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What is this?

Boomerang UK 'Who's Your Favourite?' era theme

Ihave a freind whoisatuter and student.He and his wifebought ther frist house not tofar frome the college.And they are remoldeling the house .he told me the other day hes finding lotsof marblesand pilesof broken glass inhis yard .I said he should let my class exzamin the site for class. the house was built in 1913 but itsunknown what wasther beforethe house?

Case#: Female with DCM symptoms beginning at age 30

DiseaseAssertion: Dilated cardiomyopathy (DCM) associated with a heterozygous missense variant in MYBPC3, c.3373G>A (p.Val1125Met). The authors propose autosomal dominant inheritance in this DCM case.

FamilyInfo: NR – Detailed family relationships, segregation testing, and individual relatives' phenotypes are not described for the current DCM proband.

ParentalTesting: NR

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0002094 (Dyspnea); HP:0001962 (Palpitations); HP:0004756 (Ventricular tachycardia)

CaseHPOFreeText: The patient experienced symptoms beginning at age 30, including frequent palpitations and dyspnea. ECG monitoring revealed multiple premature ventricular contractions and nonsustained ventricular tachycardia. Echocardiography demonstrated severe spherical left ventricular enlargement, severe systolic and diastolic dysfunction, LVEF of 10%, and mild pulmonary hypertension. She was classified as NYHA functional class II–III and received medical therapy and an implantable cardioverter-defibrillator.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR – Article describes patient's clinical evaluation, including ECG monitoring and echocardiography, before genetic analysis.

Genotyping Method: Genomic DNA was extracted from peripheral blood. Targeted next-generation sequencing was performed using a custom NimbleGen panel covering the coding regions and exon–intron boundaries of 23 genes associated with DCM. Sequencing was conducted on an Illumina HiSeq 2000 platform. Reads were aligned to the hg19 reference genome using BWA, and SAMtools was used for variant analysis. MYBPC3 variant confirmed using Sanger sequencing.

FunctionalAnalysis: In silico analyses were performed to investigate the potential functional consequences of MYBPC3 p.Val1125Met. SIFT, PolyPhen-2, and MutationTaster predicted potentially damaging effects, while CADD produced a score of 33. Multiple-sequence alignment demonstrated that Val1125 is highly conserved across species. Protein modeling using I-TASSER and Phyre2 predicted structural differences involving the region surrounding residue 1125, located within the C9 fibronectin type III domain of cardiac myosin-binding protein C (cMyBP-C). The authors proposed that the substitution could affect protein structure and function. No direct experimental functional validation of this variant was reported.

Variant: MYBPC3 NM_000256.3:c. 3373G>A (p.Val1125Met); rsID: rs121909378; missense; heterozygous

ClinVar: 8604

CAID: CA014038

gnomAD: MYBPC3 c.3373G>A (p.Val1125Met), GRCh38: 11-47332931-C-T. In gnomAD v4, the reported allele frequencies are 0.00001920 (exomes), 0.00003943 (genomes), and 0.00002111 (total). The highest ancestry-specific allele frequency identified was in the Ashkenazi Jewish population (AC = 5; AF = 0.0001695).

AdditionalInfo: Authors propose variant dosage, interactions with other variants, and genetic modifiers may contribute to differences in disease phenotype. However, the proposed autosomal dominant association with DCM was not supported by documented segregation testing in the current proband's family, and the functional analyses were computational rather than experimental.

PMID: 29493010

Gene: MYBPC3

HGNC ID: 7551

Case#: 80-year-old male (I-1) diagnosed with HCM at approximately 50–55 years of age; familial case with his 3 adult offspring (II-2, II-3, and II-4)

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with a heterozygous frameshift variant in MYBPC3.

FamilyInfo: The proband (I-1) is an elderly male with familial hypertrophic cardiomyopathy. Three adult offspring (II-2, II-3, and II-4) were evaluated and diagnosed with HCM based on interventricular septal hypertrophy. All four individuals carried the heterozygous MYBPC3 c.1042_1043insCGGCA variant. Individual II-2 experienced chest discomfort and palpitations, whereas II-3 and II-4 were asymptomatic at evaluation. These findings demonstrate segregation of the variant with HCM in the examined family members and are consistent with autosomal dominant inheritance.

ParentalTesting: NR – Genetic testing of the proband's parents was not reported but the variant was identified in his three adult offspring, supporting familial segregation.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001635 (Congestive heart failure)

CaseHPOFreeText: The proband experienced chest tightness, dyspnea, and recurrent heart failure. Echocardiography demonstrated marked interventricular septal hypertrophy (39 mm during diastole and 41 mm during systole), a left atrial diameter of 44 mm, and a left ventricular ejection fraction of 60%. Additional findings included premature atrial beats, intraventricular conduction block, and NYHA functional class II. A history of hypertension was reported.

CaseNotHPOs: HP:0001279 (Syncope); HP:0001681 (Angina pectoris); HP:0001695 (Cardiac arrest)

CaseNotHPOFreeText: The proband had no reported history of syncope, angina pectoris, or cardiac arrest. No surgical myectomy was reported.

CasePreviousTesting: NR – Previous genetic testing was not reported but the proband underwent clinical cardiovascular evaluation, including electrocardiography, echocardiography, and BNP measurement.

Genotyping Method: Whole-genome sequencing (WGS) was performed using peripheral blood DNA on an Illumina NovaSeq 6000 platform with 150-bp paired-end reads and approximately 30× sequencing depth. Reads were aligned to the hs37d5 reference genome using BWA, and variants were annotated using ANNOVAR.

FunctionalAnalysis: Cardiac tissue from the proband was analyzed using RT-qPCR and Western blotting. MYBPC3 mRNA expression and cardiac myosin-binding protein C (cMyBP-C) abundance were significantly reduced (P < 0.05), supporting a haploinsufficiency mechanism. These findings do not independently establish the functional effect of the specific variant, and the Western blot analysis lacked biological replicates.

Variant: MYBPC3 NM_000256.3.1038_1042dup (p.Met348ThrfsTer4). Five-base-pair duplication resulting in a frameshift and premature termination codon. Reported in Zhang et al. (2025) as c.1042_1043insCGGCA.

ClinVar: No exact match identified for MYBPC3 c.1042_1043insCGGCA using the reported HGVS notation. ClinVar Variation ID not established.

CAID: CA273429

gnomAD: No exact matching entry identified in gnomAD v4 for MYBPC3 NM_000256.3:c.1038_1042dup (CA273429). Population allele frequency could not be established.

AdditionalInfo: The variant was identified in the proband and three adult offspring with interventricular septal thickening. The study proposed MYBPC3 haploinsufficiency as a disease mechanism based on reduced transcript and protein abundance. The available familial and functional evidence supports an association with HCM, although the specific variant's pathogenicity requires interpretation alongside the limitations of the study.

PMID: 41134850

Gene: MYBPC3

HGNC ID: 7551

Case#: female, age 43

FamilyInfo: Two paternal cousins had genetic cardiomyopathies requiring ICD implantation and carried the same pathogenic TNNT2 p.R92W variant.

CasePresentingHPOs: HP:0001638 HP:0012664 HP:4000141 HP:0002094

CaseHPOFreeText: Progressive nonischemic cardiomyopathy; reduced left ventricular ejection; left ventricular dilation; regional wall-motion abnormalities; myocardial enhancement and edema; chest pain; exertional dyspnea

Genotyping Method: Familial variant genetic testing; not specified

Variant: TNNT2 c.274C>T (p.Arg92Trp; p.R92W); missense single-nucleotide variant

ClinVar: 43627

CAID: CA004266

PMID: 40615189

Gene: TNNT2

HGNC ID: HGNC:11949

Case#: AD-FDC27, II:11, male, age 35

DiseaseAssertion: Familial dilated cardiomyopathy

FamilyInfo: second multigenerational DCM family

CasePresentingHPOs: HP:0001644 HP:4000141

CaseHPOFreeText: Dyspnea on exertion; left ventricular dilation; severe systolic dysfunction

Genotyping Method: Whole-exome sequencing using Agilent SureSelect 50 Mb exome; HiSeq 2000 sequencing followed by Sanger sequencing confirmation

Variant: TNNT2 c.517C>T (p.Arg173Trp); missense single-nucleotide variant; heterozygous

ClinVar: 228409; Pathogenic

CAID: CA10576372

Case#: AD-FDC1, IV:14, male, age 45

DiseaseAssertion: Familial dilated cardiomyopathy

FamilyInfo: multigenerational DCM family

CasePresentingHPOs: HP:0001644 HP:4000141 HP:0012664

Genotyping Method: Whole-exome sequencing using Agilent SureSelect 50 Mb exome; HiSeq 2000 sequencing followed by Sanger sequencing confirmation

Variant: TNNT2 c.517C>T (p.Arg173Trp); missense single-nucleotide variant; heterozygous

ClinVar: 228409

CAID: CA10576372

PMID: 41440877

Gene: TNNT2

HGNC ID: HGNC:11949

Case#: Patient 3; male; 60 years old at first observation; 14 mm LV wall thickness; family history of HCM

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the heterozygous MYBPC3 intronic splice-altering variant c.1224-80G>A, classified as likely pathogenic by the study authors.

FamilyInfo: Patient was reported to have positive family history of HCM. Echocardiography demonstrated a maximum left ventricular wall thickness of 14 mm without left ventricular outflow tract obstruction. The study did not identify specific affected relatives or provide a family pedigree.

ParentalTesting: NR – Patient had a positive family history of HCM but parental genotypes and variant segregation were not documented.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Echocardiography demonstrated a maximum left ventricular wall thickness of 14 mm without left ventricular outflow tract (LVOT) obstruction. NYHA functional classification was not reported.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction)

CaseNotHPOFreeText: Echocardiographic evaluation showed no left ventricular outflow tract (LVOT) obstruction.

CasePreviousTesting: Patient 3 previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel, which included 174 genes associated with inherited cardiac conditions. The initial genetic analysis was negative. Subsequent reanalysis of existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA obtained from peripheral blood was analyzed using the Illumina TruSight Cardio targeted next-generation sequencing panel on an Illumina MiniSeq platform. Previously generated sequencing data were reexamined using an intronic hotspot analysis approach, with variant visualization in Integrative Genomics Viewer (IGV). The MYBPC3 c.1224-80G>A variant was subsequently confirmed by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a cryptic splice acceptor site within intron 13, resulting in retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons. Previous functional studies demonstrated altered RNA splicing and an approximately 50% reduction in MYBPC3 transcript abundance. SpliceAI predicted a strong splice-altering effect (Δscore = 0.94). The current study did not perform patient-specific RNA functional experiments. Instead, researchers identified the variant through reanalysis of existing next-generation sequencing data and confirmed its presence using Sanger sequencing.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: Although Patient 3 carried the same variant as Patient 2, their reported cardiac phenotypes differed. Patient 2 exhibited a maximum left ventricular wall thickness of 27 mm and LVOT obstruction with a gradient of 50 mmHg. These differences are consistent with variable clinical expression of MYBPC3-associated HCM, although the study did not determine their underlying causes.

Case#: Patient 1; female; 56 years old at first observation with diagnosis of HCM; 13 mm LV wall thickness

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the heterozygous MYBPC3 intronic splice-altering variant c.1224-80G>A, classified as likely pathogenic by the study authors.

FamilyInfo: The study reports a negative family history of HCM. No family pedigree or detailed clinical information about relatives was provided.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001712 (Left ventricular hypertrophy); HP:0031656 (Systolic anterior motion of the mitral valve)

CaseHPOFreeText: Hypertrophic cardiomyopathy and a maximum left ventricular wall thickness of 13 mm. Echocardiography demonstrated systolic anterior motion (SAM) of the mitral valve without left ventricular outflow tract (LVOT) obstruction. The patient had no reported family history of hypertrophic cardiomyopathy. NYHA functional classification was NR.

CaseNotHPOs: HP:0032092 (Left ventricular outflow tract obstruction)

CaseNotHPOFreeText: No left ventricular outflow tract (LVOT) obstruction was reported despite the presence of systolic anterior motion of the mitral valve.

CasePreviousTesting: Patient 1 previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel covering 174 genes associated with inherited cardiac conditions. Initial genetic analysis was negative. Subsequent reanalysis of existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA from peripheral blood was analyzed using the Illumina TruSight Cardio targeted next-generation sequencing panel on an Illumina MiniSeq platform. Existing sequencing data were reexamined using an intronic hotspot analysis approach and Integrative Genomics Viewer (IGV). The MYBPC3 c.1224-80G>A variant was subsequently confirmed by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a cryptic splice acceptor site within intron 13, resulting in the retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons in the resulting transcript. Previous functional studies demonstrated abnormal RNA splicing and approximately 50% reduction in MYBPC3 transcript abundance. SpliceAI predicted a strong splice-altering effect (Δscore = 0.94). The current study did not perform patient-specific RNA functional experiments. Instead, the researchers identified the variant through reanalysis of existing next-generation sequencing data and confirmed its presence using Sanger sequencing.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: Unlike Patients 2 and 3, Patient 1 had no reported family history of HCM. Echocardiography demonstrated systolic anterior motion of the mitral valve without left ventricular outflow tract obstruction, and maximum left ventricular wall thickness was 13 mm. Although all three patients carried the same splice-altering variant, their reported cardiac phenotypes differed. This observation is consistent with variable clinical expression of MYBPC3-associated HCM, although the study did not establish the underlying causes of these differences.

PMID: 39355877

Gene: MYBPC3

HGNC ID: 7551

Case#: Patient 2; male; 74 years old at first observation; 27 mm LV wall thickness; family history of HCM

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) associated with the MYBPC3 intronic splice-altering variant c.1224-80G>A (authors classify as likely pathogenic).

FamilyInfo: Reported family history of hypertrophic cardiomyopathy. Echocardiographic evaluation demonstrated a maximum left ventricular wall thickness of 27 mm and left ventricular outflow tract (LVOT) obstruction, with a gradient of 50 mmHg. The patient was classified as NYHA functional class II.

ParentalTesting: NR – Patient had a positive family history of HCM but parental genotypes and variant segregation were not documented.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0032092 (Left ventricular outflow tract obstruction); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: Echocardiography demonstrated a maximum left ventricular wall thickness of 27 mm and left ventricular outflow tract (LVOT) obstruction with a measured gradient of 50 mmHg. The patient was classified as New York Heart Association (NYHA) functional class II, indicating mild limitation of physical activity.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: The patient previously underwent targeted next-generation sequencing using the Illumina TruSight Cardio panel covering 174 genes associated with hereditary cardiac diseases. The initial analysis produced a negative molecular result. Subsequent reanalysis of the existing sequencing data identified the MYBPC3 intronic variant c.1224-80G>A.

Genotyping Method: Genomic DNA was extracted from peripheral blood and sequenced using the Illumina TruSight Cardio panel on a MiniSeq platform. Initial bioinformatics analysis was performed using Illumina BaseSpace software. Raw sequencing data were subsequently reanalyzed using an intronic-variant hotspot approach, with variant visualization in Integrative Genomics Viewer (IGV). The identified MYBPC3 variant was validated by Sanger sequencing.

FunctionalAnalysis: The MYBPC3 intronic variant c.1224-80G>A creates a novel splice acceptor site within intron 13, resulting in the retention of 78 intronic nucleotides upstream of exon 14. This produces an in-frame insertion of 26 codons and is associated with approximately 50% reduction in MYBPC3 transcript abundance. Previous studies demonstrated the splice-altering effect through functional analyses, while SpliceAI predicted a strong effect on splicing (Δscore = 0.94). The current study identified the variant through reanalysis of existing NGS data and confirmed its presence using Sanger sequencing; it did not perform new patient-specific RNA functional experiments.

Variant: MYBPC3 NM_000256.3.1224-80G>A.

ClinVar: 693982

CAID: CA221697326

gnomAD: The MYBPC3 variant c.1224-80G>A (GRCh38: 11-47343342-C-T) is present at a low frequency in gnomAD v4; Exome allele frequency: 0.00001637; Genome allele frequency: 0.00005261; Total allele frequency: 0.00002005; The highest ancestry-specific allele frequency reported was in the African/African American population, with an allele count (AC) of 8 and allele frequency (AF) of 0.0001113.

AdditionalInfo: The variant was detected by expanding the analysis to include previously characterized intronic splice-altering regions and was subsequently confirmed by Sanger sequencing. Functional evidence for altered splicing was obtained from previously published research rather than new patient-specific RNA experiments.

Case#: 38 year old woman

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Father and one brother had HCM, no sudden deaths reported in family

ParentalTesting: Father carried the same heterozygous variant

CasePresentingHPOs: HP:0001962, HP:0031352 “palpitation and chest distress”

CaseHPOFreeText: myocardial fibrosis

CaseNotHPOs: N/A

CaseNotHPOFreeText: Unremarkable

CasePreviousTesting: N/A

Genotyping Method:PCR

FunctionalAnalysis: N/A

Variant: TNNI3 heterozygous c.235C>T (p.Arg79Cys)

ClinVar: Variation ID: 43367

CAID:N/A

gnomAD:N/A

AdditionalInfo: authors describe the variant as novel

PMID: 33817105

Gene: TNNI3

HGNC ID: HGNC:11947

Case#:27-year-old woman

DiseaseAssertion: Familial restrictive cardiomyopathy (RCM)

FamilyInfo: Strong family history of cardiac disease and sudden cardiac death

ParentalTesting:N/A

CasePresentingHPOs: “ Fatigue, dyspnoea , palpitations, atrial fibrillation, pulmonary hypertension, and fluid congestion.”

CaseHPOFreeText: age 27, she presented with progressive fatigue and limited exercise capacity, 13-year symptom-free interval, she developed rapid clinical deterioration with dyspnoea and palpitations

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: focused screening of MYH7, TNNT2, and MYBPC3 was unremarkable,

Genotyping Method: NGS

FunctionalAnalysis:N/A

Variant: TNNI3, NP_000354.4: p.Lys193Glu; NC_000019.9: g.55663258T>C. Heterozygous reported as novel

ClinVar: N/A

CAID:N/A

gnomAD: N/A

AdditionalInfo: patient improved with restored sinus rhythm and low-dose diuretic treatment and was symptom-free at the time of reporting. later had an ischaemic stroke

PMID: 35174310 Gene: TNNI3 HGNCID: HGNC:11947

Case#: Family B, Case IV.2; 8-year-old male; diagnosed at age 6

DiseaseAssertion: Dilated cardiomyopathy (DCM)

FamilyInfo: Positive family history of sudden cardiac death (SCD). The proband's brother (IV.1) died at age 2 of SCD and renal failure. Both parents (III.1 and III.2) were asymptomatic heterozygous carriers of MYL3 c.106G>T. Two unaffected siblings were tested: IV.3 was wild-type and IV.4 was heterozygous (Fig. 1b; Supplementary Fig. S2b).

ParentalTesting: Both parents (III.1 and III.2) were confirmed heterozygous carriers of MYL3 c.106G>T by PCR and bidirectional Sanger sequencing, supporting autosomal recessive inheritance (Supplementary Genetic Findings; Fig. S2b).

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0000085 (Horseshoe kidney); HP:0005162 (Reduced left ventricular ejection fraction).

CaseHPOFreeText: DCM diagnosed at age 6; heart transplantation performed shortly after diagnosis. Clinical evaluation revealed horseshoe kidney, severe left ventricular dysfunction (LVEF 15–20%), moderate right ventricular dysfunction (TAPSE 9 mm), chamber cardiomegaly on coronary CT angiography, and rapid ventricular tachycardia on ECG (Main text, Family B; Supplementary Results, p. 6).

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR (no prior diagnostic genetic testing reported before the study's exome sequencing)

Genotyping Method: Exome sequencing identified the homozygous MYL3 c.106G>T (p.Glu36Ter) variant in the proband (IV.2). PCR and bidirectional Sanger sequencing validated the variant and confirmed segregation in the parents and two unaffected siblings (Supplementary Methods; Supplementary Genetic Findings; Fig. S2b).

FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA containing c.106G>T (p.Glu36Ter). Unlike wild-type MYL3 RNA, the mutant RNA failed to rescue the cardiac phenotype, with persistent cardiac edema, ventricular dysfunction, and atrial dilation (Fig. 2; Supplementary Methods; Supplementary Movie S7).

Variant: MYL3 NM_000258.2:c.106G>T (p. Glu36Ter); homozygous nonsense variant

ClinVar: NR

CAID: CA352499542

gnomAD: NR

AdditionalInfo: The authors classified the homozygous MYL3 c.106G>T (p.Glu36Ter) nonsense variant as pathogenic. The variant introduces a premature termination codon at amino acid 36. The proband was born to asymptomatic, consanguineous (first-cousin) parents of Bakhtiyari ancestry. Family segregation and zebrafish functional studies provide supporting evidence (Supplementary Results; Supplementary Genetic Findings; Supplementary Table S2).

Case#: Family C, Case VI.1; female; diagnosed at age 2.5 years; died at age 8

DiseaseAssertion: Unclassified cardiomyopathy

FamilyInfo: Family C has a positive family history of childhood-onset cardiomyopathy and sudden cardiac death. The affected individual (VI.1) was diagnosed with cardiomyopathy at age 2.5 years and died at age 8. Three maternal relatives (V.5, V.6, and V.8) are depicted as affected and deceased in the pedigree (Fig. 1C). Both parents (V.1 and V.2) were clinically unaffected heterozygous carriers of the MYL3 c.482-1G>A splice-acceptor variant. The genotype of VI.1 could not be confirmed because DNA was unavailable.

ParentalTesting: PCR and bidirectional Sanger sequencing confirmed that both parents (V.1 and V.2) were heterozygous carriers of MYL3 c.482-1G>A. Direct testing of the affected daughter (VI.1) was not possible because DNA was unavailable. Her homozygous genotype was therefore suspected but not confirmed (Fig. 1C; Supplementary Genetic Findings).

CasePresentingHPOs: HP:0001638 (Cardiomyopathy); HP:0001645 (Sudden cardiac death).

CaseHPOFreeText: Female diagnosed with unclassified cardiomyopathy at age 2.5 years; died of sudden cardiac death at age 8 (Family C, Fig. 1C).

CaseNotHPOs: NR (no patient-specific negative HPO findings confirmed for VI.1).

CaseNotHPOFreeText: The authors reported no evidence of muscle weakness by neurological examination or history among affected individuals from the three families; however, it is unclear whether this assessment specifically included VI.1.

CasePreviousTesting: NR (no prior genetic testing reported for VI.1).

Genotyping Method: Genetic analysis of the affected individual's mother (V.2) identified MYL3 c.482-1G>A. PCR and bidirectional Sanger sequencing validated the variant and confirmed both parents (V.1 and V.2) as heterozygous carriers. VI.1 was not directly genotyped because DNA was unavailable (Supplementary Genetic Findings; Fig. 1C and S2C).

FunctionalAnalysis: A minigene splicing assay in human HEK293FT cells demonstrated that MYL3 c.482-1G>A causes abnormal RNA splicing. The predominant outcome (~75%) was skipping of the 78-bp exon 5, producing an in-frame deletion (p.Gly161_Glu186del). A less frequent outcome (~25%) was deletion of the first nucleotide of exon 5, causing a frameshift (p.Gly161Valfs*4). Both outcomes are predicted to disrupt EF-hand domains. The authors note that the minigene assay may not fully reflect in vivo splicing frequencies (Supplementary Results, pp. 7–8; Fig. 2E–I).

Variant: MYL3 c.482-1G>A (rs727503300)

ClinVar: 164486

CAID: CA013932

gnomAD: NR MYL3 c.482-1G>A was not found in the gnomAD v4 (GRCh38) region results at chr3:46,860,813. Allele frequency not reported for this variant in the searched dataset.

AdditionalInfo: The affected individual (VI.1) died at age 8, and DNA was unavailable for direct genetic testing. Both clinically unaffected parents (V.1 and V.2) were confirmed heterozygous carriers of MYL3 c.482-1G>A, suggesting that VI.1 may have inherited the variant from both parents; however, her genotype remains unconfirmed. A minigene assay demonstrated that the variant disrupts RNA splicing, predominantly causing exon 5 skipping, with a less frequent frameshift-producing splicing event. These functional findings support a damaging effect of the variant but do not establish VI.1's genotype (Fig. 1C; Fig. 2E–I; Supplementary Genetic Findings and Minigene Assay Results).

Case#: Family A, Case III.7; 38-year-old female; diagnosed at age 26

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Positive family history of HCM and SCD. Mother (II.4), brother (III.8), uncle (II.7), and cousin (III.11) died of SCD at ages 55, 26, 57, and 24, respectively. The proband's three children (IV.3, IV.4, IV.5) were homozygous for the MYL3 variant but had normal echocardiograms at ages 18, 13, and 6.

ParentalTesting: Supplementary Table S2 reports parental testing supportive of PM3 (variants in trans). However, DNA was unavailable for the proband's deceased mother (II.4), and individual parental genotypes were not specified in the supplementary genetic findings.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001653 (Mitral regurgitation); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: HCM diagnosed at age 26 following dyspnea. At age 38, echocardiography showed reverse-curvature HCM with asymmetric left ventricular hypertrophy involving anterior, anterolateral, and lateral segments; maximum wall thickness 22 mm; severe mitral regurgitation; LVEF 55%; E/e' ratio 16.4; resting LVOT gradient 9 and post-maneuver gradient 30. Holter monitoring showed no arrhythmias (Supplementary Results, pp. 5–6; Table S1; Fig. S1).

CaseNotHPOs: HP:0001324 (Muscle weakness)

CaseNotHPOFreeText: Neurological evaluation revealed normal muscle tone, strength 5/5 in upper and lower limbs, no distal or proximal muscle atrophy or fasciculations, and normal creatine phosphokinase levels.

CasePreviousTesting: Exome sequencing was performed; no rare, likely pathogenic variants in other cardiomyopathy-associated genes identified after filtering.

Genotyping Method: Exome sequencing identified the MYL3 variant; bidirectional Sanger sequencing validated the variant. Familial genotyping supported recessive inheritance (Fig. 1a).

FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA carrying c.170C>A (p.Ala57Asp). Mutant RNA showed partial phenotypic rescue but no statistically significant improvement in ventricular contractility compared with knockdown alone (Fig. 2a-d).

Variant: MYL3 NM_000258.2:c.170C>A (p.Ala57Asp); homozygous missense variant; rs139794067

ClinVar: 43121

CAID: CA013575

gnomAD: Allele frequency 0.000163 (0 homozygotes), as reported in Supplementary Table S2.

AdditionalInfo: Family A, Case III.7. Clinical characteristics and genetic findings described in the Results section (Fig. 1a and 1d-e). Functional experiments described in Fig. 2. The authors classified c.170C>A as a variant of uncertain significance (VUS).

PMID: 39682617

Gene: MYL2

HGNC ID: 7583

Case#: P2 female; age 2 years; Vietnamese family

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: MYL2 variant was reported as de novo in P2

ParentalTesting: Sanger sequencing of family members; variant was absent in the parents

CasePresentingHPOs: HP:0001644 HP:0012664 HP:4000141

CaseHPOFreeText: Dilated cardiomyopathy; reduced ejection fraction of 30%; increased diastolic cardiac diameter of 37 mm

Genotyping Method: Whole-exome sequencing using the SureSelect Human All Exon V7 kit, followed; Sanger sequencing confirmation

Variant: MYL2 c.284C>G, p.Pro95Arg; heterozygous missense variant

PMID: 34213952

Gene: TNNT2

HGNC ID: 11949

Case#: CMP-83-03; sex NR; pediatric age, exact age NR

CasePresentingHPOs: HP:0001644

CaseHPOFreeText: Biopsy proven myocarditis with dilated cardiomyopathy

Genotyping Method: Targeted next-generation sequencing

Variant: TNNT2 c.460C>T (p.Arg154Trp); heterozygous; missense single-nucleotide variant

ClinVar: 132943

CAID: CA004554

gnomAD: 0.000032

Case#:7 ¾ year old girl

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), with ventricular tachycardia and Stokes–Adams syndrome.

FamilyInfo: Parents not consanguineous, no family history of cardiovascular disease or sudden cardiac death.

ParentalTesting: Parents not consanguineous, no symptoms

CasePresentingHPOs: HP:0001639, HP:0001695, HP:0001663, HP:0001250, HP:0001678, HP:0001712 “Hypertrophic cardiomyopathy, cardiac arrest, ventricular tachycardia, seizures, atrioventricular block, left ventricular hypertrophy:”

CaseHPOFreeText: Diagnosed with cardiomyopathy in utero. Frequent cardiac arrests from 3-7, multiple seizures a year, cardiac mri showed heart enlargement, hypertrophy, after icd implant no cardiac arrests after 1 year.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: diagnosed with cardiomyopathy in utero, no other testing stated.

Genotyping Method: Whole exon sequencing

FunctionalAnalysis: protein modeling only, revealed to be “probably damaging” score 1.0

Variant: MYH7 NM_000257.3:c.2723T>C (p.Leu908Pro; p.L908P)

ClinVar: no id but is listed under https://www.ncbi.nlm.nih.gov/clinvar/RCV000158849.1/?cmd=HTOn&utm_source=chatgpt.com

CAID: N/A

gnomAD:N/A

AdditionalInfo: patient underwent ICD implantation and had no further arrests after a years time.

** PMID** : 35004917

** Gene** :MYH7

** HGNC ID** : HGNC:7577

PMID:41703309

Gene: MYBPC3

HGNC ID: 7551

PMID: 41440877

Gene: TNNT2

HGNC ID: HGNC:11949

Case#: Patient 14, male, age 6 at diagnosis; age 16 at heart transplantation

CasePresentingHPOs: HP:0001639 HP:0001723 HP:0001712

CaseHPOFreeText: interventricular septal thickness of 18 mm; ejection fraction of 77%; end-diastolic volume of 42 mL/m³; heart transplant

Genotyping Method: Next-generation sequencing using a 172-gene panel with SureSelect target enrichment and Illumina HiSeq sequencing; Sanger confirmation

Variant: TNNT2 c.311G>A (p.Arg104His); missense single-nucleotide variant; heterozygous

ClinVar: 43628

CAID: CA004294

Case#: Male, 47

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0025169, HP:0034307, HP:0001712,

CaseHPOFreeText: Severe alterations in inter ventricular septum thickness and left ventricular posterior wall thickness

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NA

Variant: NM_001276345.2:c.423G>A

ClinVar: NR

CAID: CA422532259

gnomAD: NR

AdditionalInfo: IVST, average of 19.2 mm and LVPWT; average of 11.5 mm

PMID:37067544

Gene: TPM1

HGNC ID: 12010

PMID: 36143383

Gene: MYBPC3

HGNC ID: 7551

Case#: Jenni a 7 year-old female

DiseaseAssertion: Dilated cardiomyopathy with LVNC

FamilyInfo: MYH7 maternally inherited and MYBPC3 paternally inherited

ParentalTesting: Mother has PPCM

CasePresentingHPOs: HP:0004755

heart failure and supraventicular tachycardia

CaseHPOFreeText: Intermittent Wolff-Parkinson- White

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Echocardiogram and MRI

Genotyping Method: Segregation analysis, targeted next generation sequencing

FunctionalAnalysis: electrophysiology, transplant evaluation, CT angiography

Variant: NM_000256.3(MYBPC3):c.2672G>A (p.Arg891Gln)

ClinVar:177884

CAID: CA012826

gnomAD: 11-47357493-C-T

AdditionalInfo:

PMID:41728227

Gene: MYBPC3

HGNC ID: 7551

Case#: Patient 1, individual II.1 (Fig. 2A); 22-year-old Salvadoran female

DiseaseAssertion: Restrictive cardiomyopathy (RCM) with advanced heart failure

FamilyInfo: Patient denied a family history of cardiomyopathy, although supporting records were unavailable. Her mother (I.2) was clinically unaffected at age 45 and heterozygous for both MYL3 p.Glu143Lys and MYL2 p.Gly57Glu. Other family members were unavailable for evaluation (Fig. 2A; Table I).

ParentalTesting: Mother (I.2) was confirmed heterozygous for MYL3 c.427G>A (p.Glu143Lys) and MYL2 c.170G>A (p.Gly57Glu). Paternal testing was not reported.

CasePresentingHPOs: HP:0012764 (Orthopnea); HP:0004749 (Atrial flutter); HP:0031295 (Left atrial enlargement); HP:0030718 (right atrial enlargement)

CaseHPOFreeText: Worsening fatigue and exertional dyspnea over 12 months, paroxysmal nocturnal dyspnea, palpitations, NYHA Class III–IV heart failure, and ascites suggestive of congestive hepatopathy. Echocardiography showed severe biatrial enlargement and advanced left ventricular diastolic dysfunction with preserved systolic function. Additional findings included myocardial fibrosis and myofiber disarray on biopsy.

CaseNotHPOs: NR

CaseNotHPOFreeText: At initial presentation, patient denied dizziness, syncope, and lower-extremity edema. No S4 heart sound was detected. Recurrent syncope developed later.

CasePreviousTesting: Targeted sequencing of eight sarcomere genes (ACTC, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1). Genome-wide analysis was not reported. An additional heterozygous MYL2 variant, c.170G>A (p.Gly57Glu), was identified (ClinVar Variation ID: 43458; CAID: CA009910).

Genotyping Method: Sequencing of coding exons and intron–exon boundaries of MYL3 and seven additional sarcomere genes, performed by a commercial CLIA-certified laboratory (Correlagen Diagnostics, Inc.). The specific sequencing platform was not reported.

FunctionalAnalysis: NR

Variant: MYL3 NM_000258.2:c.427G>A (p.Glu143Lys); homozygous

ClinVar: 14063

CAID: CA013774

gnomAD: MYL3 c.427G>A (p.Glu143Lys). Highest reported ancestry-specific allele frequency: 0.0002333 (0.02333%) in the Admixed American population (AC = 14). Overall AF (exomes): 0.000008209; AF (genomes): 0.00001314; AF (total): 0.000008674. https://gnomad.broadinstitute.org/variant/3-46859529-C-T?dataset=gnomad_r4.

AdditionalInfo: Patient developed recurrent syncope and received an implantable cardioverter-defibrillator. She underwent orthotopic heart transplantation six months after RCM diagnosis. Authors considered the homozygous MYL3 and heterozygous MYL2 variants likely contributors to disease, although their individual contributions were not established. Clinical and family findings are reported in Patient 1, Figure 2A, and Table I.

PatientID: IV-23

KindredID: 1

Case: M, 35Y0M, Iranian

DiseaseAssertion: assumed VHL

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

CasePresentingHPOs: HP:0002666 (Pheochromocytoma)

CaseHPOFreeText: Patient had a bilateral PCC at 31Y which was surgically removed at the time. He presently has no abnormal findings.

CaseNotHPOs: HP:0000077 (abnormality of the kidney)

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

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

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

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: R167Q (c.500G>A)

MultipleGeneVariants: N/A

Five patients with apparent sporadic pheochromocytoma/paraganglioma which turned out to be associated with an inheritable familial disease were summarized. Patient #2 was 28 Y and presented with bilateral pheochromocytoma and a mutation in the VHL gene, p.R167Q. The patient had a negative family history for VHL but genetic testing on parents was not described. Pheochromocytoma is highly specific to VHL disease.

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. Two patients were listed with this mutation, c.301_302delinsGG.

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.D121G (c.362A>G) mutation, stated in the paper as c.575A>G due to an older transcript. It was seen in family [pedigree No] 21, with an unknown number of members described as ‘VHL-affected’ with RCC. Other manifestations are possible but not clear.

Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations and 71% of the families had renal involvement. This missense mutation was detected in a patient with renal cell carcinoma (family no. 113).

GroupID: 7

DiseaseAssertion: VHL

GroupSize: 4

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: French

GroupAgeRange: N/A

GroupInfo: 4 members of this family presented with the c.525C>A germline variant of the VHL gene. Members 6548 and 6362 had unknown renal involvement. Member 6364 presented with mild renal disease. Member 6728 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, where 1 individual with this mutation is reported. It is unclear which of the current family members the previously published individual corresponds to.

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

Variant: p.Y175* (c.525C>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 1298905, https://www.ncbi.nlm.nih.gov/clinvar/variation/1298905/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion; stop_gained

CivicName: Y175* (c.525C>A)

MultipleGeneVariants: N/A

PMID: 22133049

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 398

KindredID: 398

Case: Sex Unknown, 28Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CaseHPOFreeText: CNS hemangioblastoma and pancreatic cyst or tumor.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0000107; HP:0009711 (Pheochromocytoma, Clear cell renal cell carcinoma, Renal cyst, Retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Exon 2 Deletion (c.341-?_463+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant; deletion

CivicName: Exon 2 Deletion

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 Y175* (c.525C>A) germline variant of the VHL gene was found in a 15 year old patient (ID 1) presenting with CNS hemangioblastoma and renal cystic lesion. The variant is noted as likely de novo (i.e. “parents were unaffected even if one or both parents were not available (n/a) for genetic testing”). Father and siblings were analyzed but no details were provided. Based on likely de novo assertion, it’s assumed that father and siblings were negative for this mutation.

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 V155G (c.464T>G) germline mutation of the VHL gene was found in a 43 yr old VHL patient with retinal hemangioblastomas and pheochromocytoma (index case 2). Parents, siblings and nephew were negative for the mutation confirming that this variant was de novo in the proband. No phenotype details are noted for these family members.

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 N141Ifs*12 (c.422_440del) germline variant of the VHL gene was found in a 23 year old patient (ID 80) presenting with CNS hemangioblastoma and renal cystic lesion. Parents were negative for the mutation, confirming it as de novo in the proband. No phenotype details are noted for these family members.

426 unrelated subjects with a clinical diagnosis ranging from VHL syndrome to sporadic potentially VHL-related tumours were analyzed for mutation in the VHL gene. The analysis was carried out by the VHL referral laboratory, Department of Pediatrics at the University of Padua. High-molecular-weight genomic DNA was extracted from peripheral blood leucocytes by standard protocols. Mutation scanning of the VHL gene for identification of point- or small-size mutations was conducted on the entire coding sequence and intron–exon boundaries by polymerase chain reaction (PCR) amplification, denaturating high-performance liquid chromatography (DHPLC), and direct sequence analysis. Genetic analysis was also carried out for 200 unaffected control individuals. A VHL alteration was found in 111 unrelated probands and 2 unaffected control. Mutation Q195*(c.583C>T) was identified in proband 262. The proband had a family history of VHL disease. Proband 262 presented with CNS hemangioblastoma, retinal capillary hemangioma. ACMG: 'PP4' because the patient's phenotype and family history are highly specific for a disease with single genetic etiology.

PatientID: II-1

KindredID: 1

Case: F, 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

KindredID: 105

GroupID: 37

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

DiseaseAssertion: VHL

GroupInfo: Kindred no.105 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

GroupPresentingHPOs: N/A

GroupHPOFreeText: No phenotypic information is listed for this kindred.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: c.694C>T (p.R232*)

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence:

MutationType: stop_gained

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

MultipleGeneVariants: N/A

GroupID: 53

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.194C>G variant causing a Ser65Trp missense mutation (noted in the paper as c.407C>G due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: This family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.S65W (c.194C>G)

LegacyVariant: p.S65W (c.407C>G)

ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: S65W (c.194C>G)

MultipleGeneVariants: N/A

PMID: 9829911

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

GroupID: 141

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: Unknown

GroupNumberFemales: Unknown

GroupEthnicity: Unknown

GroupAgeRange: Unknown

GroupInfo: This family group had a history of clinically confirmed VHL disease. Members of this family were found to harbour the c.490C>T variant causing a p.Gln164* stopgain (noted in the paper as c.703C>T due to Latif reference transcript being used). It was noted that this family had no history of pheochromocytoma's.

GroupPresentingHPOs: N/A

GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: This family had no history of pheochromocytoma's.

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Q164* (c.490C>T)

LegacyVariant: p.Q164* (c.703C>T)

ClinVarID: 223228 https://www.ncbi.nlm.nih.gov/clinvar/variation/223228/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: Q164* (c.490C>T)

MultipleGeneVariants: N/A

93 families examined at the Clinical Center of the National Institutes of Health (Bethesda, MD) underwent genetic testing for germline mutations of the VHL gene. Whole blood was extracted and genomic DNA was amplified by PCR and products were sequences using a cycle sequencing kit with dye-labeled terminators and automatically sequenced. This missense mutation was found in a VHL type 1 family (lineage 6). The variant was reported as c.475T>A (AF010238.1) and was mapped to W88R (c.262T>A) (NM_000551.3). This family is stated as being previously reported in PMID 7728151 and/or 8956040. Both these reports include a family presenting with this variant and it is unclear if one or both coincide with the current family.

PatientID: None

KindredID: VHL26

Case: F, 36Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

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

CasePresentingHPOs: HP:0002668 (Paraganglioma)

CaseHPOFreeText: The patient had one malignant abdominal paraganglioma.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHC/SDHD

PreviouslyPublished: N/A

SupplementalData: Table 1 of Supplementary

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: The patient had no LOH found in the BAC array CGH data. Somatic VHL variant c.302T>A was found in the tumor tissue.

MutationType: exon_loss_variant

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, were analyzed using expression profiling, BAC array comparative genomic hybridization and somatic mutation screening. The authors describe 25 patients with germline VHL mutations and pheo/pg tumours in the Supplementary Material Table S1. Family history and other phenotypes of the patients are not described. Age reported represents age of diagnosis. Three patients were found with the same mutation in the VHL gene (c.500G>A; p.Arg167Gln): a 25Y male, 15Y female, and a 16Y female all with benign pheochromocytoma.

PatientID: III-2

KindredID: 1

Case: F, Age Unknown, Chinese (East Asian)

DiseaseAssertion: Asymptomatic

FamilyInfo: A total of 9 of family members (4 male; 5 female) in a 3 generation family were associated with VHL at the splice mutation: c.464-1G>C. 5 members underwent cerebellar HB lesion resections, including her mother and uncles, and 1 member had RCC. (See Fig 4).

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.464-1G>C

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223220 https://www.ncbi.nlm.nih.gov/clinvar/variation/223220

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: splice_site_variant

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

MultipleGeneVariants: N/A

PatientID: 18

KindredID: 18

Case: F, 50Y0M, Ethnicity unknown

DiseaseAssertion: pancreatic endocrine tumor

FamilyInfo: None

CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumor)

CaseHPOFreeText: See Table 1 for more information

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: CA040847 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.407T%3EC

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.481C>G) was recorded in the paper as c.694C>G due to a difference in transcript sequence. It was found in one patient with a hemangioblastoma of the central nervous system. Any family information is unknown. No other phenotypes described.

PatientID: 35

GroupID/ KindredID: 35

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: hemangioblastoma

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: other phenotypes unknown.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.C162W (c.486C>G)

LegacyVariant: p.C162W (c.699C>G)

CaseProblemVariantFreeText: N/A

ClinVarID: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

41 non-related patients with retinal capillary hemangioma 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 in 33 patients based on the presence of other severe VHL lesions (spinal hemangioblastoma, cerebellar hemangioblastoma, renal cysts, pancreatic cyst, renal carcinoma, and pheochromocytoma), molecular genetic testing, and/or family history. VHL germline mutations were identified in 27 out of 29 VHL families screened with molecular genetics. Blood samples were genetically tested using PCR-SSCP sequencing. One patient with VHL-related retinal angiomatosis was found to have germline nonsense (c.499C>T) mutation in the VHL gene. This variant was reported as c.712C>T (AF010238.1) and mapped to p.R167W (c.499C>T) (NM_000551.3).

GroupID: None (14)

DiseaseAssertion: VHL

GroupSize: 1

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: This family group of 1 individual has clinically confirmed VHL disease presenting with retinal angiomatosis. This individual was found to harbor a c.340+1G>A splice variant (noted in the paper as c.553+1G>A 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

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+1G>A

LegacyVariant: c.553+1G>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: missense_variant;transition; splice_site_variant

CivicName: Splice Site (c.340+1G>A)

MultipleGeneVariants: N/A

PatientID: VHL-1

KindredID: 1

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: Positive family history.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

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

CaseHPOFreeText: Multiple hemangioblastoma of the CNS and spinal cord.

CaseNotHPOs: HP:0001737, HP:0002666, HP:0009711 (pancreatic cysts, pheochromocytoma, retinal capillary hemangioma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113*(c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113*(c.337C>T)

MultipleGeneVariants: N/A

PatientID: VHL-17

KindredID: 17

Case: Sex Unknown, Age Unknown, Italian

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: Forty-three index cases were referred to the Service of Medical Genetics, Genova, for germline mutation analysis in the VHL gene between 1995 and 2008.

CasePresentingHPOs: HP:0010797; HP:0002666; HP:0001732 (Hemangioblastoma, Pheochromocytoma, Abnormality of the pancreas)

CaseHPOFreeText: CNS hemangioblastoma and multiple pheochromocytomas. Clinical classification: A2.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

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

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: 0.000007954, 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: III.1

KindredID: 3

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: The patient inherited this mutation from his healthy mother (II:2). The patient's father (II:1) was the proband and had two VHL mutations, one of which he passed down to his son (exon 1-3 deletion). The father had hemangioblastomas and pancreatic cysts. The grandfather (I:1) had a P81S mutation but was otherwise healthy. Refer to pedigree in Figure 1-C.

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

CasePresentingHPOs: HP:0001737, HP:0006880, HP:0009711 (pancreatic cysts, cerebellar hemangioblastoma, retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: RET/SDHB/SDHD/SDHC

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

SupplementalData: Yes, File 1 for methods.

Variant: Exon 1-3 loss

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion and Splice Region (c.340+5G>C)

MultipleGeneVariants: Germline, VHL, c.340+5G>C

GroupID: 5

DiseaseAssertion: 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:0005553; HP:0006748; HP:0030405 (hemangioblastoma, renal cell carcinoma; adrenal pheochromocytoma, pancreatic endocrine tumor)

GroupHPOFreeText:  All 3 family members had cerebral or spinal hemangioblastomas, 2 had adrenal pheochromocytomas with an adrenalectomy, 2 had renal cell carcinomas with a nephrectomy, and one had a pancreatic endocrine tumor (see table S2).

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2.

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

PMID: 26622630

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: 30

KindredID: 7

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 2 members of this family, IDs #30 (24Y, F) and #31 (8Y, M) presented with the same variant and pheochromocytoma.

CohortInfo: Thirty-one subjects were included in this study consisting of 16 SDHB mutation carriers and 15 subjects with VHL disease followed-up between 1975 and 2008. Subjects were included in the study if they had complete imaging from the base of the skull to the pelvis and measurements of urinary or plasma catecholamines. The case-notes and hospital databases were examined for the required data, which included: age at first symptom/diagnosis, family history, disease penetrance, site and size of tumor, symptoms, secretion of catecholamines, multifocal disease, metastatic disease, treatment and disease outcome.

CasePresentingHPOs: HP:0009711 (Pheochromocytoma)

CaseHPOFreeText: Synchronous multifocal pheochromocytoma. 24Y at VHL diagnosis.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V155E (c.464T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351756032, https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=CA351756032

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V155E (c.464T>A)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation, VHL T152fs (c.455insA) is also mapped to p.L153Tfs*21 (c.456dupA) due to a redundancy in the codon here. It was found in a VHL patient with retinal angiomas diagnosed at 24Y.

GroupID: 71

DiseaseAssertion: assumed VHL

GroupSize: 5

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 5 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.407T>C) was found in 2 VHL families with 5 patients altogether.

GroupPresentingHPOs: HP:0009711; HP:0006880; HP:0005584 (retinal capillary hemangioma; cerebellar hemangioblastoma; renal cell carcinoma)

GroupHPOFreeText: 4 patients had cerebellar hemangioblastoma (CHB), 3 had renal cell carcinoma (RCC); and 3 had retinal capillary hemangioma (RH). Mean ages for each diagnosis follows: 25Y (RH), 43Y (CHB) and 41Y (RCC).

GroupNotHPOs: HP:0002666 (pheochromocytoma)

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplementary Table S1.

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

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation: VHL H125fs (c.374insA) was found in a VHL type 1 family of 3. One family member had retinal angiomas diagnosed at15Y, one had hemangioblastomas of the cerebellum diagnosed at 20Y, and one had renal cell carcinoma diagnosed at 38Y.

Genotype-phenotype correlations of 573 VHL patients from 200 kindreds were analyzed and confirmed that higher risk of pheochromocytoma is associated with missense mutations that result in substitution of a surface amino acid or that disrupt the structural integrity of the VHL gene product (pVHL). Age-related risks of retinal hemangoblastomas and renal cell carcinoma were higher in patients with nonsense or frameshift mutations. Southern blot and/or MLPA analysis by whole blood detected this mutation. The E94* (c.280G>T) nonsense mutation was found in 2 VHL families with 6 patients altogether. All six had retinal hemangioblastomas and 2 had cerebellar hemangioblastomas.

PMID: 19215943

Gene: VHL

StandardizedReferenceSequence: NM_000551.3

PatientID: V-6

KindredID: 1

Case: F, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma. Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: V-4

KindredID: 1

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: 13 affected individuals in this family were found. The p.Tyr112Asn (c.334T>A) mutation of the VHL gene cosegregated with the disease in all five tested affected individuals from the family (V-5, VI-1, VI-2, VI-3, and VII-1). 7/13 have had renal cell carcinoma. Other manifestations of the disease in this family include renal cysts, retinal angioma, and CNS hemangioblastoma. There was one case of pheochromocytoma (VII-1). No other pheochromocytomas or related neuroendocrine tumors of the pancreas or adrenal gland have been diagnosed or recognized retrospectively by review of medical records and recall of relatives. The mutation was also found in three asymptomatic relatives (VII-2, VII-3, and VII-4).

CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

CaseHPOFreeText: Age of onset not provided. Deceased.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.Y112N (c.334T>A)

LegacyVariant: T547A

CaseProblemVariantFreeText: N/A

ClinVarID: 2228, https://www.ncbi.nlm.nih.gov/clinvar/variation/2228/

CAID: N/A

gnomAD: N/A

VariantEvidence: Variant is inferred in this patient from clinical findings and family history.

MutationType: missense_variant;transversion

CivicName: Y112N (c.334T>A)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: M, 39Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: None: Among missense mutations observed in our patients, 486C>G (C162W) was reported in Caucasian type 2 VHL families, but no member with pheochromocytoma has been found in this patient's families

CasePresentingHPOs: HP:0010797 (hemangioblastoma)

CaseHPOFreeText: Multiple involvements of the CNS HB. '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 1 has all. (See Table 1).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

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

SupplementalData: N/A

Variant: p.C162W (c.486C>G)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVar: 223227 https://www.ncbi.nlm.nih.gov/clinvar/variation/223227/

CAID: CA357016 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.486C%3EG

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: C162W (c.486C>G)

MultipleGeneVariants: N/A

PatientID: 19

KindredID: 6

Case: F, Age unknown, Chinese

DiseaseAssertion: Asymptomatic

FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband's uncle's granddaughter (ie. the granddaughter of uncle 2), patient 19, was asymptomatic at the time of the study.

CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, 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: p.S65L (c.194C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

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

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: S65L(c.194C>T)

MultipleGeneVariants: N/A

A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. Seven unrelated probands were genetically confirmed with this familial mutation. The first proband was a male patient from family #71 who was diagnosed with RCC at 27Y, multiple pancreatic cysts/tumors at 24Y, and pheochromocytoma at 24Y. His mother, of unknown age, was asymptomatic. This kindred was also published in an earlier paper by Wang et al., 2014 (PMID 24581539). The second proband was a female patient from family #72 who was diagnosed with CNS hemangioblastoma at 37Y, RCC at 37Y, multiple pancreatic cysts/tumors at 37Y, and pheochromocytoma at 39Y. Her father was diagnosed with CNS hemangioblastoma at age 65Y, RCC at 54Y, and multiple pancreatic cysts/tumors at 67Y. Her first sister, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 22Y. Her second sister was diagnosed with CNS hemangioblastoma at 39Y and multiple pancreatic cysts/tumors at 36Y. Her third sister was diagnosed with retinal angioma at 34Y and multiple pancreatic cysts/tumors at 32Y. The third proband was a female from family #73 who was diagnosed with CNS hemangioblastoma at 26Y and retinal angioma at 13Y. Her mother was diagnosed with CNS hemangioblastoma at 38Y, retinal angioma at 25Y, and multiple pancreatic cysts/tumors at 52Y. This kindred was also published in an earlier paper by Wang et al., 2014 (PMID 24581539). The fourth proband was a female from family #74 who was diagnosed with CNS hemangioblastoma at 16Y. Her mother was diagnosed with pheochromocytoma at 36Y. The fifth proband was a male from family #75 diagnosed with pheochromocytoma at 32Y. The sixth proband was a male from family #76 who was diagnosed with pheochromocytoma at 26Y. His father, who was not genetically confirmed with the mutation, was diagnosed with pheochromocytoma at 64Y. His uncle, who was not genetically confirmed for the mutation, was diagnosed with pheochromocytoma at 53Y. His cousin (son of uncle) was diagnosed with RCC at 36Y and pheochromocytoma at 36Y. The seventh proband was a female from family #77 who was diagnosed with CNS hemangioblastoma at 25Y. Her mother, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 51Y, pancreatic lesions at 46Y, and pheochromocytoma at 25Y. Her first aunt, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 27Y. Her cousin (daughter of first aunt), who was not genetically confirmed with the mutation, was diagnosed with pheochromocytoma at 31Y. The grandson of her first aunt, who was not genetically confirmed with the mutation, was diagnosed with pheochromocytoma at 9Y. Her second aunt, who was not genetically confirmed with the mutation, was diagnosed with CNS hemangioblastoma at 43Y, RCC at 36Y, and multiple pancreatic cysts/tumors at 48Y. Her cousin (son of second aunt), who was not genetically confirmed with the mutation, was diagnosed with RCC at 21Y, multiple pancreatic cysts/tumors at 21Y, and pheochromocytoma at 16Y. All seven kindreds were also published in a later paper by Wang et al., 2018 (PMID: 29330336.)

PatientID: 123

KindredID: 43

Case: M, Age 60Y0M, Chinese

DiseaseAssertion: VHL

FamilyInfo: The proband (patient 122) had a father who was genetically confirmed with the mutation. The patient's father presented with a CNS hemangioblastoma at 27, renal cell carcinoma at 48, and multiple pancreatic cysts/ tumors at 60.

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

CaseHPOFreeText: The proband's father (patient 123) presented with a CNS hemangioblastoma at age 27, renal cell carcinoma at age 48, and multiple pancreatic cysts/tumors at age 60.

CaseNotHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, 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.W117R (c.349T>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: CA351753664; https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_000551.3%3Ac.349T%3EA

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: W117R (c.349T>A)

MultipleGeneVariants: N/AcDNAposition:349