NonPatientCell Sarcoplasmic reticulum of cardiac muscle cell, FMA:62390

GeneAlteration The D307H mutant was generated using Quick Change (Life Sciences). Substitution of the CAC codon with GAC resulted in a BamH1 restriction site that was used along with complete sequencing of the DNA inserts to verify sequence.

FunctionalEvidence (fig. 3) Diminished sensitivity to Ca2+ leading to more intercellular Ca2+

FAVariant NM_001232.3(CASQ2):c.919G>C (p.Asp307His), 17610

CaseAddInfo Fig 4&5 show evidence for the conformation change responsible for the sensitivity difference.

gnomAD 0.00003249 link

Case# Monnier 2:3, male, French

CasePresentingHPOs HP:0002047

CasePreviousTesting N/A

CaseMethod1 sequenced all cDNA

CaseGenotypingMethod single strand conformation analysis and sequencing

Variant NM_000069.2(CACNA1S):c.3257G>A (p.Arg1086His)

ClinVar 17626

gnomAD 0.00002978 link<br /> gnomAD did not include the G>A mutation, only C>T but it was the same amino acid change

VariantEvidence N/A, all of these case studies claim ICVT verifies the phenotype but that doesn't seem like enough to pass for variant evidence since it is tested in patient muscle tissue.

CaseAddInfo Family not counted, too few segregations for the R1086H variant.

CaseFSIP2_2 male, 52yo report, Tunisian

CasePresentingHPOs HP:0003251, HP:0012207, HP:0012868

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 4.7mL, sperm concentration: 1.25 million/mL, total motility: 0h, vitality: 7%, normal spermatozoa: 0%, absent flagella: 16%, short flagella: 50%, coiled flagella: 18%, flagella of irregular caliber: 36%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.2282dup (p.Asn761Lysfs)

ClinVar 586973

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

CaseFSIP2_1 male, 44yo report, Tunisian

CasePresentingHPOs HP:0003251, HP:0012207, HP:0012868

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 2.5mL, sperm concentration: 6.7 million/mL, total motility: 1h, vitality: 47%, normal spermatozoa: 0%, absent flagella: 2%, short flagella: 32%, coiled flagella: 26%, flagella of irregular caliber: 57%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.910del (p.Gln304Lysfs)

ClinVar 586972

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

NonPatientCell Mouse cell line, EFO:0002887 "Myotubes of the homozygous CaVα1S-null (dysgenic) mouse cell line GLT were cultured on 35-mm culture dishes as described previously (32)."

GeneAlteration Mouse GLT line myotubes were transfected with GFP-tagged α1S cDNA constructs at the onset of myoblast fusion using FuGENE 6 transfection reagent according to the manufacturer's protocols (Roche Diagnostics).

FunctionalEvidence Fig 3: faster voltage-gated activation than WT. Fig 6: increased release of calcium ions in the presence of caffeine vs WT.

FAVariants NM_000069.2(CACNA1S):c.4060A>T (p.Thr1354Ser), ClinVar ID: 161208

Case# Chakarova P, European

CasePresentingHPOs HP:0007675, HP:0001133

CasePreviousTesting no

CaseMethod1 PCR

CaseMethod2 DHPLC and direct sequencing

Variant NM_004698.3(PRPF3):c.1477C>T (p.Pro493Ser)

ClinVar 3353

CasePMIDs 16799052

Case#: Family 1, Individual III-3, Male, 8yo, dx at 6mo

CasePresentingHPOs: HP:0000639, HP:0012389, HP:0001270, HP:0002078, HP:0002070, HP:0001260, HP:0007256

CaseNotHPOs:

CasePreviousTesting: MRI

CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

gnomAD: n/a

VariantEvidence:

CaseAddInfo: Wheelchair bound at 8 yo.

CasePMIDs:

FamilyName: Family 3 (individuals 6 and 7)

FamilyPresentingHPOS: HP:0000639, HP:0012736, HP:0001252, HP:0001257

FamilyNotHPOs:

CountryOrigin: Saudi Arabia

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: MRI showed brain hypomyelination

FamilyGenotypingMethod: combination of homozygosity mapping and WES, autozygosity mapping

Affected: 3

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo: consanguineous family

ProbandLabel: IV-6 (individual 6), Female, 6yo, dx at 1mo

Variant: NM_177400.2(NKX6-2):c.487C>G (p.Leu163Val)

ClinVar: 430623, https://www.ncbi.nlm.nih.gov/clinvar/variation/430623/

gnomAD: n/a

CasePresentingHPOs:

CasePresentingHPOTerm:

CaseNotHPOs:

AddCaseInfo:

VariantEvidence:

Case#: Consequence 14 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

Variant: NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln)

ClinVar: 14087 https://www.ncbi.nlm.nih.gov/clinvar/variation/14087/

CAID: n/a

gnomAD: absent

CaseMYH7-9: N/A

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

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.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

gnomAD: European (Non-Finnish) 1.548e-5, Overall 7.070e-6 https://gnomad.broadinstitute.org/variant/14-23896866-C-T

CaseMYH7-28: 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.2782G>A (p.Asp928Asn)

ClinVar: 164313 https://www.ncbi.nlm.nih.gov/clinvar/variation/164313/

gnomAD: Not in gnomAD

CaseMYH7-20: 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.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

gnomAD: European (Non-Finnish) 1.416e-3, Overall 8.484e-4 https://gnomad.broadinstitute.org/variant/14-23892910-A-G

CaseMYH7-31: 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.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

gnomAD: European (Non-Finnish) 8.792e-6, Overall 3.977e-6 https://gnomad.broadinstitute.org/variant/14-23900635-A-G

Case6: Male, 40 yrs report

CasePresentingHPOs: N/A

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Son of Case 4, Sibling of Case 5

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case3: Male, 41 yrs report

CasePresentingHPOs: HP:0012432, HP:0003738, HP:0003236, HP:0003273, HP:0003044, HP:0012785, HP:0006466, HP:0005997, HP:0003798, HP:0100295, HP:0031237, HP:0003201, HP:0012548 (Chronic fatigue, Exercise-induced myalgia, Elevated serum creatine phosphokinase, Hip contracture, Shoulder flexion contracture, Flexion contracture of finger, Ankle contracture, Neck flexion contracture, Nemaline bodies, Muscle fiber atrophy, Internally nucleated skeletal muscle fibers, Rhabdomyolysis, Skeletal muscle fatty infiltration)

HPOsFreeText: Jaw contractures, Core-like regions

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo via parental testing

CasePreviousTesting: ACTA1 and TPM3 were sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case2: Male, 14 yrs report

CasePresentingHPOs: HP:0002355, HP:0002527, HP:0000023, HP:0001763, HP:0002942, HP:0001276, HP:0006466, HP:0003089 (Difficulty walking, Falls, Inguinal hernia, Pes planus, Thoracic kyphosis, Hypertonia, Ankle contracture, hamstring contracture)

HPOsFreeText: In-toe gait, Tendo-Achilles release performed

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Son of Case 1, Variant is de novo in mother

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#4: Smith 2014 FALS R320C, M, 64 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.958C>T (p.Arg320Cys)

ClinVar: 180182

gnomAD: 2-220115463-G-A; Total overall AF (non-neuro) = 0.000009609; TUBA4A_p.Arg320Cys_gnomAD

CaseAddInfo: This variant found in 0/13023 control samples.

FamilyName: PLAA L752F Founder families

FamilyPresentingHPOs: HP:0002061, HP:0002191, HP:0006986, HP:0002273, HP:0002493, HP:0001332, HP:0001332, HP:0011344, HP:0031826, HP:0002267

FamilyHPOFreeText: Posture deformation, including dystonic posturing, rigidity and freezing.Motor delay was severely impaired and classified as Level V according to the Gross Motor Function Classification System.

FamilyNotHPOs:

CountryOrigin: Israel

Ethnicity:

Race:

FamilyPreviousTesting:

FamilyMethod1: Linkage and haplotype analysis

FamilyMethod2: mIPs-Gene panels

FamilyGenotypingMethod: Linkage and haplotype analysis revealed a common founder mutation between Families 1/A and 2/B (Figure 2). mIP technology was used for gene sequencing to confirm the genetic alteration of the PLAA gene, in homozygosity. Confirmation of the PLAA variant was done by Sanger Sequencing.

Affected: 7

Unaffected: 23

Segregations:

PublishedLOD: 3.24

eLOD: n/a

AddSegregationInfo: Families 1/A and 2/B were found to share a common ancestor, and thus revealed a founder mutation.

ProbandLabel: Family A-VI3, female, AoO= 4 months, AaR= 15 years

Variant: NM_001031689.2(PLAA):c.2254C>T (p.Leu752Phe)

ClinVar: 427940

Hoomzygous, Asserted Pathogenic on ClinVar, no star, updated June 21, 2017

gnomAD: n/a

FamilyAddInfo:

FamilyPMIDs: n/a

CasePresentingHPOs: HP:0001508, HP:0000253, HP:0003487, HP:0007103, HP:0012448, HP:0012444, HP:0002808, HP:0000768, HP:0000998, HP:0005692, HP:0001371, HP:0001838, HP:0007410, HP:0012713, HP:0007377, HP:0009051

CasePresentingHPOsFreeText: The delayed myelination was noted along corticospinal tract and posterior genu of capsula interna at age 13 months of age. Brain atrophy noted at 3.5 years old. Central bilateral disturbance in central tract conduction above the brainstem noted by somatosensory evoked potentials (SSEP). Sedimentation of glycogen like material (PAS positive) in muscle biopsy.

CaseNOTHPOs: HP:0001250

CaseNOTHPOSFreeTExt: Normal respiratory chain.

VariantEvidence: Molecular modeling revealed the the Leu752Phe variant is likely to disrupt the PUL domain and may result in an alteration of the protein structure that could affect function (Fig. 2E). Examination in patient derived cells shows that the Leu752Phe variant disrupts the ability of PLAA to induce prostoglandin biogenesis (Fig. 4). As this mechanism is not known to be disease related, it does show an alteration of the protein function by the variant, thus supporting pathogenicity.

Variant NM_001198868.1(CAPN1):c.1579C>T (p.Gln527Ter)

ClinVar 225766

Case# III-1, Female, Caucasian

CasePresentingHPOs HP:0001643

CaseMethod1 WES

CaseMethod2 PCR

Variant NM_001136239.3(PRDM6):c.788G>C (p.Cys263Ser)

ClinVar 243050

VariantEvidence Functional in vitro characterization of PRDM6 p.Cys263Ser in HEK293 cells and human aortic VSMCs showed that the variant protein significantly loses its capability for nuclear localization (Fig 3). DNA overexpression in adenovirus virus infected WT and mutant variants showed MYH11 is also not suppressed by mutant where it is suppressed in WT (Figure 4). Immunoblots of histones in WT human aortic smooth muscle transfected with the variant showed reduced histone modification and and suppression of contractile proteins. (Fig. 5)

Case# B1-3, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case12 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001841, HP:0010066, HP:0001627, HP:0000157, HP:0002101, HP:0002323, HP:0000316, HP:0000445, HP:0001162, HP:0030449

(Oral Cleft, Micrognathia, Preaxial foot polydactyly, Duplicated hallux, Congenital heart defect, Tongue abnormality, Defective lung lobation, Anencephaly, Hypertelorism, Broad nose, Postaxial hand polydactyly, Therapeutic abortion)

HPOsFreeText Crown-heel length 19.5cm, body weight 245g, abnormal larynx trachea, uterus duplex, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, gliovascular tissue on the base of the cranium, hypertelorism, broad nose, postaxial polydactyly in hands, and preaxial polydactyly in feet

CaseNotHPOs HP:0001161

(Hand polydactyly)

NotHPOsFreeText true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 24+0wk gestational age

CasePMIDs n/a

PatientCell CL:0000057 (Fibroblast)

GeneFunction GO:0032006, (regulation of TOR signaling)

GeneAlteration n/a

FunctionalEvidence Western blot of PS6 isoforms, a product of mTOR signalling, were 74% reduced in patient 2-1 fibroblasts compared to control (Fig 3).

Western blot of PS6 in subject 1-1&1-2 fibroblasts also demonstrated 78% reduced PS6 compared to controls (Fig 2b).

As S6 is phosphorylated during normal mTOR activation, reduced PS6 suggests reduced mTOR signalling.

29283439 (fig 3) suggests that the p.Arg126Ter variant in patient fibroblasts causes increased autophagy compared to controls due to the increase in autophagiosomes. (fig 5) the same variant also leads to excess oligosaccharides as a downstream effect of increased autophagy as show using mass spec.

FAVariants (Fig 3) NM_001163435.2(TBCK):c.831_832insTA (p.Pro278Tyrfs), ClinVar: 225238, (Fig 2) NM_033115.4(TBCK):c.1708+1G>A, ClinVar: 183338

Variants 1. NM_000512.5:c.1156C>T 2. NM_000512.5:c.901G>T 3. NM_000512.5:c.337A>T 4. NM_000512.5:c.346G>A 5. NM_000512.5:c.120+1G>A[‐] 6. NM_000512.5:c.860C>T 7. NM_000512.5:c.1171A>G 8. NM_000512.5:c.953T>G 9. NM_000512.5:c.1023C>G 10. NM_000512.5:c.415G>A

Case 4: HP:0001639, NM_005655.3:c.610G>A (p. Ala204Thr), gnomAD= 2.03e-5, Other= 1.823e-4

Proband 2: male, Dx at 41 years, LV septal wall thickness = 22mm, improved following transseptal alcohol ablation, 3 unaffected children

HP:0001639, HP:0011103

Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract

Variant: NM_145046.4(CALR3):c.245A>G (p.Lys82Arg)

ClinVar ID: 30907

https://www.ncbi.nlm.nih.gov/clinvar/variation/30907/

ExAC Score: Overall 0.0005987

http://gnomad.broadinstitute.org/variant/19-16601330-T-C

NonHumanModel Mus musculus

GeneAlteration oligonucleotide-directed mutagenesis of lambda phage to make a p.T494M vector to inject mice.

ModelPhenotype HP:0031531

HumanPhenotype HP:0000572

ModelEvidence Electron microscopy of retina showed degeneration of RPE indicated by abnormal basal morphology (fig. 5)

ModelVariant NM_004698.3(PRPF3):c.1481C>T (p.Thr494Met), 3352

Family#PresentingHPOs HP:0001999, HP:0003155, HP:0003124, HP:0003141, HP:0012347, HP:0012358, HP:0001399 (Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Increased LDL cholesterol, Abnormal protein N-linked glycosylation, Abnormal protein O-linked glycosylation, Liver failure)

HPOsFreeText elevated AT

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic work up: Elevated AT, ALP, total cholesterol and LDL cholesterol, abnormal N- and O- glycosylation

Family#Method1 Sanger

Family#Method2 n/a

Family#GenotypingMethod Sanger on proband targeting CCDC115

Affected 2

Unaffected 0

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguinity

ProbandLabel F4-II1, male,9yo death

Case1PreviousTesting Metabolic results: AST 192–669 U/l[normal range, 0–50 U/l], ALT 83–308 U/l [normal range, 0–50 U/l], ALP 702 U/l[normal range, < 360 U/l]

Case2 F4-II2, female, 8yo diagnosis

Case2PreviousTesting Metabolic results: AST 98–422 U/l [normal range, 0–50 U/l], ALT 98–178 U/l [normal range, 0–50 U/l], ALP 710–985 U/l [normal range, < 360 U/l]. AT and CDG profile normalized after liver transplant.

Variant NM_032357.3(CCDC115):c.31G>T (p.Asp11Tyr), homozygous

ClinVar 218963

gnomAD n/a

VariantEvidence n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

Case# Subject 2, F, 5mo died, Kurdish

CasePresentingHPOs HP:0001319, HP:0008872, HP:0002033, HP:0003128, HP:0002490, HP:0001531, HP:0040288, HP:0001712, HP:0001410, HP:0002098, HP:0002910, HP:0002126, HP:0000365, HP:0002151 (Neonatal hypotonia, Feeding difficulties in infancy, Poor suck, Hyperlactatemia, Increased CSF lactate level, Failure to thrive in infancy, Nasogastric tube feeding, Left ventricular hypertrophy, Decreased liver function, Respiratory distress, Elevated transaminases, Polymicrogyria, Deafness, Elevated serum lactate)

HPOFreeText: After caesarean delivery, neonatal hypotonia, poor feeding, and sucking. (3 months) failure to thrive, nasogastric feeding, left ventricular hypertrophy and impaired liver function. Brain MRI: bifrontal polymicrogyria and acoustic oto-emissions suggested deafness (4 months). Died of respiratory distress at 5 months.

CaseNotHPOs n/a

CasePreviousTesting Serum lactate (7.4 mmol/L; normal range 0.90–1.70 mmol/L), lactate to pyruvate ratio (170; normal range 30–50), CSF lactate (3.1 mmol/L; control < 2.2 mmol/L), liver function (AST: 84 UI/L, normal range 15–60; ALT: 52 UI/L, normal range 7–40; gGT: 262 UI/L, normal range 6–25 UI/L). Screened panel of known mitochondrial disease genes. Analysis of mtDNA and mtDNA copy number from patient muscle DNA were normal, thus excluding mtDNA rearrangements and point mutations.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger in patient and parents to confirm in trans

Variant NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu) -homozygous

ClinVar 224316

gnomAD 0.0003508(Latino), 0.0001121(Total) -no homozygotes on record

VariantEvidence n/a

CaseAddInfo non-consanguineous, healthy older brother, c.542G>T variant in ExAC (10/120,324 alleles) and ESP6500 (1/11,824 alleles)

CaseAddPMIDs n/a

CaseP7 male, 59yo, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 5mL(lower reference limit: 1.5), sperm concentration: 15.5million/mL(reference: 15), total motility after 1hr: 4%(reference: 40), vitality: 47%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 95%, abnormal head morphology: 7%, abnormal base: 3%, absent flagella: 30.5%, short flagella: 25%, coiled flagella: 27%, flagella of irregular caliber: 33%, multiple anomalies index: 2.56%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP6 male, 28yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0003251

(reduced sperm motility, male infertility)

HPOsFreeText Patient's sperm volume: 3mL(lower reference limit: 1.5), sperm concentration: 7.8million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), normal spermatozoa: 0%(reference: 4).

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP5 male, 31yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 3.4mL(lower reference limit: 1.5), sperm concentration: 60million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), vitality: 62%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 80%, abnormal head morphology: 8%, abnormal base: 2%, absent flagella: 24%, short flagella: 50%, coiled flagella: 8%, flagella of irregular caliber: 68%, multiple anomalies index: 2.5%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo nonconsanguineous

CasePMIDs 29449551

Case#: KMP 11, female, 57 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: yes

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case# Patient 5, Caucasian, Female, age 61

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10580G>A (p.Arg3527Gln)

ClinVar 17890

gnomAD 0.0005791 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P5=240, PMID: 3477815- reduced LDLR affinity

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

Case#: II.4 - male, 23, European descent II.5 - male, 28, European descent CasePresentingHPOs: Both patients II.4 and II.5 - HP:0003233 (low HDL cholesterol), HP:0012153 (hypotriglyceridemia), HP:0003563(decreased LDL cholesterol)

CaseMethod1: Exome CaseMethod2: Sanger

Variant: NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)

ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

VariantEvidence: 12 other individuals from the Dallas Heart Study with ANGPTL3 frameshift mutations with phenotypes in Supplementary doc (PMID 19075393), additive dosage model with 2 mutations, 1 mutation and 0 (in supplementary table 5), “key enzymes in the metabolism of circulating triglycerides and HDL cholesterol, respectively, are elevated in Angptl3-knockout mice, suggesting that increased activity of these enzymes may explain the low levels of triglycerides and HDL cholesterol in humans with ANGPTL3 nonsense mutations” (PMIDs 17110602, 12097324, and 17681148)

MiltingF1

FamilyNotHPOs HP:0100660, HP:0004756, HP:0001645, HP:0031317

CountryOrigin Germany

Ethnicity Danish

Family#PreviousTesting: whole genome Family#Method1 PCR

Family#GenotypingMethod Liquid Chromatography screening

Affected 8

Unaffected 6

Segregations 7

eLOD 2.1

ProbandLabel Milting3:1 female

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

Case: TTD218UT

Demographics: Female, 1.5 years at diagnosis. Moroccan origin.

CasePresentingHPOs: HP:0004779, HP:0045055, HP:0008064, HP:0000252, HP:0001263, HP:0004322, HP:0001935, HP:0004840, HP:0040082, HP:0100025

Individual showed recurrent aggravation of hair-loss by tufted breakage at the scalp boundary immediately following episodes of infection-induced fever, and upon long-term exposure to the heat of the sun, she appears to have increased hair-loss. She had an IQ of 54 (at 7 years) and limited physical endurance.

CaseNOTHPOs: Progressive deterioration at 8 years

CasePreviousTesting: None

CaseGenotypingMethod: Whole genome sequencing, confirmed by Sanger sequencing.

Variant: NM_002095.5(GTF2E2):c.C559T [p.Asp187Tyr]

ClinVar ID: 225841

Pathogenic, non-LOF variant gnomAD: hypomorphic, homozygous missense. Not in gnomAD.

AddCaseInfo: The parents of this individual were consanguineous and were heterozygous for the mutation. Of 3 siblings, two (a brother and a sister) were found to be heterozygous carriers, while one was found to have the homozygous wild type alleles (a sister).

VariantEvidence: The variant has been previously reported by Kauschal et al (26996949) in a 16-yr old Moroccan girl. The identification of this variant in four individuals of Moroccan origin suggests the possibility of a founder mutation. Since the variant has been already scored, this proband is not being scored.

Case# Baskin RW, Female, 31

CasePresentingHPOs HP:0004756, HP:0011841, HP:0002013

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

ArticleReferenceSequence: Not specified- Assumption: Nucleotide change is not specified in the paper, only protein coding change is. cDNA variant was inferred based on protein coding change, and reported based on VHL reference sequence NM_000551.3

GenotypingMethod: PCR amplification using genomic DNA as template was carried out followed by single-strand polymorphism analysis. After PCR, the BigDye® Terminator V3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA) was used to sequence samples.

SamplingMethod: tissue resection

PatientID: 5

KindredID: 7

Case: M, 17Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No family history, assumed de-novo, but unclear if parents were tested to confirm de-novo assertion.

CohortInfo: 36 pediatric patients with pheochromocytomas and/or parangangliomas.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: The patient had a benign bilateral pheochromocytoma that was secreting norepinephrine at age 10. At age 17, the pheochromocytoma reoccured but this time was malignant and metastasized to the lungs.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX

PreviouslyPublished: Yes source unknown.

SupplementalData: N/A

Variant: p.R167W (c.499C>T) *The authors of this paper have seemingly called the wrong protein change for this variant.

CaseProblemVariantFreeText: N/A

LegacyVariant: 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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 14

Case: 15Y0M, F, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: The patient has no family history of VHL disease. Genetic testing reveals no mutation in patient's parents indicating that the mutation in patient is sporadic. This was further said to have occurred de novo.

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: bilateral pheochromocytoma diagnosed at age 11 years. She was said to have single-organ involvement and did not fulfill diagnostic criteria of VHL. 

CaseNotHPOs: HP:0009711; HP:0005584; HP:0010797; HP:0000107; HP:0001737 (retinal capillary hemangioma, renal cell carcinoma, hemangioblastoma, renal cyst, pancreatic cysts)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

Variant: p.V166A (c.497T>C)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 43605 https://www.ncbi.nlm.nih.gov/clinvar/variation/43605/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: V166A (c.497T>C)

MultipleGeneVariants: N/A

PatientID: 21

KindredID: 21

Case: M, 32Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: Family history positive for VHL. No details provided.

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:0002666 (Hemangioblastoma, Pheochromocytoma)

CaseHPOFreeText: CNS hemangioblastoma. Multiple or bilateral pheochromocytoma. Pheochromocytoma. Diagnosed with VHL Type 2A.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16142346

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

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

GenotypingMethod: Direct sequencing was performed using the BigDye Terminator Cycle Sequencing Ready Reaction kit on an ABI Prism 3130 genetic analyzer (Applied Biosystems).

SamplingMethod: peripheral blood leukocytes

PatientID: 13

KindredID: AD

Case: M, 50Y0M, Indian

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: Multi-cystic pancreatic lesions, RCC.

CaseNotHPOs: HP:0002666; HP:0030393; HP:0009711; HP:0010797 (Pheochromocytoma, Endolymphatic sac tumor, Retinal capillary hemangioma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G114D (c.340+1G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant; missense_variant;transition

CivicName: G114D (c.340+1G>A) and c.340+5G>C

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A - Unclear

SamplingMethod: N/A - Unclear

PatientID: 224

KindredID: 83

Case: M, 53Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The patient had the same germline mutation as his sister (the proband). His sister presented with a pheochromocytoma at age 38. His mother had a CNS hemangioblastoma at 52, but no genotyping information is available for her.

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: The patient presented with renal cell carcinoma at age 53.

CaseNotHPOs: HP:0009711; HP:0001737; HP:0001732; HP:0010797; HP:0002666 (Retinal capillary hemangioma, Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma, Pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 276

KindredID: 107

Case: M, 50Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband, patient 276, presented with a retinal angioma at age 31, and a CNS hemangioblastoma and multiple pancreatic cysts/tumors at age 37. The proband has a father who presented with a CNS hemangioblastoma at age 50.

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

CaseHPOFreeText: The proband's father presented with a CNS hemangioblastoma at age 50.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: N/A

PatientID: 208

KindredID: 79

Case: M, 49Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0009711; (Retinal Capillary Hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

PatientID: 186

KindredID: 72

Case: F, 39Y0M, Chinese

DiseaseAssertion: VHL

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

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

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

CaseNotHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

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

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 2

Case: M, 16Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: None

CasePresentingHPOs: HP:0002666, HP:0030405, HP:0011732 (pheochromocytoma, pancreatic endocrine tumour, Abnormality of adrenal morphology)

CaseHPOFreeText: The patient had three tumours.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: Previously published in 24301059.

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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: The patient had a mosaic mutation with a mutated allele frequency of 5.7%. Copy number events of the mutated and wild type allele are available in table S4 of the supplemental.

MutationType: missense_variant;transition

CivicName: R167Q (c.500 G >A)

MultipleGeneVariants: N/A

PatientID: WM06

KindredID: 12

Case: Sex Unknown, 10Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: N/A - Unspecified

LegacyVariant: Given as an unspecified germline mutation

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: N/A

CivicName: N/A

MultipleGeneVariants: N/A

PatientID: VCB.14T

KindredID: 6

Case: Sex Unknown, 34Y0M, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

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

CaseHPOFreeText: Presented with bilateral pheochromocytoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

PreviouslyPublished: 25545346 (see table S1 and S10)

SupplementalData: Yes

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

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

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summariezed the phenotypes of the families together. Family 7 was found with p.Asn78Thr mutation in the VHL gene: 1/2 members had CNS hemangioblastoma and 2/2 has renal cell carcinoma. ACMG PP4

27 index patients suspected of having VHL disease from unrelated Chinese families and their relatives were studied. The nucleotide were numbered according to the sequence numbering by Latif et al, 1993 and this was converted to NM_000551.3. The paper did not differentiate between a pancreatic cysts and tumor and presented these together as a 'pancreatic lesion'. The paper summarized the phenotypes of the families together. Family 20 was found with an intron mutation in the VHL gene (paper reported as IVS1-38C>T which was converted to recommended HGVS notation): both members had CNS hemangioblastomas and retinal capillary hemangioblastomas.

This intron variant (IVS1-38 C>T) is unknown. The entered coordinates do not agree with the intron/exon boundaries for the selected transcript; The base at c.340 not "C". Authors were contacted and could not confirm.

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

PatientID: 8

KindredID: 8

Case: M, 66Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: N/A

CohortInfo: 55 patients treated at Asan Medical Center in Korea treated between January 1995 and February 2013 clinically diagnosed with VHL disease and presenting with pancreatic lesions.

CasePresentingHPOs: HP:0001737, HP:0030405 (Pancreatic cysts, Pancreatic endocrine tumor)

CaseHPOFreeText: At age 56, the patient had a serous cystadenoma of the pancreas and a pancreatic endocrine tumour. A Pylorus-preserving pancreaticoduodenectomy was performed and the largest tumour resected was 40 mm. On follow up 170 months later the patient had no evidence of disease.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: 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.500 G >A)

MultipleGeneVariants: N/A

PatientID: II-2

KindredID: 1

Case: F, 10Y0M, Ethnicity Unknown

DiseaseAssertion: Adrenal pheochromoyctoma

FamilyInfo: The patient’s brother (II-1) was found to harbor the same germline mutation the patient harbored and had bilateral adrenal pheochromocytoma at 14Y. The same germline missense mutation was detected in another sister (II-4) with right adrenal pheochromocytoma and her asymptomatic daughter (III-1). The father was not available for genetic testing because he had died, apparently secondary to a hypertensive crisis. The five other family members which underwent genetic testing did not have the mutation.

CasePresentingHPOs: HP:0006748 (Adrenal pheochromocytoma)

CaseHPOFreeText: At 10Y, the patient reported palpitations, weight loss, diaphoresis, and shooting pain attacks. Her urinary metanephrines were elevated to 12.2 mg/g creatinine. A CT of the abdomen revealed a mass in the left adrenal gland. Histology and immunohistochemistry confirmed diagnosis of left adrenal pheochromocytoma. Additional screening revealed no other tumours, so this fit the criteria of VHL type 2C.

CaseNotHPOs: HP:0002668; HP:0012090; HP:0012210 (Paraganglioma, abnormal pancreas morphology, abnormal renal morphology)

CaseNotHPOFreeText: There were no lesions in the pancreas or the kidney, there was also no suggestion that the paraganglia would also be involved. Her MRI of the brain, and her echocardiogram were both normal.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F(c.496G>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: PCR amplified VHL gene was analyzed by Sanger sequencing.

SamplingMethod: peripheral blood

KindredID: 1112

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0030405; HP:0005584 (Pancreatic endocrine tumor, Renal cell carcinoma)

CaseNotHPOFreeText: The patient had no cysts (type or location was not specified).

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: p.R161* (c.694C>T)

ClinVarID: 2217, https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant reported as 694, C to T (Arg to stop), assumed to be reported in legacy nomenclature (AF010238.1) and mapped to c.481C>T, p.Arg161* (NM_000551.3).

MutationType: stop_gained; missense_variant;transition

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: Analysis of the RET and VHL genes in patients was done using direct bidirectional DNA sequencing

SamplingMethod: peripheral blood

PatientID: None

KindredID: 1

Case: F, 20Y0M, Caucasian

DiseaseAssertion: VHL

FamilyInfo: The patient’s mother had died of pulmonary edema during pregnancy at the age of 40.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: The patient presented with decreased vision in the right eye with a 4-month evolution. The patient’s vital signs were within normal limits, and no abnormalities were noticed upon physical and neurological examination. Similarly, her past medical history was unremarkable. Upon ophthalmoscopic examination, a red-colored globular lesion of 3 disk diameters with prominent feeder vessels was noticed in the superior temporal region of the retina. A structural OCT B-scan showed a diffuse cystoid macular edema, which involved the posterior pole and expanded outside the vascular arcades. The other eye was normal.

CaseNotHPOs: HP:0012443; HP:0011732 (Abnormality of brain morphology, abnormality of renal morphology)

CaseNotHPOFreeText: Results of renal ultrasonography and magnetic resonance imaging of the brain were both negative for visceral lesions.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112C (c.335A>G)

LegacyVariant: N/A

ClinVarID: 223189, https://www.ncbi.nlm.nih.gov/clinvar/variation/223189/

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: Y112C(c.335A>G)

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A

SamplingMethod: N/A

GroupID: 85

Case: 27Y0M, Sex Unknown, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: 1 of the 573 patients discussed in this paper were found to have this variant. This mutation (c.538A>G) was found in 1 VHL family with a single patient.

CasePresentingHPOs: HP:0005584 (renal cell carcinoma)

CaseHPOFreeText: patient had RCCs diagnosed at 27Y

CaseNotHPOs: HP:0009711; HP:0006880; HP:0002666 (retinal capillary hemangioma; cerebellar hemangioblastoma; pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

Variant: p.I180V (c.538A>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 161401 https://www.ncbi.nlm.nih.gov/clinvar/variation/161401/

CAID: N/A

gnomAD: 0.00001061 https://gnomad.broadinstitute.org/variant/3-10191545-A-G

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: I180V (c.538A>G)

MultipleGeneVariants: N/A

PatientID: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A - Not specified

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: VHL syndromic HB

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Null (Complete deletion)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: A VHL subject in our patient population had a full length deletion (FLD) in the germline VHL gene, but a VHL gene tumor second hit mutation (c.360-362 del AGA) causing an amino acid change of p.RD120-121S detected in the HB tumor

MutationType: deletion

CivicName: Deletion AND R120_121S (c.360_362delAGA)

MultipleGeneVariants: Somatic, VHL, c.360_362delAGA, p.Arg120_121Ser

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

GenotypingMethod: The three exons of the VHL gene (coding region of 852 nucleotides) were sequenced. PCR products were purified with the QiA quick PCR purification kit (Qiagen, Hilden, Germany), and the sequencing reactions were done using the ABI PRISM DYE Terminator sequencing kit (Perkin-Elmer Applied Biosystems Division, Foster City, CA), and were analysed on the ABI 373 A sequencer.

SamplingMethod: Peripheral blood

GroupID: 91

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family were found to harbor the c.388G>C germline variant of the VHL gene. Member 6200 had no renal involvement. Member 6410 presented with mild renal disease. Members 5838 and 5839 presented with moderate 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).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531 and/or 9829912, where 3 and 1 individuals respectively with this mutation are reported. It is unclear if one or both of these previously reported groups are the same as the current family.

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

Variant: p.V130L (c.388G>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2229, https://www.ncbi.nlm.nih.gov/clinvar/variation/2229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V130L (c.388G>C)

MultipleGeneVariants: N/A

GroupID: 394

DiseaseAssertion: VHL

GroupSize: 3

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 3 members of this family were found to harbor a germline large rearrangement of the VHL gene. Member 9248 presented with moderate renal disease (RCC). Member 9313 and 2222 presented with severe renal disease (RCC). Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

GroupPresentingHPOs: HP:0005584 (Renal cell carcinoma)

GroupHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Severe renal disease (any solid lesion before 25 years of age, five or more solid lesions within one or two kidneys, or metastasis of renal cell carcinoma).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Paper states that this family is previously reported in PMID 12202531, where 12 individuals with this mutation are reported. It is unclear which of the previously reported individuals correspond to which of the currently reported families/individuals (i.e. families 40, 90, 174, 237, 264, 284, 307 or 394).

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

Variant: Rearrangement

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: rearrangement_region

CivicName: Rearrangement

MultipleGeneVariants: N/A

PatientID: 26

KindredID: 31

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: None

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R177_L178ins6 (c.531_532ins18)

LegacyVariant: N/A

CaseProblemVariantFreeText: Stated in the paper as: p.R177_L178ins6 (c.531_532ins18) - NM_000551.3:c.531_532ins18: char 24: Syntax error - due to it's non specific nomenclature. (Can't verify coordinates of specific insertion).

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: inframe_insertion

CivicName: R177_L178ins6 (c.531_532ins18) 

MultipleGeneVariants: N/A

PatientID: 30

KindredID: 64

Case: Sex unknown, Age unknown, French

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666 (pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence:N/A

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 27B

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: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 4 patients with the given mutation were grouped as group 27(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.S183* (c.548C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2215 https://www.ncbi.nlm.nih.gov/clinvar/variation/2215/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: S183* (c.548C>A)

MultipleGeneVariants: N/A

PatientID: None

KindredID: B

Case: M, 27Y0M, Hungarian

DiseaseAssertion: VHL

FamilyInfo: The parents of the patient rejected clinical and genetic screening, whereas clinical screening in a younger brother of the index patient revealed no abnormality.

CasePresentingHPOs: HP:0009711, HP:0000107, HP:0001737, HP:0001901, HP:0006880 (retinal capillary hemangioma, renal cyst, pancreatic cysts, polycythemia, cerebellar hemangioblastoma)

CaseHPOFreeText: Retina involvement presented at age 19. The patient had cerebellar hemangioma as well as renal and pancreatic cysts at the age of 27 years.

CaseNotHPOs: HP:0005584, HP:0002666 (renal cell carcinoma, pheochromocytoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R161* (c.481C>T)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 2217 https://www.ncbi.nlm.nih.gov/clinvar/variation/2217/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R161* (c.481C>T)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 15

Case: Sex Unknown, 23Y0M, Danish

DiseaseAssertion: Asymptomatic

FamilyInfo: 2 other family members presented with the same VHL variant. Patient 15-II presented with 2 pheochromocytoma (8Y) 2 CNS hb (12Y and 13Y) and 2 retinal hemangioblastomas (8Y, 12Y). Patient 15-III presented with 2 pheochromocytoma (15Y).

CasePresentingHPOs: N/A

CaseHPOFreeText: Diagnosed with VHL at age 6Y. Age at the end of study: 23Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V166F (c.496G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V166F (c.496G>T)

MultipleGeneVariants: N/A

PatientID: V-20

KindredID: 2

Case: M, Age Unknown, German

DiseaseAssertion: VHL

FamilyInfo: Family 2 is comprised of 131 individuals over six generations including 65 members (50% of those at risk) with VHL type 2A (72% clinically affected, 12% obligate carriers, and 15% positive genetic analysis alone) and nearly equal gender distribution for affected status (54% male). An additional six members (II-3, II-4, II -5, III-1, III-2, and III-3) are suspected to have VHL without confirmation. Of note, the nuclear family (branch IV-13) contains 13 siblings, of whom 12 have been diagnosed with pheo. The presenting tumor types in Family 2 were pheo (70%), HB (17%), and RA (13%). No Family 2 member had RCC as the initial manifestation. Distribution of HB and RA are not described except for patient IV-8.

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0005584 (Renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 7759077

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 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: None

KindredID: 3

Case: M, 22Y0M, Ethnicity Unknown

DiseaseAssertion: Clear Cell Renal Cell Carcinoma

FamilyInfo: N/A

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

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

CaseHPOFreeText: One of the samples from this patient had few variants and clustered with the normal samples. Further inspection showed these samples were cyst-like rather than tumours, so they were excluded from further analysis. This suggests that the patient had renal cysts alongside ccRCC at age 22.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.P86R(c.257C>G)

LegacyVariant:N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223170 https://www.ncbi.nlm.nih.gov/clinvar/variation/223170/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: P86R(c.257C>G)

MultipleGeneVariants: N/A

PatientID: P5

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: pheochromocytoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0002666 (pheochromocytoma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

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: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: No family information provided.

CasePresentingHPOs: HP:0002666; HP:0002668 (Pheochromocytoma; paraganglioma)

CaseHPOFreeText: Patient had pheochromocytoma and/or paraganglioma (table 2).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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: 2

KindredID: 2

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: Hereditary PNET with a confirmed germline mutation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E55Gfs*77 (c.163_164insG)

LegacyVariant: N/A

CaseProblemVariantFreeText: c.163_164insG automapped to NM_000551.3:c.163dupG

ClinVarID: 223159 https://www.ncbi.nlm.nih.gov/clinvar/variation/223159/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant; duplication

CivicName: E55fs (c.163dupG)

MultipleGeneVariants: N/A

PatientID: N/A

KindredID: 442

Case: Age unknown, Sex unknown, Ethnicity unknown

DiseaseAssertion: assumed VHL

FamilyInfo: Paper states: Germline, de novo (no clear confirmation)

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

CaseHPOFreeText: Bilateral RCC and a hemangioblastoma

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes (Specifically Supp. Table S2)

Variant: p.G144* (c.430G>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223208 https://www.ncbi.nlm.nih.gov/clinvar/variation/223208/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: G144* (c.430G>T)

MultipleGeneVariants: N/A

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

GenotypingMethod: N/A

SamplingMethod: N/A

PatientID: 2

KindredID: A

Case: M, Age unknown, Turkish

DiseaseAssertion: assumed VHL

FamilyInfo: 5 family members are grouped with this deletion (ages 16-37Y; mean 31Y). VHL was clinically diagnosed in, at minimum, the proband. See Fig. 2 for family pedigree. This patient’s last two brothers were not tested for the DNA deletion however it is assumed by the authors due to the segregation observed.

CasePresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma; hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0002666; HP:0005584 (pheochromocytoma; renal cell carcinoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Deletion of exons 1 and 2

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID:N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: HindIII and revealed an aberrant banding pattern in three affected family members (1, 2, and 9)

MutationType: exon_loss_variant

CivicName: exon 1-2 deletion

MultipleGeneVariants: N/A