePreviousTesting: gene panel testing that identified a single variant

Genotyping Method:clinical gene panel testing

FunctionalAnalysis: rapid insertion of TNNT2 gene variants into induced pluripotent stem cell-differentiated cardiomyocytes (iPSC-CMs) for functional annotation of the variants for (E251D)(Figure B)

Variant:c.753G>T (p.Glu251Asp)

ClinVar:not found

CAID:CA090003

gnomAD:not found

AdditionalInfo:not reported

Case#: 1. Patient II-4 43 years

DiseaseAssertion: Hypertrophic cardiomyopathy and left ventricular noncompaction

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

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

Genotyping Method: Next- generation sequencing and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 2 Patient II-5 46 years old

DiseaseAssertion: HCM and LVNC

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 3 Patient II-1 10 years

DiseaseAssertion: left ventricular noncompaction

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 4 Patient III-2 14 years

DiseaseAssertion: HCM and LVNC

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case: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.

PMID: 42458772 Gene: ACTC1 HGNCID: 143

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.

PMID:41969674

Gene:TNNT2

HGNC ID:11949

Case#:male, 41, DCM

DiseaseAssertion:dilated cardiomyopathy

FamilyInfo:The proband reported that his mother died suddenly at approximately 35 years of age (specific cause unknown). Other family members were healthy with no history of cardiac disease. Written informed consent was obtained from all participants.

ParentalTesting:no parental testing reported. Sanger sequencing of available family members (daughter, half-brother, maternal uncle and maternal aunt) confirmed that none carried the variant, supporting its de novo origin

CasePresentingHPOs:HP:0002875, HP:0001644, HP:4000141, HP:6000313

CaseHPOFreeText: ECG showed sinus bradycardia, occasional atrial premature beats, delayed atrioventricular conduction, left atrial enlargement, left ventricular high voltage, incomplete right bundle branch block, and ST-T changes (Figure 1C). CMR revealed late gadolinium enhancement (LGE) in the basal to mid-septal and anterolateral segments of the left ventricle (Figure 1D).

CaseNotHPOs:HP:0000822, HP:0003077

CaseNotHPOFreeText:He denied a history of hyperlipidemia, hypertension, or substance abuse.

CasePreviousTesting:No reports of previous testing

Genotyping Method:whole-exome sequencing and Sanger sequencing

FunctionalAnalysis:not reported

Variant:c.547C>T p.Arg183Trp

ClinVar:43628

CAID:CA004294

gnomAD:Overall allele frequency: 0.000001239

AdditionalInfo:not reported

Case2: Full term male

DiseaseAssertion: poor feeding, respiratory distress, and cyanosis

FamilyInfo: Healthy non‐consanguineous parents. Positive for HCM on the mother's side: the maternal grandfather died from HCM at the age of 52 years, and a brother of the maternal grandfather was also affected. The parents and siblings of the patient showed no abnormalities on cardiological examination.

ParentalTesting:

CasePresentingHPOs: HP:0001714, HP:0011623, HP:0010438

CaseHPOFreeText: On cardiac catheterisation, both ventricles were found to be hypertrophic. There was mild shunting at the level of the foramen ovale. The pressures in the right ventricle and pulmonary artery were pathologically high, while the pressures in the left atrium and ventricle were normal (though with high A waves). There was a total left to right shunt of 43% of the pulmonary circulation, partly caused by a low muscular ventricular septal defect.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NM_001242672.3(TTC34):c.2827C>T (p.Arg943Trp)

ClinVar: 3329883

CAID: NR

gnomAD: 1-2573220-G-A

AdditionalInfo: NR

Case1: gestational age 40 weeks female

DiseaseAssertion: Poor feeding, cyanosis, and difficulty with breathing.

FamilyInfo: Healthy non‐consanguineous parents. Echocardiographic in the mother and sister were normal. Father had mild dilatation of the left atrium with an abnormal flow pattern in the mitral valve, otherwise healthy.

ParentalTesting: c.2373_2374insG mutation found in the mother

CasePresentingHPOs:HP:0025169,

CaseHPOFreeText: hypertrophic non‐obstructive cardiomyopathy with poor left and right ventricular systolic function. The left ventricular end diastolic diameter measured 17.3 mm (99% of normal), end systolic diameter 12.9 mm (116% of normal), and left ventricular posterior wall 3.6 mm (111% of normal). The intraventricular septum measured 11.8 mm (288% of normal). The shortening fraction of the left ventricle was decreased to 25%. Multiple abnormal small communications with a minimal flow between a coronary artery and the right ventricle were observed in the apical portion of the interventricular septum. There were no structural congenital heart defects.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method:

FunctionalAnalysis: NR

Variant: NM_006073.4(TRDN):c.1624+1G>A

ClinVar:2152664

CAID: CA147231745

gnomAD:NR

AdditionalInfo:NR

PMID: 16679492

Gene: MYBPC3

HGNC ID:7551

Case3: Male, 44,57,17, 2 Native American, European, Guaranda, Zaruma, Ibarra

DiseaseAssertion: asymmetric septal hypertrophy, dynamic left ventricular outflow tract obstruction, HCM, fatigue and presyncope

FamilyInfo: family history included parental hypertension and cancer, Relatives had cardiovascular conditions, including a paternal uncle with myocardial infarction at 58, another with a heart murmur, and a grandmother with hypertension

ParentalTesting: Family history of first degree relatives with myocardial infarction

CasePresentingHPOs: HP: 000256.3, HP: 033118.3, HP:000540.2 “Gene encodes the cardiac isoform of myosin-binding, Gene encodes an enzyme that is expressed in adult skeletal muscle, gene encodes a ryanodine receptor found in skeletal muscle”

CaseHPOFreeText: N/A

CaseNotHPOs: HP: 004168.3, HP: 000384.2, HP: 020433.4

CaseNotHPOFreeText: “Mutations in gene are linked to Leigh syndrome, mutations to gene are linked to diseases affecting plasma cholesterol, gene encodes a protein to mediate cross talk between cell surface and intracellular ion channels”

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Next-generation sequencing (NGS)

FunctionalAnalysis: N/A

Variant: NM_000256.3 c.772G>A MANE select

ClinVar: 42792

CAID: CA015823

gnomAD: 0.00003

https://www.ncbi.nlm.nih.gov/clinvar/variation/42792/?term=%22p.Glu258Lys%22%5BVARNAME%5D+AND+%22MYBPC3%22%5BGENE%5D

Case2: 12 year old Male, 9 month old Female

Disease Assertion:Double atrial and right ventricular hypertrophy, intermittent chest pain and left ventricular hypertrophy

FamilyInfo: No family history of sudden cardiac death, HCM, or coronary artery disease, granduncle had HCM history and died at 67

ParentalTesting: Heterozygous mutation myosin binding protein C gene(MYBPC3) is confirmed in mother

CasePresentingHPOs: “enlarged left and right atria, double ventricular hypertrophy, interventricular septal thickness”

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: TruSight Cardio panel for inherited cardiac disorders

Genotyping Method: Sanger sequencing

FunctionalAnalysis: N/A

Variant: TNN c.50171G>T, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA012326&

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

PMID: 41561115

Gene: MYBPC3

HGNC ID: 7551

Case1: 40-year-old Chinese male

DiseaseAssertion: exertional dyspnea for one year and substernal chest pain for one week.

FamilyInfo: Father experienced sudden cardiac death (SCD) at the age of 41. Targeted region capture and second-generation high throughput sequencing were performed on the proband’s cousin, cousin sister, and sister. Results demonstrated that all family members carried the MYBPC3 c.1827dupC variant. Pedigree in Fig. 3

ParentalTesting: NR

CasePresentingHPOs: HP:0025169, HP:0025168, HP:0031675, HP:0001714,

CaseHPOFreeText: harsh systolic ejection murmur at the left sternal border (3rd–4th intercostal spaces), accentuated by Valsalva maneuver. Echocardiography revealed the following key findings: severe asymmetric septal hypertrophy, characterized by an interventricular septal thickness (IVsd) at end-diastole of 25–30 mm and a left ventricular posterior wall dimensions (LVPWd) of 21 mm, with a preserved left ventricular ejection fraction (LVEF) of 59%

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: target-region capture sequencing and second-generation high throughput sequencing were performed to analyze all exons and their Flanking regions. Rare and known variants were validated using Sanger sequencing and cascade screening was carried out for all available relatives

Genotyping Method: target-region capture sequencing and second-generation high throughput sequencing, Sanger sequencing and cascade screening.

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1827dupC, NM_004415.4:c.1324T>C

ClinVar:NR

CAID:UnregisteredVariant

gnomAD:NR

Case2: 16-year-old male patient

DiseaseAssertion: monomorphic VT

FamilyInfo:NR

ParentalTesting:NR

CasePresentingHPOs:HP:0031676, HP:0033118, HP:0032643

CaseHPOFreeText: Moderately decreased right ventricular (RV) function and moderate RV dilation. moderate myocyte hypertrophy with mild to moderate interstitial fibrosis and rare adipose tissue. Cervical, mediastinal, abdominal, and pelvic FDG-avid lymphadenopathy. myocyte hypertrophy with patchy interstitial fibrosis.

CaseNotHPOs: NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:NR

FunctionalAnalysis:NR

Variant: NM_001005242.3:c.148_151del

ClinVar: 45028

CAID: CA011079

gnomAD:NR

AdditionalInfo:NR

Case3: 39-year-old man

DiseaseAssertion: seronegative rheumatoid arthritis

FamilyInfo: Father was diagnosed with hypertrophic cardiomyopathy

ParentalTesting: Genetic testing revealed a pathogenic MYBPC3 variant in the patient and his father (c.655G>C [p.Val219Leu])

CasePresentingHPOs: HP:5210340, HP:0006682, HP:0031971

CaseHPOFreeText: Rccentric septal hypertrophy with a maximal wall thickness of 1.7 cm, no evidence of outflow tract obstruction, and an LV EF of 65% to 70%. Rare premature ventricular complexes. Mild mediastinal lymphadenopathy, pulmonary sarcoidosis

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NM_006252.4(PRKAA2):c.148_151del (p.Gln50fs)

ClinVar:4891957

CAID:NR

gnomAD:NR

AdditionalInfo:NR

PMID:42233912

Gene:MYBPC3, FLNC, PKP2

HGNC ID:7551, 9024, 3756

Case1: 59-year-old male

DiseaseAssertion: frequent premature ventricular contractions

FamilyInfo:Significant for dilated cardiomyopathy with multiple sudden cardiac deaths. His sister’s initial genetic testing panel was negative for pathogenic variants at that time

ParentalTesting:NR

CasePresentingHPOs: HP:0006682, HP:0025169, HP:0004751, HP:5210340

CaseHPOFreeText: Transthoracic echocardiogram (TTE) demonstrated a left ventricular (LV) ejection fraction (EF) of 20%-25% and an LV diastolic diameter of 6.6 cm. revealed bulky mediastinal adenopathy. A transbronchial biopsy of lung parenchyma showed noncaseating granulomas, and ultimately the patient was found to have pulmonary sarcoidosis.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting:NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant:NM_001458.5(FLNC):c.4737+5G>A

ClinVar: 934656

CAID: CA1139660256

gnomAD: NR

AdditionalInfo: NR

PMID:17347475

Gene:MYOZ2

HGNC ID:1330

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

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

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

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

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

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

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

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

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

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

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

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

ClinVar: 1473634

CAID: Not reported.

Gene:MYBPC3

HGNC: HGNC: 7551

PMID: 33803538

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

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

Case#: P16, 17 year old male

DiseaseAssertion: left ventricular noncompaction cardiomyopathy

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

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

FunctionalAnalysis: NR

Variant: NM_005159.5:c.329>T

Clinvar: 2137647

CAID: CA391631478

gnomAD: Exact frequency not provided

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

Case#: 33 year-old female; first cardiologic evaluation at age 24 (LV wall thickness 13 mm); re-evaluated at 33 after recurrent palpitations

DiseaseAssertion: Noonan syndrome (PTPN11) with sarcomeric hypertrophic cardiomyopathy (MYBPC3); non-obstructive HCM, mild phenotype

FamilyInfo: Father carries the MYBPC3 c.1790G>A variant and has HCM; the PTPN11 variant was absent in both parents, consistent with de novo. Both parents and the proband's brothers underwent full cardiologic evaluation, no cardiovascular disease in the other family members. Parents declined genetic testing of the underage siblings. Grandparents (I-1, I-2) and II-2, II-3 have unknown phenotypes (pedigree Fig. 2).

ParentalTesting: Both parents genotyped for the two proband variants (Table 1). Father heterozygous for MYBPC3 c.1790G>A; neither parent carries PTPN11 c.1510A>G, supporting de novo status. Phase between the two variants therefore established as in trans (different genes).

CasePresentingHPOs: HP:0001639; HP:0001962; HP:0004322; HP:0000271; HP:0001647; HP:0000508

CaseHPOFreeText: Regular psychophysical development. First echo at 24 showed mild increase in LV wall thickness (13 mm). At 33, presented with several episodes of palpitations; exam showed mild facial dysmorphisms (wide mouth, sloping forehead, prominent nasal bridge, prominent nose, low-set ears), short stature, and a systolic heart murmur. Echo: asymmetric LV hypertrophy, maximum wall thickness 16 mm at the anterior interventricular septum, mild mitral regurgitation, non-obstructive. No other cardiovascular signs.

CaseNotHPOs: HP:0001635; HP:0001650; HP:0001642; HP:0001250

CaseNotHPOFreeText: No heart failure, no LV outflow obstruction, no pulmonary stenosis, no other congenital heart defect. No intellectual disability; psychophysical development was regular. No other signs of cardiovascular disease on examination.

CasePreviousTesting: NGS panel of 325 cardiomyopathy-associated genes (Supplementary Table S1); MAF threshold 5%; variants validated by Sanger sequencing; cascade testing restricted to the two proband variants.

Genotyping Method: NGS targeted panel (Maxwell 16 DNA extraction, Agilent Alyssa analysis, Illumina Variant Interpreter, in-house pipeline) with Sanger validation; parental Sanger genotyping for the same two variants.

FunctionalAnalysis: None performed by the authors. They cite prior HeLa cell work showing the MYBPC3 c.1790G>A change causes exon 18 inclusion in the transcript and an almost undetectable 248 bp product.

Variant 1: PTPN11 NM_002834.3:c.1510A>G (p.Met504Val); heterozygous missense; de novo; classified pathogenic, explains Noonan syndrome

ClinVar: Not stated in the paper; verify the current record before submitting.

CAID: N/A

gnomAD: Not reported in the paper; I have not checked gnomAD for this variant.

Variant 2: MYBPC3 NM_000256.3:c.1790G>A (p.Arg597Gln); heterozygous missense; exon 18, last nucleotide of the exon, affecting a highly conserved residue and causing a splicing variation; inherited from the father

ClinVar: Not stated in the paper; authors note it is classified pathogenic/likely pathogenic for HCM in several genetic databases.

CAID: N/A

gnomAD: N/A

PMID: 32824488

Gene: MYBPC3

AdditionalInfo: Authors describe this as the first reported young adult with HCM and mild NS carrying variants in both PTPN11 and MYBPC3. Note the terminology problem: the abstract calls them "compound heterozygous," but the variants are in different genes on different chromosomes, so this is digenic (double heterozygosity), not compound heterozygosity. The authors argue the mild phenotype contrasts with the usual expectation that multiple sarcomeric hits worsen the disease, and that red flags justified the broad panel.

Case#:a 40-year-old woman with a history of hypokinetic-dilative cardiomyopathy and heterozygous for TNNT2 gene mutation

DiseaseAssertion:hypokinetic-dilative cardiomyopathy

FamilyInfo: her family appreciated the clear communication, and as her condition improved without further complications, she expressed gratitude for the care provided.

ParentalTesting:n/r

CasePresentingHPOs:HP:0001644, HP:0002094, HP:0002094, HP:0001695,

CaseHPOFreeText:Progressive dyspnea and fatigue began in January 2017. In February 2018, the patient had cardiac arrest due to ventricular fibrillation at 26 weeks’ gestation, followed by emergency caesarean section. She carried a heterozygous TNNT2 variant (c.547C>T, p.Arg183Trp)

CaseNotHPOs: HP:0031972, HP:0031972

CaseNotHPOFreeText:Coronary angiography showed no significant stenosis.

CasePreviousTesting:Testing method and scope

GenotypingMethod:n/a

FunctionalAnalysis:not reported

Variant: c.547C>T p.Arg183Trp)

Clinvar:not known

CAID:CA391630526

gnomAD:n/r

AdditionalInfo:n/r

PMID : 40008267

Gene: TNNT2

HGNC ID: 11949

PMID: 29367541

Gene: TNNT2

HGNC ID: 11949

Case#: 64-year-old male, non-smoker, first admitted June 2014; Russian family; died 2019 at age 69

DiseaseAssertion: MYBPC3-related cardiomyopathy with a predominantly restrictive phenotype in combination with left ventricular noncompaction (LVNC) and cardiac sarcoidosis

FamilyInfo: Son (39) and daughter (35) both heterozygous for the same variant and both have non-obstructive asymmetric HCM, with no LVNC on cardiac CT; both essentially asymptomatic on beta-blocker monotherapy. Five-year SCD risk 4.82% (son) and 2.07% (daughter); ICD implanted in the son, no shocks in three years. Authors mention another family of theirs with a father who died suddenly young and children with HCM and LVNC.

ParentalTesting: Not performed; the proband is the index case; his parents were not evaluated. Transmission to both children confirmed by Sanger.

CasePresentingHPOs:HP:0001639

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Genotyping Method: Next-generation sequencing panel; variants confirmed by Sanger.

FunctionalAnalysis: N/A

Variant 1: MYBPC3 NM_000256.3:c.278delA; heterozygous frameshift

Variant 2: KCNJ5 c.464G>A; heterozygous missense

ClinVar: N/A

CAID:N/A

gnomAD: N/A

Gene:MYBPC3

PMID:36011256

PMID:39905734

Gene:TNNT2

HGNC ID:11949

Case#: a 50‐year‐old male who was clinically diagnosed with isolated CS and prescribed with prednisolone without much effect, and subsequent genetic analysis revealed pathogenic variants in LMNA and TNNT2, representative genes for cardiomyopathy.

DiseaseAssertion:Dilated cardiomyopathy

FamilyInfo: not reported

ParentalTesting: He had no family history of heart disease or sudden death

CasePresentingHPOs:HP:0002094,HP:0005110,HP:0025169, HP:0005110

CaseHPOFreeText:Progressive cardiac conduction disease: first-degree AV block with left axis deviation on an earlier ECG progressed to high-grade and then complete AV block. At age 50, the patient also had mild dyspnoea on exertion (New York Class ll) and atrial fibrillation. The authors later stated that it was dilated cardiomyopathy.

CaseNotHPOs:HP:0033608,HP:0002716

CaseNotHPOFreeText:CT showed no enlarged lymph nodes, pulmonary nodules, or other organ abnormalities

CasePreviousTesting: whole‐exome sequencing analysis to evaluate the risk of inherited cardiomyopathies and identified two missense variants in TNNT2 (chr1:201364335(hg38), NM_001001430.3, c.422G>A, p.Arg141Gln) and LMNA (chr1:156136096(hg38), NM_170707.4, c.1132A>C, p.Lys378Gln) (Figure 3). Sanger sequencing analysis identified a heterozygous single‐base substitution (c.1132A>C) in the LMNA gene and c.422G>A in the TNNT2 gene (red arrows).

Genotyping Method:Whole-exome sequencing (WES) identified the variants; Sanger sequencing of the TNNT2 and LMNA variants is shown in Figure 3.

FunctionalAnalysis:Not reported

Variant:TNNT2: NM_001001430.3:c.422G>A (p.Arg141Gln),LMNA: NM_170707.4:c.1132A>C (p.Lys378Gln)

ClinVar:43637

CAID:CA004540

gnomAD:not reported

AdditionalInfo:not reported

PMID: 42112275

Gene: MYBPC3

HGNC ID: 7551

Case2: 40 year old Male, 37 year old Female

DiseaseAssertion: HCM, basal septal hypertrophy, dilated phase HCM

FamilyInfo: Family was notable for end stage HCM in father and in younger brother, family history was notable for HCM in grandmother and sudden cardiac death(SDC) due to HCM in mother

ParentalTesting: No parental testing done

CasePresentingHPOs: “Inguinal Hernia surgery, exertional dyspnea”

CaseHPOFreeText: Transthoracic echocardiography unveiled hypertrophy of the interventricular septum and left ventricular anterior wall, systolic anterior motion of the mitral valve

CaseNotHPOs: N/A

CaseNotHPOFreeText: ECG demonstrated a sinus rhythm at 58 bpm with complete right bundle branch block, heart failure progressively worsened

CasePreviousTesting: Cardiac magnetic resonance reveals ring like late gadolinium enhancement(LGE) as a imaging phenotype

Genotyping Method: Cardiac magnetic resonance

FunctionalAnalysis: N/A

Variant: NM_000257.4 c.2302G>A, NM_000256.3 c.2459G>A MANE select

ClinVar: 8617

CAID: CA012326

gnomAD: chr11-47337534

https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA012326

Case1: 48 year old male

DiseaseAssertion: . Two missense variants in MYBPC3 (NM_000256.3): c.2533C>G in exon 26 (C6 domain) were identified and, classified as a variant of uncertain significance (VUS, score 2), and c.1696T>A in exon 18 (C4 domain), a VUS with a score of 5.

FamilyInfo: There was no family history of cardiomyopathy or SCD.

ParentalTesting: NR

CasePresentingHPOs: HP:0004751, HP:0006682, HP:0001712

CaseHPOFreeText: 38 year old man, suffering from contractions, and one short run of non-sustained ventricular tachycardia lasting four beats. Asymmetric septal hypertrophy with a maximum thickness of 19 mm. In addition, marked biatrial enlargement was evident, with a left atrial volume index of 79 mL/m² and right atrial area of 25 cm². Importantly, extensive diffuse late gadolinium enhancement (LGE) was detected in the basal and mid-septal and anterior segments, involving 17% of the myocardial mass

CaseNotHPOs: NR

CasePreviousTesting: genetic testing was performed using the Health in Code HCM panel, which includes the following 18 genes: ACTC1, DES, FHL1, FHOD3, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, TRIM63, and TTR.

Genotyping Method: Health in Code HCM panel

FunctionalAnalysis:

Variant: NM_000256.3:c.2533C>G, NM_000256.3:c.1696T>A

ClinVarID:180973, 915724

CAID:CA380324353, CA012504

gnomAD:

AdditionalInfo:NR

PMID: 28815794

Gene: TNNT2

HGNC ID: 11949

Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction

FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.⁠

ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.

CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678

CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.

CaseNotHPOs: HP:0000822; HP:0000819

CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.

CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.

Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.

FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.

Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)

ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!

CAID: N/A

gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.

AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

PMID:20973921

Gene:TNNT2

HGNC ID:11949

Case#:A 70‐year‐old woman, previously healthy with a left ventricular ejection fraction presented with DCM

DiseaseAssertion:dilated cardiomyopathy and a 4-month history of progressive heart failure

FamilyInfo:"Family history was negative for IDC or heart failure (Figure 3), although an uncle (II‐3) reportedly had an enlarged heart, and three other relatives (II‐1, II‐2, and III‐4) had cardiac related deaths confirmed by death certificate. The proband’s father (II‐1) died of myocardial failure and pulmonary edema; her mother (II‐2) died of pulmonary embolism; and her sister (III‐4) died suddenly of coronary artery disease in her 60s. Her daughter, the proband’s niece (IV‐3), had a history of palpitations and lower extremity swelling, intermittent numbness, and blanching of the fingers at age 49. Her echocardiogram was normal. Her ECG showed nonspecific ST‐T wave changes and left anterior hemiblock."

ParentalTesting:no parental testing reported because both parents were deceased. The two offsprings that were reported were tested and carried both variants.

CasePresentingHPOs:HP:0001644, HP:0001635, HP:0002875, HP:0012378

CaseHPOFreeText:symptoms of progressive dyspnea on exertion and fatigue that began 2–3 months prior to her presentation. Also, she had an unrelenting progression of symptoms and was hospitalized with advanced NYHA Class IV heart failure 6 weeks later. Lastly, she received a heart transplant.

CaseNotHPOs:not reported

CaseNotHPOFreeText:no myocarditis or infiltrative process and no histological evidence of hemochromatosis,

CasePreviousTesting:Oligonucleotide hybridization‐based DNA sequencing was conducted in the proband for a panel of 19 DCM genes ( Table 1 )

Genotyping Method:Oligonucleotide hybridization‐based DNA sequencing and genomic DNA was extracted from whole blood and was sequenced in our laboratory in both directions to detect and/or confirm nucleotide variants in TNNT2 in the proband and the proband’s relatives using an Applied Biosystems 3130XL capillary sequencer

FunctionalAnalysis:R139H (Figure 4): Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca2+ sensitivity at pH 7, characteristic of DCM.

Variant:416G>A (R139H) in exon 10 and 690–6G>A in intron 13.

ClinVar:not found

CAID:CA004513

gnomAD:not found

AdditionalInfo:not reported

GroupID: 24a

DiseaseAssertion: VHL

GroupSize: 2

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 2/4 patients with a P86H (c.257C>A) mutation 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: N/A

Variant: p.P86H (c.257C>A)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351750632 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.257C>A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: P86H (c.257C>A)

MultipleGeneVariants: N/A

GroupID: 19a

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: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R79G (c.235C>G)

MultipleGeneVariants: N/A

GroupID: 35a

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: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This was 1 of 2 patients discussed with this mutation. The individual had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064 https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: 0.000003976 https//gnomad.broadinstitute.org/variant/3-10188264-T-C?dataset=gnomad_r2_1

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

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: 18

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: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: This individual patient was the only one discussed with this mutation. They had retinal hemangiomas; Other VHL manifestations were discussed but not per- variant.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes - Supplementary Table S1

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

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID: 19b

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 was 1 of 2 patients discussed with this mutation. The individual did NOT have retinal 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: p.R79G (c.235C>G)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 411988 https://www.ncbi.nlm.nih.gov/clinvar/variation/411988/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: R79G (c.235C>G)

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: 30

KindredID: 11

Case: F, 37Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 30) has a son (patient 31) who was genetically confirmed with the mutation, who was asymptomatic at the time of analysis. She also has a father (patient 32, CNS hemangioblastoma at 42), a brother 1 (patient 33, CNS hemangioblastoma at 28), brother 2 (patient 34, CNS hemangioblastoma at 30), and uncle (patient 35, retinal angioma at 60) who passed away before they could be diagnosed/ genetically confirmed with the mutation.

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

CaseHPOFreeText: The proband presented with CNS hemangioblastoma at 28, retinal angioma at 26, renal cell carcinoma at 37, and multiple pancreatic cysts/tumors at 28.

CaseNotHPOs: HP:0002666 (Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in a later paper by Wang et al., 2018 (PMID: 29330336). This mutation was also published in PMID 32179488 in reference to one patient with VHL disease type 1 in this paper with the c.227_229del variant. However, it is unclear whether patient #27, #28, or #30 is specifically published in PMID 32179488.

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

Variant: p.F76del (c.227_229del)

LegacyVariant: F76del (c.224_226delTCT)

CaseProblemVariantFreeText: The protein coding change for this variant is listed in this paper as p.F76Cfs*138. However the DNA change listed in this paper (c.224_226delTCT) is equivalent to c.227_229delTCT, and results in p.F76del. This variant is entered on CIViC with p.F76del. As a note the latter c. nomenclature is preferred due to the 3' rule.

ClinVarID: N/A

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

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_deletion

CivicName: F76del (c.224_226delTCT)

MultipleGeneVariants: N/A

PatientID: 192

KindredID: 73

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 191, has a mother who was also found to have the same germline mutation. The proband's mother (patient 192) had a retinal angioma at 25, a CNS hemangioblastoma at 38, and multiple pancreatic cysts/tumors at 52.

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

CaseHPOFreeText: The patient presented with a CNS hemangioblastoma at 38, retinal angioma at 25, and multiple pancreatic cysts/tumors at 52.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: This patient was also published in an earlier paper by Wang et al., 2014 (PMID 24581539) as well as a later paper by Wang et al., 2018 (PMID: 29330336).

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 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

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This missense mutation was confirmed in 2 families (#18 and #19). Family #18: Male proband was diagnosed with CNS hemangioblastoma at 31Y, renal cell carcinoma at 32Y, and pancreatic cysts or pancreatic tumours at 32Y (mutation confirmed); daughter diagnosed with retinal angioma at 11Y (mutation confirmed); father diagnosed with renal cell carcinoma at 52Y (passed away before diagnosis/ genetic confirmation). Family #19: female proband diagosed with retinal angioma at 12Y, renal cell carcinoma at 33Y (mutation confirmed), and multiple pancreatic cysts or pancreatic tumours at 33Y; her daughter has no clinical manifestations and her age is unknown (mutation confirmed). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. This nonsense mutation was found in two families (#30 and #31). Family #30: a male proband (patient 93) was diagnosed with CNS hemangioblastoma at 31Y (mutation confirmed). No other family information was provided. Family #31: a male proband (patient 94) was diagnosed with CNS hemangioblastoma at 56Y, renal cell carcinoma at 53Y, multiple pancreatic cysts or tumours at 53Y (mutation confirmed); his son (patient 95) was diagnosed with retinal angioma at 29Y, renal cell carcinoma at 29Y, multiple pancreatic cysts or tumours at 29Y, and pheochromocytoma at 29Y. This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

A previous study of 26 Japanese, VHL families was extended to 41 additional families. Germline mutations were detected in 55 of 77 Japanese families using SSCP, direct sequencing, and Southern Blot analysis of peripheral blood samples. The L198Gfs*57 (c.592_593del) germline mutation was found in a VHL type 1 patient presenting with CNS hemangioblastoma, retinal angioma, pancreatic cyst or tumor (unspecified) and renal cell carcinoma (family ID 67).

PatientID: None

KindredID: 58

Case: Sex Unknown, Age Unknown, Japanese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Renal cell carcinoma.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N90I (c.269A>T)

LegacyVariant: c.482A>T

CaseProblemVariantFreeText: N/A

ClinVarID: 223172, https://www.ncbi.nlm.nih.gov/clinvar/variation/223172/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: N90I (c.269A>T)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: A-704 (cell line)

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Renal cell carcinoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: Described as sporadic RCC from cell line A-704

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.I180N (c.539T>A)

LegacyVariant: p.I251N (c.752T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756277 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.539T%3EA

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant; transversion

CivicName: I180N (c.539T>A)

MultipleGeneVariants: N/A

KindredID: 21

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This is a family belonging to prefigure No. 21. They are described as ‘VHL-affected’.

GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)

GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D121G (c.362A>G)

LegacyVariant: p.D192G (c.575A>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223200 https://www.ncbi.nlm.nih.gov/clinvar/variation/223200/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: D121G (c.362A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 2

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

FamilyInfo: 3 affected members belong to this VHL type 2A family. One representative affected member was analyzed with this mutation, and VHL was diagnosed clinically in this index person. It is unclear as to whether the additional patients had this precise mutation, although assumed.

GroupPresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)

GroupHPOFreeText: all 3 individuals had Pheos, whereas only 1 person had a retinal capillary hemangioma.

GroupNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)

GroupNotHPOFreeText: No patients had the above tumors

GroupPreviousTesting: N/A

PreviouslyPublished: 11134110, 9681856, 11850829

SupplementalData: N/A

Variant: p.Y98H (c.292T>C)

LegacyVariant: p.Y98H (c.505T>C)

CaseProblemVariantFreeText: N/A

ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/

CAID: N/A

gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y98H (c.292T>C)

MultipleGeneVariants: N/A

PatientID: V-10

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: III-10

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PatientID: IV-15

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family’s roots were traced to the German town of Leipzig in Saxony, from whence the original 11 siblings had immigrated to America around 1670. The following report is a 2011 updated pedigree on the previously reported Tisherman kindred. At the time of this study, 43/49 patients have undergone mutational analysis revealing the VHL familial mutation (Y112H) and 35/49 patients have clinical VHL manifestations. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. 6 members of the family (all deceased; 4 males, 2 females) had suspected VHL and 2 (males) of these were suspected to have had Pheo/PGL.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma, Paraganglioma)

CaseHPOFreeText: Phenotype noted as: Pheo/PGL (unclear which of the two or if both apply to this patient).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 9201016; 8239848 (no genetic information; only phenotypes)

SupplementalData: N/A

Variant: p.Y112H (c.334T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112H (c.334T>C)

MultipleGeneVariants: N/A

PMID: 34109129

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. A mutation, F76del(c.227_229del) (noted as g.941_943delTCT in the paper originally) was found in a patient with cerebellar hemangioblastomas, renal cyst, and pancreatic cyst, the pateints age on onset was 31 years old. No family history was mentioned, other than a note of no familial antecedents with the disease.

PatientID: 1

KindredID: 95

Case: Sex, Age, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: one pheochromocytoma was detected in this patient

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: 0.000007954 https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: LOH detected

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5

KindredID: 5

Case: 28Y0M, Sex unknown, Chinese

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: CNS hemangioblastoma first presenting at age 28Y and RCC at age 28Y

CaseNotHPOs: HP:0009715; HP:0002666 (Papillary cystadenoma of the epididymis, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

The data of 18 patients with solid renal tumours associated with VHL disease were analyzed. Seventeen patients had a VHL family history, the only patient that had no family history of VHL was patient 12. The patients came from 12 Chinese families and 5 were from the same family. Extrarenal manifestations of VHL disease were detected in 17 patients. Of 18 patients, 15 (including 6 asymptomatic) volunteered for DNA testing as previously described. Patient 16 had genetic testing and was found to have a germline mutation c.286C>T (Gln96*). This missense mutation is noted as c.499C>T in the paper due to a difference in the VHL reference sequence notation used. Patient 16 was a 50-year-old female with a medical history of solid renal tumour and CNS hemangioblastoma.

PatientID: 4

KindredID: 4

Case: F, 52Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009726; HP:0005562; HP:0009711; HP:0001737; (Renal neoplasm, Multiple renal cysts, Retinal capillary hemangioma, Pancreatic cysts)

CaseHPOFreeText: Patient 4 was a 52-year-old female a medical history of synchronous bilateral solid renal tumors, multiple renal cysts, retinal angioma, pancreatic cyst.

CaseNotHPOs:None

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.446A>G

CaseProblemVariantFreeText: N/A

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

CAID: CA351749194

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_transition

CivicName: N78S (c.223A>G)

MultipleGeneVariants: N/A

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. Whole blood was isolated from patients and sequenced using sanger sequencing and whole-genome sequencing performed at the clinically accredited Molecular Diagnostics Laboratory at the John Radcliffe Hospital using the Hi-Sequation 4000 platform (Illumina Inc., San Diego, CA) in high-throughput mode. As well, paired-end sequencing was carried out in a single lane on the HiSeq 2500 system (Illumina).In this study, the authors show that the mutations in E1' induced dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. Three patients were found with both the c.598C>T germline VHL mutation and the c.340+770T>C mutation resulting in p.Ser179Pro mutation on potential X1 protein encoded by E1' exon. In family 2, II.1 was the only person who had both of these mutations. In family 3, brothers II.1 and II.2 had these two mutations. Biological material from the parents of these three children were not available but chuvash core haplotype analysis demonstrated that all patients were compound heterozygous with one mutation being inherited from each parent. All three cases described above had erythrocytosis.

PatientID: II.1

KindredID: 2

Case: M, 21Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Positive family history. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+770T>C

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 816685 https://www.ncbi.nlm.nih.gov/clinvar/variation/816685/

CAID: N/A

gnomAD: 0.00003186 https://gnomad.broadinstitute.org/variant/3-10184641-T-C

VariantEvidence: N/A

MutationType: intron_variant

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.598C>T (p.Arg200Trp)

PatientID: II.2

KindredID: 3

Case: M, 0Y6M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: The patient had an affected brother (II.1) with the same mutation and polycythemia. Biologic material from parents were unavailable but Chuvash core haplotype analysis demonstrated that all patients were compound heterozygous, with 1 mutation being inherited from each parent. See Figure 2B for family pedigree.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901 (Polycythemia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232 https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: N/A

gnomAD: 0.0002016 https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: c.340+770T>C and R200W (c.598C>T)

MultipleGeneVariants: Germline, VHL, c.340+770T>C

The authors identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. Mutations in E1' are identified in 7 families with erythrocytosis and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, the authors show that the mutations in E1' induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. Patient II.1 of family F4, was found to have two germline mutations in the VHL gene: R200W (c.598C>T) and c.340+694_340+711dup. This patient was diagnosed with erythrocytosis, deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990). This patient's asymptomatic mother was also genetically tested and found to have the germline c.340+694_340+711dup variant of the VHL gene. Her father was not tested but is assumed to carry the R200W (c.598C>T) germline variant in VHL.

PatientID: 11

KindredID: 4

Case: M, 27Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: 2 other family members (relation unclear) presented with the same variant. Patient 9 (Gen 2) of these presented with unilateral pheochromocytoma and PNET. Patient 10 (Gen 1) presented with bilateral pheochromocytoma and sympathetic paraganglioma and PNET.

CohortInfo: This retrospective study was conducted at Department of Endocrinology of a tertiary care health centre in Western India. Patients presented to our institute between 2008 and 2016 were included in the study. During the study period a total of 33 patients were suspected to have VHL syndrome based on clinical features among whom 31 patients were found to have mutation in VHL gene. All patients are of Asian Indian descent.

CasePresentingHPOs: HP:0002666; HP:0002668; HP:0030405; HP:0009711; HP:0010797 (Pheochromocytoma, Paraganglioma, Pancreatic endocrine tumor, Retinal capillary hemangioma, Hemangioblastoma)

CaseHPOFreeText: Bilateral pheochromocytoma and sympathetic paraganglioma. Metastasis found at age 27. Age of onset for pheochromocytoma and paragangliomas is stated as 12Y and 15Y but it is not clear which age pertains to which phenotype.

CaseNotHPOs: HP:0001737; HP:0005584 (Pancreatic cysts, Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y98S (c.293A>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 219160, https://www.ncbi.nlm.nih.gov/clinvar/variation/219160/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: Y98S (c.293A>C)

MultipleGeneVariants: N/A

PMID: 23298237

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 5

KindredID: 3 (C)

Case: F, 38Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: Family C consists of two parents and their two daughters. Patient's 14 year old daughter (see patient 4) shares the same mutation as him. She developed a retinal angioma at 12 years of age and a spinal cord hemangioma was detected at 14 years. The mother and the other daughter were free from any manifestations of the disease and showed no mutations in the VHL gene.

CasePresentingHPOs: HP:0009713; HP:0006880; HP:0009711; HP:0006770 (spinal hemangioblastoma, cerebellar hemangioblastoma, retinal capillary hemangioma, clear cell renal cell carcinoma)

CaseHPOFreeText: Radiological investigations detected bilateral kidney tumors, a cerebellar and a spinal cord hemangioma at 34 years of age. Histological analysis of the kidney verified RCC. Four years later (38 years of age), retinal angioma developed in both of his eyes.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 223190 https://www.ncbi.nlm.nih.gov/clinvar/variation/223190/

CAID: CA357042 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.340%2B1G%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

CivicName: c.340+1G>A

MultipleGeneVariants: N/A

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

PatientID: None

KindredID: 1

Case: M, 38Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient’s niece, age 27, presented with two right renal masses and several pancreatic cysts at 22Y. The patient’s brother, age 45, presented with right ccRCC and pancreatic cysts. Both the patient’s daughter and brother were found to carry the mutation the patient carried.

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

CaseHPOFreeText: The patient presented with unilateral ccRCC.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: SDHB, SDHC, SDHD

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: (c.-77_-32del)

LegacyVariant: N/A

CaseProblemVariantFreeText: The mutation was a deletion in the VHL 5’ UTR, including the promoter.

ClinVarID: 433541, http://www.ncbi.nlm.nih.gov/clinvar/variation/433541

gnomAD: N/A

VariantEvidence: N/A

MutationType: 5_prime_UTR_variant

CivicName: c.-77_-32del

MultipleGeneVariants: N/A

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 452delG) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.239del (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS hemangioblastoma (Hb) renal cell carcinoma (RCC), and pheochromocytoma was available. Case 22 had p.Ser80Ilelfs*79 (c.239del) mutation. One member was affected with retinal capillary hemangioma and hemangioblastoma. Other demographics of the members were not described.

Germline mutations in 45 unrelated Japanese VHL patients were determined from blood samples using PCR-SSCP or Southern blot analyses. The authors reported a nucleotide deletion (i.e. 445A>C) which coincides with legacy variant nomenclature (AF010238.1) and was mapped to c.232A>C (NM_000551.3). PCR-SSCP or Southern blot analyses of the DNA from family members showed that mutations were segregated with disease phenotype in VHL families, although this data was not shown. Data on the presence of retinal angioma, CNS Hb, RCC, and Pheo was available. Case 1 had p.Asn78His mutation and one affected member with retinal angioma and hemangioblastoma.

PatientID: 8

KindredID: 6

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0030405 (Retinal capillary hemangioma; pancreatic endocrine tumor)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: MEN1/ RET

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: G114R (c.340G>C)

MultipleGeneVariants: N/A

PatientID: 138 (Second cousin)

KindredID: 18

Case: M, 49Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 11 members of this family tested positive for the c.712C>T/c.499C>T germline variant of the VHL gene. 14 members of this family were assumed to carry this variant due to family history/personal medical history. Members of this family range from asymptomatic to multi-organ involvement (pheochromocytoma, pancreatic and renal cysts/tumors and hemangioblastomas). The family was previously reported in PMID 3942913.

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

CaseHPOFreeText: This patient presented with pheochromocytoma (11Y). Age of diagnosis of retinal angioma is unknown.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 3942913 (some members of this family are previously reported (phenotypes only) but unable to match patients across papers with confidence)

SupplementalData: Supplementary Table 1.

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

LegacyVariant: c.712C>T

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: A point mutation (c.712C>T) was found. Being that this variant is out of bound with respect to the NM_000551.3 reference sequence, it was concluded that this variant is noted in the Latif et al. (1993) reference and was translated to c.499C>T (NM_000551.3).

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (C162Y (c.485G>A)) was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 11YO. It was reported in the paper as c.698G>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (L89P (c.266T>C)) was taken from multiple databases including: the Cambridge, Department of Pathology database and the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family IDs 8CE, 59CA, 21CE. It was reported in the paper as c.479T>C due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.

GroupID/ KindredID: 22YO

DiseaseAssertion: VHL

GroupSize: N/A

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This germline familial VHL mutation was taken from the Department of Uroglogy, Yokohama database, with an unknown number of members belonging to Family ID 22YO. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S80Ifs*79 (c.239delG)

LegacyVariant: FS (c.452delG)

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA913189245 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.239delG

gnomAD: N/A

VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.

MutationType: minus_1_frameshift_variant

CivicName: S80fs (c.239delG)

MultipleGeneVariants: N/A

An Israeli specialized centre identified 32 VHL patients belonging to 16 different kindreds. This retrospective collection and analysis of clinical, laboratory and imaging data of VHL patients involved 3 individuals belonging to kindred V. Genetic analysis via direct VHL gene sequencing and quantitative Southern blot identified the L188del (c.562_564delCTG) mutation. This kindred includes 3 patients: a father and his two children. The father, 55Y, had bilateral adrenal pheochromocytoma, along with his two children (13Y, 17Y).

PatientID: 4

KindredID: 5

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Patient’s father is presented with renal cell carcinoma, renal cysts, adrenal pheochromocytoma, spinal hemangioblastoma, pancreatic cysts, endolymphatic sac tumor and salivary gland neoplasm at age 19Y0M. This patient is 1 of 3 carrier children of this mutation, without any further phenotypic information.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93R (c.277G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223174, https://www.ncbi.nlm.nih.gov/clinvar/variation/223174

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant, transversion

CivicName: G93R (c.277G>C)

MultipleGeneVariants: N/A

PatientID: 7

KindredID: 7

Case: F, 40Y0M, Korean

DiseaseAssertion: Assumed VHL

FamilyInfo: No information provided.

CasePresentingHPOs: HP:0006748; HP:0005584; HP:0030405; HP:0006880 (adrenal pheochromocytoma, renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma)

CaseHPOFreeText: The patient presented with adrenal pheochromocytoma. She also had other tumours, including renal cell carcinoma, pancreatic endocrine tumor, cerebellar hemangioblastoma (see table 3).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000007954, http://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: 5299

KindredID: 235

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:0009726 (Renal neoplasm)

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]). Individual RCC phenotype is noted as negative.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 1 and 1 individuals respectively with an equivalent mutation (i.e. 473insT) are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

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

Variant: p.K159Efs*15 (c.473dup)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA432423097, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.473dup

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication; plus_1_frameshift_variant

CivicName: K159Efs*15 (c.473dup)

MultipleGeneVariants: N/A

GroupID: 17

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 5 members of this family presented with the c.485G>A germline variant of the VHL gene. Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease. Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

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

Variant: p.C162Y (c.485G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223225, https://www.ncbi.nlm.nih.gov/clinvar/variation/223225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: C162Y (c.485G>A)

MultipleGeneVariants: N/A

GroupID: 77

DiseaseAssertion: VHL

GroupSize: 13

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 13 members of this family were found to harbor the c.286C>T germline variant of the VHL gene. Members 5314, 6288, 6290, 5228 and 2499 had unknown renal involvement. Patients 5226, 6293 and 5340 presented with severe renal disease (RCC). Member 666 and 5223 presented with moderate renal disease (RCC). Members 5808 and 6380 had no renal involvement. Member 6277 presented with mild renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

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

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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 3 individuals with this mutation are reported but relation between patients and to this patient is unknown.

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; stop_gained

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

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: F, 11Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Her cousin (case 2) underwent a bilateral adrenalectomy and had the same VHL mutation.

CasePresentingHPOs: HP:0006748, HP:0002865 (Adrenal pheochromocytoma, Medullary thyroid carcinoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584, HP:0010797 (renal cell carcinoma, hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128F (c.382C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496060 https://www.ncbi.nlm.nih.gov/clinvar/variation/496060/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L128F (c.382C>T)

MultipleGeneVariants: N/A

PatientID: V-9

KindredID: 1

Case: M, Age Unknown, Iranian

DiseaseAssertion: asymptomatic

FamilyInfo: Familial history was positive. See Fig 1. A total of 43 members of the kindred, 24 males and 19 females, aged 2-77 years were reached for evaluation. It is stated in the paper that all affected subjects (13) were positive for the same mutation (c.500G>A). Additionally, gene sequencing revealed that 4 asymptomatic members of the kindred also harbored the pathogenic mutation, one of which was this patient. Phenotypes include pheochromocytoma, hemangioblastoma, and retinal HB.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

CaseNotHPOFreeText: There was no case of kidney tumors among the kindred.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/3-10191507-G-A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 10

KindredID: 10

Case: F, 59Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None

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

CasePresentingHPOs: HP:0010797, HP:0030405, HP:0000107(hemangioblastoma, pancreatic endocrine tumour, renal cyst)