DiseaseAssertion: None

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

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

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

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

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

Supplementary Data: Table 2

Case I: proband, Male

DiseaseAssertion: Dilated Cardiomyopathy

CasePresentingHPOs: HP:0001644 (dilated cardiomyopathy)

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

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

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

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

gnomAD: n/a

Supplementary Data: Table S3

Case 90:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

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

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

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.745C>T (p.Arg249Ter)

ClinVar: 407183, https://www.ncbi.nlm.nih.gov/clinvar/variation/407183/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23900678-G-A

MultipleGeneVariants:

(1) TPM1 Variant:

Variant: NM_001018004.1(TPM1):c.775A>G (p.Lys259Glu)

ClinVar: 43687, https://www.ncbi.nlm.nih.gov/clinvar/variation/43687/

gnomAD: 0.0008382, https://gnomad.broadinstitute.org/variant/15-63363291-A-G

(2) PRKAG2 Variant:

Variant: p.Lys133Ile no ClinVar or CAID

Supplementary Data: Table S3

Case 12:

DiseaseAssertion: left ventricular noncompaction

CasePresentingHPOs: HP:0030682 (left ventricular noncompaction)

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

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

CaseGenotypingMethod: WES, variant enrichment analysis

Variant: NM_000257.3(MYH7):c.5786C>T (p.Thr1929Met)

ClinVar: 181397, https://www.ncbi.nlm.nih.gov/clinvar/variation/181397/

gnomAD: 0.00005308, https://gnomad.broadinstitute.org/variant/14-23882972-G-A

CaseHCM083: 53 yrs report, Vietnam, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0002875, HP:0001712, HP:0001667, HP:0001705 (Exertional dyspnea, Left ventricular hypertrophy, Right ventricular hypertrophy, Right ventricular outlet obstruction)

HPOsFreeText: Maximal LV thickness 18 mm

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

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

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

Variant: NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: 0.00003266, http://gnomad.broadinstitute.org/variant/14-23887429-C-T

Supplementary Data: Online Table 3

Case:

CasePreviousTesting: Full sarcomere testing (MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1), Additional testing (ABCC9, ACTN2, ANKRD1, BAG3, CALR3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, GLA, JPH2, JUP, LAMA4, LAMP2, LMNA, MYH6, MYPN, MYOZ1, MYOZ2, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TTN, VCL and LDB3)

CaseGenotypingMethod: DNA isolated from peripheral blood, targeted enrichment, next-gen sequencing with panel of 46 genes

Variant: NM_000257.3(MYH7):c.5534G>A (p.Arg1845Gln)

ClinVar: 181286, https://www.ncbi.nlm.nih.gov/clinvar/variation/181286/

gnomAD: 0.000004023, https://gnomad.broadinstitute.org/variant/14-23884229-C-T

Case: Case 9, male, 69yo

CasePresentingHPOs: HP:0031318 (myocardial fiber disarray)

HPOsFreeText: BMI = 25.2kg/m^2, cause of death: accidental head injury, heart weight = 624g, left ventricular thickness = 1.8cm, distribution of myocyte disarray in ventricular septum, area of disarray = 7.8%, grade of fibrosis = 3

CaseNotHPOs: HP:0031296 (atrial septal hypertrophy)

CasePreviousTesting: NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

CaseGenotypingMethod: genomic DNA extracted from whole blood, PCR, NGS of 81 cardiovascular disorder-related genes (Supplemental Table S1)

Variant: NM_000257.4(MYH7):c.2822G>A (p.Arg941His)

ClinVar: 636633, https://www.ncbi.nlm.nih.gov/clinvar/variation/636633/

gnomAD: 0.00001590, https://gnomad.broadinstitute.org/variant/14-23893216-C-T?dataset=gnomad_r2_1

CaseMYH7-31: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 1 other proband shares this genotype

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.1954A>G (p.Arg652Gly)

ClinVar: 177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: Not in gnomAD

CaseMYH7-18: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.2578A>G (p.Lys860Glu)

ClinVar: 192312 https://www.ncbi.nlm.nih.gov/clinvar/variation/192312/

gnomAD: Not in gnomAD

CaseMYH7-2: Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant: NM_000257.3:c.5287G>A (p.Ala1763Thr)

ClinVar: 177846 https://www.ncbi.nlm.nih.gov/clinvar/variation/177846/

gnomAD: European (Non-Finnish) 1.238e-4, Overall 7.423e-5 https://gnomad.broadinstitute.org/variant/14-23884476-C-T

Supplementary Data Table S3

Case: 52

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2451C>A (p.Asn817Lys)

ClinVar: 235029, https://www.ncbi.nlm.nih.gov/clinvar/variation/235029/

gnomAD: absent

MultipleGeneVariants:

(1) TTN Variant

Variant: NM_001267550.2(TTN):c.74597_74599CAA[1] (p.Thr24867del)

ClinVar: 165840, https://www.ncbi.nlm.nih.gov/clinvar/variation/165840/

gnomAD: absent

Case IV-6: Female, Iranian, 34yo at diagnosis, 37yo at study

DiseaseAssertion: DCM (initially); paper notes that phenotype is more consisted with hypokinetic non-dilated cardiomyopathy based on guideline from ESC working group on myocardial and pericardial diseases (PMID: 26792875)

FamilyInfo: consanguineous family, pedigree in fig. 1

CasePresentingHPOs: HP:0001653, HP:0002375 (mitral regurgitation, hypokinesia)

CaseHPOFreeText: New York Heart Association Class = II, left ventricular ejection fraction = 35%, left ventricular internal end-diastolic diameter = 5.2cm, left ventricular internal end-systolic diameter = 4.2cm, interventricular septum = 0.9cm, posterior wall = 1.0cm, normal sinus rhythm, grade I diastolic function

CaseNotHPOFreeText:

CasePreviousTesting: ECG, Full testing (https://hyp.is/2c24ajtuEemXQ-fRmGkjTA/www.sciencedirect.com/science/article/pii/S1769721217300484)

CaseGenotypingMethod: https://hyp.is/IKjfsDtxEem3Sh8RHHdYSg/www.sciencedirect.com/science/article/pii/S1769721217300484) WES, targeted exome sequence capture using SureSelectXT Human All Excon v5 kig (Agilent), co-segregation analysis via Sanger sequencing

Variant: NM_000257.3(MYH7):c.2863G>A (p.Asp955Asn)

ClinVar: 264608, https://www.ncbi.nlm.nih.gov/clinvar/variation/264608/

gnomAD: 0.000003976, https://gnomad.broadinstitute.org/variant/14-23893175-C-T

MultipleGeneVariants:

(1) TNNT2 Variant:

Variant: NM_000364.3(TNNT2):c.247A>C (p.Asn83His)

ClinVar: 427814, https://www.ncbi.nlm.nih.gov/clinvar/variation/427814/

gnomAD: n/a

Supplementary Data table 1

Variant noted to be present in 3 individuals

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

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

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

CasePT-30: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.2606G>A (p.Arg869His)

ClinVar: 177667 https://www.ncbi.nlm.nih.gov/clinvar/variation/177667/

gnomAD: African 1.230e-4, Overall 2.386e-5 https://gnomad.broadinstitute.org/variant/14-23894051-C-T

CasePT-76: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.2334C>G (p.Asp778Glu)

ClinVar: 265252 https://www.ncbi.nlm.nih.gov/clinvar/variation/265252/

gnomAD: Not in gnomAD

CasePT-97: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.4159G>A (p.Glu1387Lys)

ClinVar: 181244 https://www.ncbi.nlm.nih.gov/clinvar/variation/181244/

gnomAD: South Asian 3.266e-5, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23887429-C-T

CaseMYH7-5: N/A

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: N/A

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Testing for all 8 sarcomeric genes, plus GLA, LAMP2, and PRKAG2 was initiated in all probands. After the direct sequencing, the variants were filtered for pathogenicity and classified.

Variant: NM_000257.3:c.2198G>T (p.Gly733Val)

ClinVar: 181177 https://www.ncbi.nlm.nih.gov/clinvar/variation/181177/

gnomAD: Not in gnomAD

Case6: 48 year old male

DiseaseAssertion: Carried the MYBPC3 E619K mutation

FamilyInfo:Three unaffected children were examined (IV:1, IV:2 and IV:3), all with normal echocardiography without signs of hypertrophy or dilatation. Both affected individuals as well as a 26-year-old unaffected daughter (M29, IV:3) carried the MYBPC3 E619K mutation

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:0011713, HP:0001635

CaseHPOFreeText: Onset of symptoms in their third decade; the index case required heart transplantation 3 years after the onset of symptoms. Has onset at the age of 37. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)) with the value of 79 mm and 3.2 cm/m2. They have a 20% of left ventricular ejection fraction. ECG as left bundle branch block. Clinical status as DCM/ congestive heart failure. CAG as normal.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

Genotyping Method:Genetically screened, also using GenBank with PCR by amplifying the coding region

FunctionalAnalysis:NR

Variant: NM_000256.3:c.1855G>A

ClinVar:161303

CAID:CA011336

gnomAD: gnomAD v2: 11:47362731 C / T gnomAD v3: 11:47341180 C / T gnomAD v4: chr11-47341180-C-T

AdditionalInfo:NR

Supplementary Data: S2 Table

Case 49: Spanish, 18yo, Male

DiseaseAssertion: Hypertrophic Cardiomyopathy

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

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

Variant1: NM_000257.3(MYH7):c.2890G>C (p.Val964Leu)

ClinVar: 42938, https://www.ncbi.nlm.nih.gov/clinvar/variation/42938/

gnomAD: 0.0004383, https://gnomad.broadinstitute.org/variant/14-23893148-C-G

Variant2: NM_000257.3(MYH7):c.3613G>A (p.Glu1205Lys)

ClinVar: 179656, https://www.ncbi.nlm.nih.gov/clinvar/variation/179656/

gnomAD: 0.000004004, https://gnomad.broadinstitute.org/variant/14-23889167-C-T

Supplemental data table e-1

Case: MYH7 Case 2

InheritancePattern: autosomal recessive

DiseaseEntity: n/a

PreviouslyPublished: PMID: 16858239, PMID: 27247418

PreviousTesting: Not specified

CaseGenotypingMethod: paper notes single gene, NGS, and WES were used, but does not specify which method was used for each individual family

Variant: NM_000257.4(MYH7):c.2594A>G (p.Lys865Arg)

ClinVar: 524996, https://www.ncbi.nlm.nih.gov/clinvar/variation/524996/

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/14-23894063-T-C

CaseCM0969: Male, 6 years diagnosis, Japan, Asian

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001939 (Abnormality of metabolism/homeostasis)

NotHPOsFreeText: Neuromuscular disease, Malformation syndromes

CaseAddInfo: Positive family history of cardiomyopathy or sudden death, Proband found in Supplementary Table 2, Variant is asserted as novel, Both father and sister with HCM tested positive for this variant

CasePreviousTesting: 8 patients with HCM and one with RCM were analyzed by NGS for the eight sarcomere-encoding genes and MYP.

CaseGenotypingMethod: Probands were subject to PCR amplification and direct sequencing of 64 cardiomyopathy-associated genes, including the eight sarcomere-encoding genes. The variants were then filtered for rarity and tested for pathogenicity.

Variant: NM_000257.3:c.2777T>C (p.Leu926Pro)

ClinVar: 525005 https://www.ncbi.nlm.nih.gov/clinvar/variation/525005/

gnomAD: Not in gnomAD

Case#: female

DiseaseAssertion: FDCM

FamilyInfo: Family B; brother also proband; brother died of SCD, niece and father asymptomatic

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Sanger sequencing, Genome Analyzer IIx, ECG,

Variant: NM_000257.4(MYH7):c.3134G>A (p.Arg1045His)

ClinVar: 651054 https://www.ncbi.nlm.nih.gov/clinvar/variation/651054/

CAID: N/A

gnomAD: absent

Medical records of 26 patients with germline mutations of the VHL gene who had been diagnosed with VHL disease in Severance Hospital (Seoul, Republic of Korea) and Samsung Medical Center (Seoul, Republic of Korea) between 2003 and 2012 were respectively reviewed. Peripheral blood leukocytes were isolated and directly sequenced. One 17Y female patient (Patient 49) presented with multiple and/or bilateral renal cell carcinoma and central nervous system hemangioblastoma. She had a germline missense mutation in the VHL gene (c.586A>T; Lys196Stop). The patient had a positive family history of VHL disease and was diagnosed with VHL Type 1. Phenotypes revised from previous report (PMID 19270817).

PatientID: 30

KindredID: 30

Case: F, 27Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0010797; HP:0005584 (Hemangioblastoma, Renal cell carcinoma)

CaseHPOFreeText: CNS hemangioblastoma. Other phenotypes presented but not specified (one or more of: pancreatic cyst or tumor, renal or hepatic cyst). Diagnosed with VHL Type 1. Phenotypes revised from previous reports (see “PreviouslyPublished” section below for PMID).

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 19270817

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1208816, https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 19

Case: Sex and Ethnicity unknown; Age >18Y0M (deceased)

DiseaseAssertion: assumed VHL

FamilyInfo: None

CasePresentingHPOs: HP:0010797;HP:0000107; HP:0001737; HP:0005584; HP:0030393 (hemangioblastoma, renal cyst, pancreatic cysts, renal cell carcinoma, endolymphatic sac tumor)

CaseHPOFreeText: At initial screening, patient was found with 1 HB, 1 renal cyst, 1 pancreatic cyst, and 1 RCC. By final screening, the 5 year follow up, there was an additional RCC, HB, and endolymphatic sac tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86S(c.256C>T)

MultipleGeneVariants: N/A

The genetic testing program for VHL disease included 17 families, ten of which had definite VHL disease and seven had possible VHL disease. 17 families (n=109 individuals) were tested for VHL mutations. Mutation analysis was performed by direct sequencing of the VHL gene. Mutations were identified in 36 patients. Mutations-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Tumor status and phenotypes were documented at initial screening and at follow ups. 1 individual from family 21 was tested positive for p.R82P mutation. 1 hemangioblastoma was diagnosed at initial screening, 2 additional hemangioblastoma, bilateral retinal capillary hemangioma, kidney cysts, pancreatic cysts, 1 renal cell carcinoma were diagnosed at follow-ups. The patient deceased at last follow-up. ACMG evidence codes: 'PP4' because the patient's phenotypes are highly specific for a disease with single genetic etiology.

A cohort of VHL patients from the Greater Toronto Area in Canada were retrospectively reviewed. 3 patients were found with this germline mutation (c.263G>A). Whether patients were related, age, and sex data was not reported in this paper, although they were previously reported under PMID: 29437867. Both patients (patient 58 and 59) were asymptomatic, and Patient ID 43 was with hemangioblastoma and clear cell renal cell carcinoma.

PatientID: 7

KindredID: 7

Case: Age, Sex, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: patient was recorded with a CNS hemangioblastoma

CaseNotHPOs: HP:0030421; HP:0006770; HP:0100634; HP:0030405; HP:0009711 (epididymal tumour, clear cell renal cell carcinoma, neuroendocrine neoplasm, pancreatic endocrine tumour, retinal capillary hemangioma)

CaseNotHPOFreeText: patient was recorded without CCRCC, and a pheochromocytoma and/or paraganglioma (neuroendocrine neoplasm), pancreatic endocrine tumour (or pancreatic neuroendocrine neoplasm), and a retinal hemangioblastoma, or a epididymal tumor

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

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

PatientID: 49

KindredID: 49

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0100634 (Neuroendocrine neoplasm)

CaseHPOFreeText: Recorded as a pheochromocytoma/paraganglioma

CaseNotHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711; HP:0030421 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.P154L (c.461C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 649525 https://www.ncbi.nlm.nih.gov/clinvar/variation/649525/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P154L (c.461C>T)

MultipleGeneVariants: N/A

PatientID: 59

KindredID: 59

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0009711; HP:0100634; HP:0030405; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma, Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.W88* (c.263G>A)

LegacyVariant: p.W88* (c.476G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: 3

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0030405; HP:0009711; HP:0100634; HP:0030421 (clear cell renal cell carcinoma, pancreatic neuroendocrine neoplasm, retinal capillary hemangioma, Neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.D92V (c.275A>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 184664 https://www.ncbi.nlm.nih.gov/clinvar/variation/184664/

CAID: N/A

gnomAD: 0.000004482 https://gnomad.broadinstitute.org/variant/3-10183806-A-T

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: D92V (c.275A>T)

MultipleGeneVariants: N/A

PatientID: 16

KindredID: 16

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0030405; HP:0009711 (hemangioblastoma; clear cell renal cell carcinoma; pancreatic neuroendocrine neoplasm, retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0100634; HP:0030421 (Neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.P86L (c.257C>T)

LegacyVariant: p.P157L (c.470C>T)

CaseProblemVariantFreeText: converted from legacy notation c.470C>T; Pro157Leu; authors contacted and confirmed this error. [from reported previously Aronoff et al, 2018].

ClinVarID: 182977 https://www.ncbi.nlm.nih.gov/clinvar/variation/182977/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: P86L (c.257C>T)

MultipleGeneVariants: N/A

PatientID: 58

KindredID: 58

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL (asymptomatic)

FamilyInfo: N/A

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797; HP:0009711; HP:0100634; HP:0030405; HP:0030421; HP:0006770 (hemangioblastoma; retinal capillary hemangioma, Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm; clear cell renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.W88* (c.263G>A)

LegacyVariant: p.W88* (c.476G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 182978 https://www.ncbi.nlm.nih.gov/clinvar/variation/182978/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: W88* (c.263G>A)

MultipleGeneVariants: N/A

This study examined the expression of hypoxia related genes in renal cell carcinoma. The authors analyzed the tumor and surrounding healthy tissue in 10 patients who had radical nephrectomy due to RCC. DNA was isolated from blood, tumor and surrounding healthy tissue for sequencing VHL gene. Only 1 patient had a hereditary form of RCC with a substitution of leucine to proline at position 25 (P25L) as a polymorphism of the VHL gene. ACMG: 'PP4' because the patient' phenotype is highly specific for a disease with single genetic etiology.

Medical records of 31 Asian Indian genetically proven VHL patients with pheochromocytoma/paraganglioma were studied. A 42 year old male (Patient 20) presented with unilateral pheochromocytoma (42Y) and central nervous system hemangioblastoma (42Y). Genetic testing (PCR and Sanger sequencing) confirmed a non-familial missense mutation at c.487C>T of the VHL gene. He has a negative family history.

PatientID: 5

KindredID: 2

Case: F, 20Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: Another member of this family (Gen 1) presented with the same mutation, bilateral pheochromocytoma, RCC as well as neural hemangioblastoma that ultimately caused his death.

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 (Pheochromocytoma)

CaseHPOFreeText: Bilateral pheochromocytoma.

CaseNotHPOs: HP:0005584; HP:0001737; HP:0009711; HP:0010797; HP:0002668; HP:0030405 (Renal cell carcinoma, Pancreatic cysts, Retinal capillary hemangioma, Hemangioblastoma, Paraganglioma, Pancreatic endocrine tumor)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: 3

KindredID: A (III-11)

Case: M, 35Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient's mother (II:7) carried the VHL mutation and presented with hemangioblastoma, renal cell carcinoma, pheochromocytoma, and renal cysts. The patient had one brother (III:12) who had the mutation and presented with renal cell carcinoma, one asymptomatic sister (III:10) who did not undergo genetic testing and a sister (III:13) who had the mutation and renal cell carcinoma, retinal angioma, and hemangioblastoma. On the mother's side of the family there was extensive history of VHL disease. Refer to Figure 1 for family pedigree and information regarding extended family members.

CohortInfo: 10 VHL patients with renal cell carcinoma and a definite VHL family history.

CasePresentingHPOs: HP:0010797, HP:0005584, HP:0000107, HP:0009711 (hemangioblastoma, renal cell carcinoma, renal cyst, retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with renal cell carcinoma and retinal angioma at age 26. Underwent radical nephrectomy of both the right and left side. There was a complication, interstitial cellular rejection and retroperitoneal abscess. The patient had five renal cell carcinomas and five renal cysts. The patient had a satellite lesion.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: F, 13Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Family history was not significant for tumor occurrence.

CohortInfo: Two cases of VHL disease in children, who presented with PCC as the first manifestation.

CasePresentingHPOs: HP:0006748, HP:0030405 (Adrenal pheochromocytoma, pancreatic endocrine tumour)

CaseHPOFreeText: At age 10, abdominal MRI revealed a 44x33 mm mass with a necrotic core in the left adrenal gland. Subtotal adrenalectomy was performed and histologic examination showed that the tumor was PCC. During two years of follow-up, a 20x19x12 mm mass was detected in the right adrenal gland and a 11x10 mm nodular lesion in the corpus of the pancreas which was found to be a pancreatic endocrine tumour. One year later, the pancreatic endocrine tumour reoccured.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L129P (c.386T>C) *the cDNA change is misrecorded in the paper as 386T>G

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625242 https://www.ncbi.nlm.nih.gov/clinvar/variation/625242/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L129P (c.386T>C)

MultipleGeneVariants: N/A

Of 31 Brazilian patients, four presented with the c.340G>A (p.Gly114Ser) mutation of the VHL gene. Genomic DNA was extracted and all VHL coding regions were analyzed by Sanger sequencing. MLPA was performed to investigate large deletions using SALSA® MLPA® P016 VHL probe mix. Data analysis was performed with Genescan 3.7. Of these four patients, three were of the same family. Individual 1 of family 1, 38 years old, presented with paraganglioma, pheochromocytoma, and pancreatic endocrine tumor. Individual 2 of family 1, age 20, had a history of sudoresis, headaches, and abdominal pain. He was diagnosed with hypertension. At 4 years old, a CT scan revealed a 5cm heterogenous mass in the right adrenal gland and he underwent a right nodulectomy. 3 years later, a bilateral recurrence was found (4cm right and 1.5cm left nodules) and he underwent a right-side adrenalectomy and a left-side nodulectomy. 13 years later he presented with a left-side reoccurance (1.3cm nodule) and elevated plasmatic normetanephrine levels. He underwent left-side adrenalectomy. He also presented with paraganglioma, pancreatic endocrine tumor (at 20Y) and CNS hemangioblastoma. Individual 3 of family 1, 26 years old, presented with paraganglioma, pheochromocytoma, pancreatic endocrine tumor, renal cyst, CNS hemangioblastoma and retinal hemangioblastoma. The relation between these familials was not specified. Individual 4 of family 2 presented with left-side pheochromocytoma (6cm) and a right-side pheochromocytoma, (5.5cm) at 8 years. She also presented with pancreatic endocrine tumor (1.5cm) at 14Y.

PatientID: 2

KindredID: 1

Case: M, 20Y0M, Brazilian (Latino/Admixed American)

DiseaseAssertion: VHL

FamilyInfo: Also belonging to family 1, patients 1 and 3 had VHL diagnoses and phenotypes. Their relation is not clear.

CasePresentingHPOs: HP:0006748, HP:0002666; HP:0030405; HP:0010797 (adrenal pheochromocytoma, pheochromocytoma, pancreatic endocrine tumor, hemangioblastoma)

CaseHPOFreeText: The patient developed PPGL at 4Y of age, and a PNET at 20Y: the 4-year-old boy with VHL disease with a history of sudoresis, headache, and abdominal pain. During evaluation, he was diagnosed with hypertension. An abdominal CT scan revealed a 5-cm heterogenous mass in the right adrenal and normal left adrenal glands. This patient underwent a right nodulectomy to preserve normal adrenal tissue. Anatomopathological diagnosis confirmed PHEO. 3 years later was a bilateral recurrence (4-cm right and 1.5-cm left nodules). The patient underwent a right-side adrenalectomy and a left-side nodulectomy. He remained without hormone replacement. After 13 years from the second surgery, the boy presented with a left-side recurrence (1.3-cm nodule) and elevated plasmatic normetanephrine levels; he underwent left-side adrenalectomy.

CaseNotHPOs: HP:0005584; HP:0009711; HP:0001737; HP:0000107 (renal cell carcinoma, retinal capillary hemangioma, pancreatic cyst, renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114S (c.340G>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 583094 https://www.ncbi.nlm.nih.gov/clinvar/variation/583094/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G114S (c.340G>A)

MultipleGeneVariants: N/A

41 non-related patients with retinal angiomatosis presenting in the Benjamin Franklin University Eye Clinic between 1988 to 1999 Germany were evaluated for the presence of other VHL lesions. VHL disease was diagnosed clinically in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma 45% prevalence, cerebellar hemangioblastoma 42% prevalence, renal cysts 39% prevalence, pancreatic cyst 39% prevalence, renal carcinoma 18% prevalence, PCC 18% prevalence). VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. This patient with VHL-related retinal angiomatosis was found to have germline nonsense (c.208G>T) mutaion in the VHL gene. 1 other affected relative was also evaluated. ACMG evidence codes: 'PP4' because the patients' phenotypes and family history are highly specific for a disease with single genetic etiology.

GroupID: None (20)

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This family group of 2 individuals have clinically confirmed VHL disease. These individuals were found to harbor a c.463+3A>G splice variant (noted in the paper as c.676+3A>G due to Latif reference transcript being used).

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease. No VHL clinical phenotypes were explicitly stated other than retinal angiomatosis in at least one patient.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+3A>G

LegacyVariant: c.676+3A>G

CaseProblemVariantFreeText: N/A

ClinVarID: 428796, https://www.ncbi.nlm.nih.gov/clinvar/variation/428796/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition; splice_site_variant

CivicName: c.463+3A>G

MultipleGeneVariants: N/A

GroupID: 10

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 41 non-related patients with retinal angiomatosis between 1988 and 1999 were evaluated.

CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

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

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: N78S (c.233A>G)

MultipleGeneVariants: N/A

GroupID/ KindredID: R-D

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 Utrecht, The Netherlands database, with an unknown number of members belonging to Family ID R-D. Table 4 lists all ID and mutations associated with individuals with pheochromocytoma.

GroupPresentingHPOs: HP:0002666 (pheochromocytoma)

GroupHPOFreeText: Described as a VHL family with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

LegacyVariant: p.V170D (c.722T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V170D (c.509T>A)

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 (E94* (c.280G>T)) was taken fromthe Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 51CA. It was reported in the paper as c.493G>T 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 (N78H (c.232A>C)) was taken from multiple databases including: the National Cancer Institute database, the Department of Uroglogy, Yokohama database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 4389NCI, 1YO, 34CA. It was reported in the paper as c.445A>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: 3563NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 3563NCI. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

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

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 7728151; 9829911

SupplementalData: N/A

Variant: p.V62Cfs*5 (c.180delG)

LegacyVariant: (c.393delG)

CaseProblemVariantFreeText: N/A

ClinVarID: 182986 https://www.ncbi.nlm.nih.gov/clinvar/variation/182986/

CAID: N/A

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: V62fs (c.180delG)

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 (W88R (c.262T>A)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 1255NCI. It was reported in the paper as c.475T>A due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

GroupID/ KindredID: 13F, 564NCI, 1239NCI

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 Neuro Olcologie database in Paris and the National Cancer Institute database, with an unknown number of members belonging to Family IDs 13F, 564NCI, 1239NCI. 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: 7728151; 9829911

SupplementalData: N/A

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

LegacyVariant: p.W117C (c.564G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 1255NCI

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 National Cancer Institute database, with an unknown number of members belonging to Family ID 1255NCI. 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: 7728151; 9829911

SupplementalData: N/A

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

LegacyVariant: p.W88R (c.475T>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 456577 https://www.ncbi.nlm.nih.gov/clinvar/variation/456577/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: W88R (c.262T>A)

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 (V62fs (c.180delG)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 3563NCI. It was reported in the paper as c.393delG due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL family without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMIDs: 7728151 and 9829911.

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 (L178Q (c.533T>A)) was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 29CE. It was reported in the paper as c.746T>A due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.

GroupID/ KindredID: 51CA

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 Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 51CA. 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.E94* (c.280G>T)

LegacyVariant: E94* (c.493G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 584477 https://www.ncbi.nlm.nih.gov/clinvar/variation/584477/

CAID: N/A

gnomAD: N/A

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

MutationType: stop_gained

CivicName: E94* (c.280G>T)

MultipleGeneVariants: N/A

GroupID/ KindredID: 4389NCI, 1YO, 34CA

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 National Cancer Institute database, the Department of Uroglogy, Yokohama database, and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 4389NCI, 1YO, 34CA. 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.N78H (c.232A>C)

LegacyVariant: p.N78H (c.445A>C)

CaseProblemVariantFreeText: N/A

ClinVarID: 625225 https://www.ncbi.nlm.nih.gov/clinvar/variation/625225/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: N78H (c.232A>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 3315NCI, 127CA

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 National Cancer Institute database and the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family IDs 3315NCI and 127CA. 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: 7728151; 9829911

SupplementalData: N/A

Variant: p.S111N (c.332G>A)

LegacyVariant: p.S111N (c.545G>A)

CaseProblemVariantFreeText: N/A

ClinVarID: 223186 https://www.ncbi.nlm.nih.gov/clinvar/variation/223186/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: frameshift_variant; transition

CivicName: S111N (c.332G>A)

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 (P86S (c.256C>T)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to two family IDs: 25BMS and 24BMS. It was reported in the paper as c.469C>T due to a difference in transcript reference. Table 5 lists all ID and mutations associated with individuals without detailed clinical information. Other phenotypes are possible, however not detailed here.

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 (P86L (c.257C>T)) was taken from the Department of Uroglogy, Yokohama database and the National Cancer Institute database, with an unknown number of members belonging to Family IDs 39YO, 3568NCI, 2612NCI. It was reported in the paper as c.470C>T due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma. Later publications reference this cohort as being reported in PMID: 7728151.

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 (Q96P (c.287A>C)) was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 98CA. It was reported in the paper as c.500A>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.

This study retrospectively reviewed the nephrectomy specimens for 20 patients, for whom histologic slides were available, from the authors respective institutes’ VHL clinics over a 15-year period (1996 to 2011). One patient (case 3) was found to have a history of VHL disease with a confirmed germline missense mutation (p.L128P (c.383T>C)) of the VHL gene. The 38 year old female proband presented with multiple bilateral renal tumors, and underwent multiple partial nephrectomies with tumor enucleations. Six of such tumors were identified and they ranged in size from 0.4-6.5 cm. Of these, 4 tumors were CCRCCs and 2 tumors showed were diagnosed as CCPRCCs confined to the kidney. Further, the tumors were classified as hemangioblastomas. ACMG evidence codes: 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

GroupID/ KindredID: None

DiseaseAssertion: dilatation of the cerebral artery

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 8 patients are listed with this SNP mutation; any relation is unknown.

GroupPresentingHPOs: HP:0004944 (dilatation of the cerebral artery)

GroupHPOFreeText: All members are stated to have intracranial aneurysms. Other manifestations are possible but not clear.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.463+43A>G

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 1244574 https://www.ncbi.nlm.nih.gov/clinvar/variation/1244574/

CAID: N/A

gnomAD: 0.01186 https://gnomad.broadinstitute.org/variant/3-10188363-A-G

VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious; polymorphism).

MutationType: splice_site_variant; intron_variant

CivicName: Splice Region (463+43A>G)

MultipleGeneVariants: N/A

GroupID: 22B

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

GroupSize: 8

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 8 patients with the given mutation were grouped as group 22(B) in this study. These patients were asymptomatic or unclear of symptoms.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupNotHPOFreeText: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

GroupID: 10A

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 2 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: F119L (c.357C>G)

MultipleGeneVariants: N/A

GroupID: 5A

Case: Sex, Age, Ethnicity unknown

DiseaseAssertion: VHL

FamilyInfo: None. The patient with the given mutation in this study was a VHL patient with pancreatic ICTs.

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Patient has islet cell tumors (ICTs), or listed as pancreatic endocrine tumor.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L89P (c.266T>C)

MultipleGeneVariants: N/A

53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 5 patients were found to have the above mutation (c.461C>T). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry.The other 4 patients were stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.

GroupID: 22A

DiseaseAssertion: VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 VHL patients with the given VHL mutation and manifestation were grouped in this study.

GroupPresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

GroupHPOFreeText: Patients have islet cell tumors (ICTs), or listed as pancreatic endocrine tumor. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed.

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The R161Q (c.482G>A) germline missense mutation of the VHL gene was found in a 8 year old VHL patient with pheochromocytoma (index case 244).

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The R161G (c.481C>G) germline missense mutation of the VHL gene was found in a 27 year old VHL patient with no family history, hemangioblastomas of the central nervous system and retinal hemangioblastomas and pheochromocytoma, and renal cysts (index case 5).

PatientID: 4

KindredID: 4

Case: Sex Unknown, 26Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0000107; HP:0009711; HP:0002666; HP:0010797 (Renal cyst, Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma, pheochromocytoma, renal cystic lesion and retinal hemangioblastoma.

CaseNotHPOs: HP:0006770; HP:0001732 (Clear cell renal cell carcinoma, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Table S1, S2 and S3

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S80I (c.239G>T)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: This patient is the father of case 2 (patient 1; kindred 2). His son was found to have a right adrenal mass detected by MRI at 13Y0M. His son has the same VHL nonsense mutation.

CasePresentingHPOs: HP:0006748, HP:0005548 (adrenal pheochromocytoma, renal cell carcinoma )

CaseHPOFreeText: This patient was previously diagnosed with VHL disease and undergone bilateral adrenalectomy for pheochromocytoma and bilateral nephrectomy for renal cell carcinoma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q195* (c.583C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 428794, https://www.ncbi.nlm.nih.gov/clinvar/variation/428794/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q195* (c.583C>T)

MultipleGeneVariants: N/A

Eligible patients were all index cases with clinical diagnosis or clinical suspicion of type 1 VHL referred for genetic testing from 2003 to 2015. Universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis was completed using peripheral blood leukocytes. This patient (ID #22) was found with this VHL nonsense mutation (c.264G>A) when they were 13Y. They did not fulfil type 1 VHL clinical diagnosis. They presented with CNS hemangioblastoma at 13Y. Family history was unremarkable.

An Israeli specialized center identified 32 VHL patients belonging to 16 diferent kindreds. This retorspective collection and analysis of clinical, labratory and imaging data of VHL patients involved one individual belonging to kindred II. Genetic analysis via direct VHL gene sequencing and quantitiative Southern blot identified the W88* (c.263G>A) mutation. This individual (49Y, M) had cerebellar hemangioblatomas, bilateral RCC and nephrectomy, as well as pancreatic surgery for his PNENs. He passed away at 54Y, without any family history reported.

PatientID: 5

KindredID: 5

Case: F, 27Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None. Sporadic

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

CaseHPOFreeText: 'Other' phenotypes found in patient. These are noted in the paper to include: pancreatic neuroendocrine tumors (PNETs), renal and pancreatic cysts and central nervous system tumors, although it is not clearly stated that patient has all. (See Table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L128P (c.383T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 1208816 https://www.ncbi.nlm.nih.gov/clinvar/variation/1208816

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L128P (c.383T>C)

MultipleGeneVariants: N/A

PatientID: III-9

KindredID: 1

Case: F, Age Unknown, Middle Eastern

DiseaseAssertion: VHL

FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009713; HP:0009711; HP:0006880 (hemangioblastoma; clear cell renal cell carcinoma; spinal hemangioblastoma; retinal capillary hemangioma; cerebellar hemangioblastoma)

CaseHPOFreeText: Member had clear cell renal carcinomas in addition to hemangioblastomas. She had undergone multiple surgeries because of tumors involving the cerebellum, cervical spine, lumbar spine, multiple abdominal and pelvic organs and the retina. The tumor had been demonstrated on angiography as very extensive and vascular. The patient had had a partial nephrectomy, adrenalectomy, distal pancreatomy for involvement of the tail of the pancreas with a hemangioblastoma and a left salpingoophorectomy.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: Lacked evidence of any pheos.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Trp117Cys (c.564G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: III-8

KindredID: 1

Case: F, Age Unknown, Middle Eastern

DiseaseAssertion: VHL

FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

CasePresentingHPOs: HP:0010797; HP:0006770; HP:0009725; HP:0030692 (hemangioblastoma; clear cell renal cell carcinoma; bladder tumour; brain tumour)

CaseHPOFreeText: Member had clear cell renal carcinomas in addition to hemangioblastomas. She was also the only member of the family to be diagnosed as having a bladder tumor, considered rare in VHL cases, and a brain tumor.

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: Lacked evidence of any pheos.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Trp117Cys (c.564G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: III-7

KindredID: 1

Case: M, Age Unknown (deceased), Middle Eastern

DiseaseAssertion: VHL

FamilyInfo: Multigenerational Kuwaiti family with Arabian and Persian genetic admixture. Thirteen members of the family had been clinically diagnosed as having VHL. Patient 1-I had 6 children, 5 of which were found with VHL and the p.W117C mutation. 7/20 of her grandchildren also found to have VHL and the same mutation.

CasePresentingHPOs: HP:0010797; HP:0006770 (hemangioblastoma; clear cell renal cell carcinoma)

CaseHPOFreeText: Member had clear cell renal carcinomas that were the main cause of mortality, in addition to hemangioblastomas

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: Lacked evidence of any pheos.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: p.Trp117Cys (c.564G>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 167827 https://www.ncbi.nlm.nih.gov/clinvar/variation/167827/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117C (c.351G>T)

MultipleGeneVariants: N/A

PatientID: proband

KindredID: 1

Case: M, Age unknown, Chinese

DiseaseAssertion: pheochromocytoma

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

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: Only non-syndromic pheochromocytomas were discussed here. See PMID: 20120764 for detailed information

CaseNotHPOs: N/A

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

CasePreviousTesting: N/A

PreviouslyPublished: 20120764 - contains detailed family and patient information

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: (proband)

KindredID: 3

Case: M, Age unknown, Chinese

DiseaseAssertion: pheochromocytoma

FamilyInfo: There is a history of non-syndromic familial pheochromocytoma in this patient’s family history, however their relatives were not available for the study. It is not perfectly clear which pedigree belongs to this family.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: non-syndromic pheochromocytoma

CaseNotHPOs: N/A

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L163F (c.487C>T)

LegacyVariant: p.L163F (c.700C>T)

CaseProblemVariantFreeText: N/A

ClinVarID: 480772 https://www.ncbi.nlm.nih.gov/clinvar/variation/480772/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: L163F (c.487C>T)

MultipleGeneVariants: N/A

PatientID: (mother)

KindredID: 2

Case: F, Age unknown, Chinese

DiseaseAssertion: unknown

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

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

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

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This mutation also found in 3 family members with VHL type 1 phenotype (family ID 3624), using PCR and SSCP sequencing. The mutation of c.526delA was referred to in the paper by c.739delA due to a difference in transcript sequence. One of 3 individuals was identified with renal cell carcinoma, two with CNS hemangioblastomas and retinal hemngioblastomas. ACMG codes as follows: PVS1, frameshift variant occurs in a gene where loss of function is a known mechanism of disease.

GroupID: 3575

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

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

GroupHPOFreeText: 2/3 members had retinal angiomas (hemangiomas), 1 had CNS hemangioblastoma and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.N150Ifs*9 (c.448delA)

CaseProblemVariantFreeText: NM_000551.3:c.448delA adjusts to up to date to NM_000551.4:c.449delA

LegacyVariant: p.221fs (c.661delA)

ClinVarID: 195093 https://www.ncbi.nlm.nih.gov/clinvar/variation/195093/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: N150fs (c.448delA)

MultipleGeneVariants: N/A

GroupID: 3624

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

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

GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040 (type 1 3624NCI)

SupplementalData: N/A

Variant: p.R176Gfs*26 (c.526delA)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R247fs (c.739delA)

ClinVarID: 625257 https://www.ncbi.nlm.nih.gov/clinvar/variation/625257/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: R176fs (c.526del)

MultipleGeneVariants: N/A

GroupID: 3314

DiseaseAssertion: assumed VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 3 family members recorded with this mutation.

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

GroupHPOFreeText: 2/3 members had retinal angioma (hemangioma), 2/3 had CNS hemangioblastoma, and 1 had RCC

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L249P (c.746T>C)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

In a study of 114 unrelated VHL families, 85 germline mutations were found. VHL mutations were detected in affected family members, but not in unaffected family members or 96 normal individuals. This missense mutation was detected in 4 VHL families (Family ID 3786, 2214, 4419, 4403), using PCR and SSCP sequencing. The mutation of c.533T>C was referred to in the paper by c.746T>C due to a difference in transcript sequence. Family 3786, with VHL type 2, had 2 members with this mutation, both with hemangioblastomas of the retina and CNS, and one with pheochromocytoma. This mutation was also found in 8 individuals with VHL type 1 phenotype (family IDs 3314, 4419, 4403). In total, three of 8 individuals were identified with retinal hemangioblastomas, 5 with CNS hemangioblastomas, and 2 with renal cell carcinoma. Supporting evidence of pathogenicity because cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

GroupID: 3786

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: Familial VHL stated; 2 family members recorded with this mutation.

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: both (2/2) members had retinal angioma (hemangioma) and had CNS hemangioblastoma, and 1 had pheochromocytoma

GroupNotHPOs: HP:0005584 (renal cell carcinoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: 8956040

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L249P (c.746T>C)

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: L178P (c.533T>C)

MultipleGeneVariants: N/A

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. Northern blot, SSCP and RT-PCR analysis from normal tissue found a germline p.G93Afs* (c.278delG) mutation, stated in the paper as c.490delG due to an older transcript. It was seen in family [pedigree No] 16, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

Tissue analysis from 61 VHL patients, 30 sporadic renal cell carcinoma (RCC) tumor samples, and 6 sporadic RCC cell lines revealed 22 variants within VHL patients, 10 variants in tumor samples and variants in all cell lines. All mutations cluster to the 3’ end of the VHL gene open reading frame, implicating this region as important for the tumor-suppressor function of the VHL protein. RT-PCR analysis in RCC cell lines found a p.R82C (c.244C>T) mutation, stated in the paper as c.457C>T due to an older transcript. It was seen in cell line ACHN. Any family information or other manifestations apart from RCC were unclear.

PatientID: 28

KindredID: 288

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: One other member belonging to family 288 was mentioned (Patient: 5). This patient was found to have a pancreatic endocrine tumour and pheochromocytoma, without renal cell carcinoma.

CasePresentingHPOs: HP:0030405; HP:0002666 (pancreatic endocrine tumour, pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: missense_variant;transition

CivicName: R161Q (c.482G>A)

MultipleGeneVariants: N/A

PatientID: III-23

KindredID: 1

Case: M, Age unknown, Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. His mom and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: None

CaseHPOFreeText: VHL found by genetic testing not clinical findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

19 members of a large family were found to harbour the deletion of a single adenosine (A) at nucleotide 688 of VHL gene through genetic testing. Converted to NM_000551.3 standards this is a E160Sfs*10 (c.477delA) mutation. 9 members were genetically confirmed, alongside phenotypic presentations. Patient I.1 had 16 kids, 8 of which were known to have VHL. Southern blot analysis and PCR were performed on germline DNA samples. The proband (I.1), female of age 48, was found to have spinocerebellar ataxia type 2 and subsequently died at age 54 of pneumonia. Two of her children (II.1, II.28) and one grandchild (III.24) were noted as having CNS and renal involvement. Another child (II.5), was reported as having renal involvement. Another daughter (II.13) and a grand daughter (III.38) were noted as having CNS involvement. Her son (II.26), age 34, presented with a haemangioblastoma in the cerebellum. One year later an oesophageal abnormality was found. 10 years later, bilateral clear cell renal cancer and a syrinx associated with a spinal cord haemangioblastoma were found. He had baseline tachycardia and cystic lesions in the pancreas. A scrotal ultrasound examination showed he had a multicystic mass above his left testis consistent with epididymal cystadenoma. Haemangioblastomas posterior to the medulla with cysts splaying the medulla were also reported as well as cervical and thoracic spine hemangioblastomas. Finally, the probands grand-daughter (III.9), age 32, had a history of retinal angiomas since teen years and retinal detachment at the age of 23. She had olivopontocerebellar atrophy since her mid-late 20's due to new onset slurred speech and illegible handwriting and cysts of the pancreas and kidney detected at 22 years. She also presented multiple renal cysts without renal tumours, neuroendocrine/islet cell carcinoma (mass in the tail of the pancreas) and liver metastatic foci. Neuroimaging showed diffuse cerebellar and brain stem atrophy with slight atrophy of the cervical cord. A neurological exam revealed ataxia, dysarthria, dysmetria, and bulbar signs. She and various members of this family were also found to have abnormal increase in CAG repeats (41 instead of the normal 15-29) in one allele of her ataxin-2 gene (SCA2). ACMG evidence codes: 'PP1' since we have cosegregation with the disease in multiple affected family members, 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.

PatientID: III-40

KindredID: 1

Case: F, Age unknown (deceased), Ethnicity Unknown

DiseaseAssertion: asymptomatic

FamilyInfo: Large multigenerational family with a history of both VHL and spinocerebellar ataxia type 2 (SCA2). Screening for clinical and genetic diagnostics were gathered as well as thorough information on non-living members. Her dad and grandmother appeared to have the VHL mutation. See family pedigree (Fig. 1).

CasePresentingHPOs: None

CaseHPOFreeText: VHL found by genetic testing not clinical findings.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E160Sfs*10 (c.477delA)

LegacyVariant: c.688delA

CaseProblemVariantFreeText: c.477del, p.Glu160Serfs10 should be used. Details: 477del same as 475delA bc that codon is AAA so doesn't matter which A gets deleted: there is an A at 475 476 477 so for HGVS we say that 477 (the latter) is deleted since that follows HGVS nomenclature. Thus use c.477del: p.Glu160Serfs10

ClinVarID: 182959 https://www.ncbi.nlm.nih.gov/clinvar/variation/182959/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_1_frameshift_variant

CivicName: E160fs (c.477del)

MultipleGeneVariants: N/A

GroupID/ KindredID: VHL 29

DiseaseAssertion: assumed VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: German

GroupAgeRange: N/A

GroupInfo: 2 patients with the given mutation belonging to VHL family 29

GroupPresentingHPOs: HP:0009711; HP:0010797; HP:0002666 (retinal capillary hemangioma, hemangioblastoma, pheochromocytoma)

GroupHPOFreeText: both (2) patients have retinal capillary hemangiomas, hemangioblastoma, and pheochromocytoma

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.L178Q (c.533T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.L178Q (c.746T>A)

ClinVarID: 625260 https://www.ncbi.nlm.nih.gov/clinvar/variation/625260/

CAID: N/A

gnomAD: N/A

VariantEvidence: allele-specific oligonucleotide (ASO) probes and hybridization conditions confirmed

MutationType: missense_variant; transversion

CivicName: L178Q (c.533T>A)

MultipleGeneVariants: N/A

GroupID:N/A

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 301 were enrolled to evaluate the natural history of vHL-associated pancreatic lesions. Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study.

CasePresentingHPOs: HP:0001732 (abnormality of the pancreas)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93V (c.278G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 625232 https://www.ncbi.nlm.nih.gov/clinvar/variation/625232/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName:G93V(c.278G>T)

MultipleGeneVariants: N/A

301 were enrolled in a prospective clinical protocol to evaluate the natural history of vHL-associated pancreatic lesions (NCT00062166). Of these, 69 patients with pancreatic manifestations of vHL disease and missense VHL mutations were included in the current study. Individual patient phenotype was not described, but overall of the 60 patients, 57 had RCC, 41 had CNS hemangioblastomas, 28 had retinal hemangioblastoma, 23 had pheochromocytoma. 36/69 patients were female and the mean age was 50.5 years old. All patients underwent genetic testing using Sanger sequencing and Southern Blotting. One patient was listed with this missense mutation, c.262T>A.

KindredID:52

GroupID: 6

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.52 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: HP:0002666 (Pheochromocytoma)

GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.407C>T (p.S136L)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence:

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.L158V (c.472C>G) variant (noted as p.L229V (c.685C>G) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 91. Pheochromocytoma was not observed in any members of this kindred (implying the affected patient(s) had VHL disease type 1). No other familial phenotypic information could be inferred from the paper.