Case#: 1. Patient II-4 43 years

DiseaseAssertion: Hypertrophic cardiomyopathy and left ventricular noncompaction

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

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

Genotyping Method: Next- generation sequencing and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 2 Patient II-5 46 years old

DiseaseAssertion: HCM and LVNC

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 3 Patient II-1 10 years

DiseaseAssertion: left ventricular noncompaction

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case#: 4 Patient III-2 14 years

DiseaseAssertion: HCM and LVNC

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

Genotyping Method: NGS and sanger sequencing

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

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

Clinvar: 410264

CAID: CA16614451

gnomAD: NR

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

Case2: Full term male

DiseaseAssertion: poor feeding, respiratory distress, and cyanosis

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

ParentalTesting:

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

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

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

ClinVar: 3329883

CAID: NR

gnomAD: 1-2573220-G-A

AdditionalInfo: NR

Case1: gestational age 40 weeks female

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

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

ParentalTesting: c.2373_2374insG mutation found in the mother

CasePresentingHPOs:HP:0025169,

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method:

FunctionalAnalysis: NR

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

ClinVar:2152664

CAID: CA147231745

gnomAD:NR

AdditionalInfo:NR

Case#:male, 41, DCM

DiseaseAssertion:dilated cardiomyopathy

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

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

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

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

CaseNotHPOs:HP:0000822, HP:0003077

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

CasePreviousTesting:No reports of previous testing

Genotyping Method:whole-exome sequencing and Sanger sequencing

FunctionalAnalysis:not reported

Variant:c.547C>T p.Arg183Trp

ClinVar:43628

CAID:CA004294

gnomAD:Overall allele frequency: 0.000001239

AdditionalInfo:not reported

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

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

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

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

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

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

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

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

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

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

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

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

ClinVar: 1473634

CAID: Not reported.

Gene:MYBPC3

HGNC: HGNC: 7551

PMID: 33803538

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

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

Case#: P16, 17 year old male

DiseaseAssertion: left ventricular noncompaction cardiomyopathy

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

ParentalTesting: NR

CasePresentingHPOs: NR

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

CaseNotHPOs: NR

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

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

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

FunctionalAnalysis: NR

Variant: NM_005159.5:c.329>T

Clinvar: 2137647

CAID: CA391631478

gnomAD: Exact frequency not provided

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

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

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

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

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

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

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

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

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

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

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

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

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

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

CAID: N/A

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

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

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

CAID: N/A

gnomAD: N/A

PMID: 32824488

Gene: MYBPC3

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

Case1: 40-year-old Chinese male

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

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

ParentalTesting: NR

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

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

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

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

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

FunctionalAnalysis:NR

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

ClinVar:NR

CAID:UnregisteredVariant

gnomAD:NR

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

DiseaseAssertion:hypokinetic-dilative cardiomyopathy

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

ParentalTesting:n/r

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

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

CaseNotHPOs: HP:0031972, HP:0031972

CaseNotHPOFreeText:Coronary angiography showed no significant stenosis.

CasePreviousTesting:Testing method and scope

GenotypingMethod:n/a

FunctionalAnalysis:not reported

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

Clinvar:not known

CAID:CA391630526

gnomAD:n/r

AdditionalInfo:n/r

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

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

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

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

CasePresentingHPOs:HP:0001639

CaseNotHPOs: N/A

CasePreviousTesting: N/A

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

FunctionalAnalysis: N/A

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

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

ClinVar: N/A

CAID:N/A

gnomAD: N/A

Gene:MYBPC3

PMID:36011256

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

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

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

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

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

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

CaseNotHPOs: HP:0000822; HP:0000819

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

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

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

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

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

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

CAID: N/A

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

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

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

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

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

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

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

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

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

CaseNotHPOs:not reported

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

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

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

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

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

ClinVar:not found

CAID:CA004513

gnomAD:not found

AdditionalInfo:not reported

Case6: 48 year old male

DiseaseAssertion: Carried the MYBPC3 E619K mutation

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

ParentalTesting:NR

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

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

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

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

ClinVar:161303

CAID:CA011336

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

AdditionalInfo:NR

Case 3: A 64 year old female

DiseaseAssertion: The case carried the novel MYH7 K637E mutation

FamilyInfo: Her mother died of a suspected but unconfirmed cardiac cause; thus, this was regarded as a non-FDC case. Two healthy sisters declined participation in the study.

ParentalTesting:NR

CasePresentingHPOs: HP:0003674, HP:0034307, HP:0002372, HP:0011675, HP:0005110

CaseHPOFreeText: Slowly from onset of symptoms at the age of 42 years, and received HTX in her sixth decade. Has left ventricular end diastolic diameter (in mm and indexed by body surface area (cm/m2)), 81mm and then 4.2m2. LVEF as 15%, ECG as normal. Arrhythmia as atrial fibrillation. NYHA as 4. Clinical status as heart transplantation. CAG has a normal level.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis: NR

Variant:NM_000257.4:c.1909A>G

ClinVar:1329402

CAID:CA389049558

gnomAD:NR

AdditionalInfo:NR

Case#: 30 year old female athlete

DiseaseAssertion: Subclinical hypertrophic cardiomyopathy

FamilyInfo: Her mother has HCM and the same ACTC1 gene change. Her grandmother and uncle on her mothers side died suddenly.

ParentalTesting: Her mother tested positive for the ACTC1 gene change and there isn't any information about the father.

CasePresentingHPOs: NR

CaseHPOFreeText: The patient did not have dizziness, fainting, trouble breathing or chest pain. Her heart muscle was not thickened.

CaseNotHPOs: NR

CaseNotHPOFreeText: The patient sometimes felt her heart beating unusually during exercise. A heart MRI showed small changes in her heart muscle and heart valve.

CasePreviousTesting: The patient had an ECG, heart ultrasound, heart monitor and heart MRI

Genotyping Method:Sanger sequencing was used to test the ACTC1 gene.

FunctionalAnalysis: NR

Variant: ACTC1 p.Val11Leu

Clinvar: 2947021

CAID: CA391633409

gnomAD: NR

AdditionalInfo: The patient continued playing competitive sports and had regular heart checkups.

Case#: Family 1, individual II-5

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The proband has a family history of DCM. His father and brother also had DCM and died from heart failure at ages 69 and 63 respectively. The disease follows an autosomal dominant inheritance pattern.

ParentalTesting: Want reported, his father had DMC but this article does not confirm genetic testing of his parents.

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644) & left ventricular systolic dysfunction (HP:0005162)

CaseHPOFreeText: The proband was diagnosed with DCM at age 45 and received medication for heart failure. At the time of the study he was 66 years old. His echocardiogram showed an enlarged left ventricle and reduced heart function with an ejection fraction of 33%.

CaseNotHPOs: NR

CaseNotHPOFreeText: The researchers reported no other structural heart diseases or conditions contributing to DCM in the affected family members, including coronary heart disease, valvular heart disease, viral myocarditis and hypertension.

CasePreviousTesting: ECG, clinical examination and routine laboratory testing were part of the study assessment. The probands echocardiogram showed a left ventricular end diastolic diameter of 63 mm and an ejection fraction of 33%.

Genotyping Method: Genome wide microsatellite screening, genetic linkage analysis, whole exome sequencing and sanger sequencing.

FunctionalAnalysis: Laboratory experiments showed that the KLF13 E144X mutation reduced the proteins ability to activate the heart related genes ACTC1 and MYH7. The mutation also affected DNA binding cooperation with GATA4 and normal nuclear localization.

Variant: KLF13 c.430G >T

Clinvar: NR

CAID: CA391891162

gnomAD: The researchers reported that the variant was absent from gnomAD and other population databases at the time of their study. No numerical allele frequency was provided.

AdditionalInfo: The proband is a male from a 4th generation Chinese family. His KLF13 mutation was associated with familial DCM. the researchers found that the mutation was shared by affected family members and was absent from unaffected family members and 418 unrelated healthy controls.

Case#: Family 3, III-4

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The family had multiple cases of DCM consistent with autosomal dominant inheritance.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText: Female age 41 with DCM. her left ventricular end diastolic diameter was 58 mm and her ejection fraction was 43%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The C199R mutation reduced KLF13 ability to activate ATC1 and MYH7 bind DNA and work together with GATA4.

Variant: KLF13 c.595T>C

Clinvar: NR

CAID: CA391512228

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The variant was associated with familial aDCM and was not detected in the 418 healthy controls.

Case#: Female, 4 months, Swedish

DiseaseAssertion: dilated cardiomyopathy

FamilyInfo: Strong family history of DCM and faily history of SCD due to DCM. Maternal grandfather had enlarged left ventricle.

ParentalTesting:

CasePresentingHPOs: HP:0005162, HP:0031295, HP:0001653,

CaseHPOFreeText: enlarged left ventricle,

CaseNotHPOs:HP:0011947

CaseNotHPOFreeText: circulatory collapse

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID: CA004727

gnomAD:NR

AdditionalInfo: During cardiac catheterization, cardiac resuscitation due to circulatory collapse was needed.

Case1: Male, 37 years old, Colombian

DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy

FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315

CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation

FunctionalAnalysis: NR

Variant: NM_000432.3:c.260G>C

ClinVar: 43461

CAID: CA009968

gnomAD: NR

AdditionalInfo: NR

Case#: 2 year old, male, from Yunnan Province, China

DiseaseAssertion: Restrictive cardiomyopathy

FamilyInfo:no family history of sudden cardiac death or cardiomyopathy

ParentalTesting: Sanger Sequencing

CasePresentingHPOs:HP:0034031, HP:0001635, HP:0002240,

CaseHPOFreeText:a little puffiness of the eyelids, jugular veins were full but not inflamed, atypical heart beat, edema of the lower limbs, bi-atrial enlargement, left ventricular ejection fraction of 64.6%, normal septal and ventricular wall thickness, trace pericardial effusion atrial and ventricular septum had uneven signals in the localized areas on perfusion imaging under resting state, and gadolinium-delayed enhancement showed a suspicious stripe enhancement of the septum, (Figures 1-3)

CaseNotHPOs:OMIM:145500, HP:0000819, HP:0001698,

CaseNotHPOFreeText: no history of connective tissue disease or radiation therapy, no endocardial thickening

CasePreviousTesting: electrocardiogram, cardiac magnetic resonance,

Genotyping Method: Whole-exome sequencing, sanger sequencing

FunctionalAnalysis: NR

Variant:heterozygous (c.574C > T, p.Arg192Cys) TNNI3

ClinVar: 165510

gnomAD: not found

Case#: Single proband ; 63-year-old female; palpitations at presentation July 2025; HCM diagnosis established at age 63

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM) complicated by apical left ventricular aneurysm and mid-ventricular obstruction⁠

FamilyInfo: No family history of cardiac disease or sudden cardiac death at a young age reported. Both parents deceased (one of cancer, one of natural causes at age 92), neither with reported cardiovascular disease; proband has no siblings. Only first-degree relative is her son, who carries the KCNJ5 c.464G>A variant but not the MYBPC3 c.278delA variant, and has a normal echocardiogram with no myocardial hypertrophy. No pedigree beyond the son (Fig. 3B).⁠

ParentalTesting: Not performed; both parents deceased, no DNA available; authors state a valid familial segregation analysis could not be performed. Only one family member (son) was available for cascade Sanger screening.⁠

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0001649 (Tachycardia), palpitations; HP:0001712 (Left ventricular hypertrophy).

CaseNotHPOFreeText: No history of hypertension, diabetes, or hyperlipidemia. Phenocopies excluded: no extra-cardiac manifestations of Fabry disease and GLA testing negative; cardiac amyloidosis excluded (no apical sparing, normal serum free light chains, negative serum protein electrophoresis and immunofixation); no significant coronary stenosis on coronary CT angiography. No QT prolongation or features of Andersen–Tawil syndrome on ECG.

CasePreviousTesting: Whole exome sequencing identified both variants; all rare and known variants validated by Sanger sequencing, with cascade Sanger screening in available one family member. No prior genetic testing reported before this episode.

Genotyping Method: Targeted region capture with next-generation high-throughput sequencing (whole exome, exonic plus flanking regions); variants confirmed by bidirectional Sanger sequencing. Cascade screening by Sanger in the son. MYBPC3 variant absent from 1000 Genomes, ESP6500, ExAC, and the Besuper local database. KCNJ5 variant absent from 1000 Genomes and ESP6500, ExAC frequency, absent from local Basenhall controls.⁠

FunctionalAnalysis: None performed; authors list absence of functional studies and lack of mRNA-level validation as limitations. MYBPC3 frameshift predicted to trigger nonsense-mediated decay.⁠

Variant: MYBPC3 NM_000256.3:c.278delA (p.Lys93ArgfsTer3); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified Likely Pathogenic by ACMG (PVS1, PM2). Second variant: KCNJ5 NM_000256.3:c.464G>A (p.Arg155Gln); heterozygous; exon 2; novel, not in ClinVar or HGMD; classified VUS (PM2, PP3). Note the paper's KCNJ5 accession is written as NM_000256.3, which is the MYBPC3 transcript, most likely a typo in the article Pepper please conform for me the correct KCNJ5 accession

ClinVar: No ClinVar record for either variant; nearby KCNJ5 missense variants c.451G>A, c.452G>A, c.470T>G, and c.473C>G are documented as pathogenic/likely pathogenic for long QT syndrome or aldosteronism, and downstream frameshift/nonsense variants at the MYBPC3 locus are classified pathogenic or likely pathogenic.

CAID:Not found.

gnomAD: No allele frequency available, so no MAF to report.

PMID: 42428486

Gene: MYBPC3

HGNC: HGNC:7551

AdditionalInfo:Single-case report, no case numbering system used. Treated with dapagliflozin, metoprolol, rivaroxaban, and recombinant human BNP for 13 days, discharged on the first three; mexiletine added at 1-week follow-up for persistent palpitations. ICD recommended but declined due to financial constraints; 3-month follow-up showed good adherence with occasional palpitations and no serious arrhythmic events. Authors conclude MYBPC3 c.278delA is likely pathogenic for HCM, while the KCNJ5 variant shows no clinical phenotype in the proband or her son and may be incidental or a modifier.⁠

Case1:eight-year-old female

DiseaseAssertion: Restrictive cardiomyopathy (RCM)

FamilyInfo: The patient's parents denied any positive family history of cardiac attacks, cardiovascular issues, hypertension, or coronary artery diseases. There was also no reported history of diabetes or obesity among family members. No inherited diseases, including cardiomyopathies or metabolic disorders, were identified in the family history

ParentalTesting: NR

CasePresentingHPOs:HP:0012378, HP:0001695, HP:0100539, HP:0031352, HP:0034030

CaseHPOFreeText:bilateral pedal edema, shortness of breath after engaging in physical activity, typically lasting for 15 min, enlarged bilateral atrium, segmental thickening of the interventricular septum, segmentally diffuse reduction and lack of coordination in ventricular wall pulse amplitude, mild mitral regurgitation, and diminished left ventricular systolic and diastolic function identified by increased parameters of early diastolic velocity (E wave) and low late filling velocity (A wave) (Figure 1A) abnormal bilateral atrial signals, premature atrial beats, junctional ectopic beats, first-degree atrioventricular block, complete right bundle branch block, prolonged QT interval, and abnormal Q wave (Figure 1B).

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: echocardiography, genetic screening, imaging assessments, blood gas analysis, blood cell counts, carbon dioxide retention

Genotyping Method: whole-exome sequencing (WES)

FunctionalAnalysis: computational analysis

Variant:TNNI3 c.509G>A p.R170Q

ClinVar:165516

gnomAD: not found

Case1: Female, 23 years old, ethnicity not stated

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Mother, brother, and sister carry the same MYL2 mutation. Mother has phenotypic HCM without scar or high-risk features for sudden cardiac death. Sister and brother remain phenotypically negative with yearly imaging.

ParentalTesting: Maternal testing confirmed — mother carries the same MYL2 mutation and has phenotypic HCM. Paternal testing not reported.

CasePresentingHPOs: HP:0011675, HP:0001279, HP:0001962, HP:0004756

CaseHPOFreeText: During a sprinting drill, she developed a 42-second episode of polymorphic VT with spontaneous termination. The ambulatory rhythm monitoring showed a ~4% premature ventricular contraction (PVC) burden without sustained or nonsustained VT. CPET 2 demonstrated monomorphic nonsustained VT at peak exertion. Given exercise-induced polymorphic VT, she underwent placement of a subcutaneous implantable cardioverter-defibrillator (ICD) for secondary prevention. In the emergency department, high-sensitivity troponin rose from 105 to 303 ng/L. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis

CaseNotHPOs:HP:0100749, HP:0002094, HP:0031972, HP:0001714

CaseNotHPOFreeText: Normal LV size and function on echocardiography. Normal strain. Repeat cardiac MRI showed complete resolution of LGE. Normal biventricular size, thickness, and function without LGE or scar on third MRI. No sustained VT/VF after ICD placement. Normal complete blood count and basic metabolic panel. Coronary CT angiography unremarkable.

CasePreviousTesting: She underwent coronary computed tomography angiography to rule out ischemia and anomalous coronary origins, which was unremarkable. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis. Follow-up transthoracic echocardiography revealed normal LV size and function with normal strain, and repeat cardiac MRI showed complete resolution of LGE. She underwent maximal cardiopulmonary exercise testing (CPET), exercising for 13 minutes and 15 seconds, achieving 15 METs with a VO2 max of 40.4 mL/kg/min, which demonstrated frequent PVCs without nonsustained ventricular tachycardia (VT). Normal complete blood count and basic metabolic panel, aspartate aminotransferase, 38 U/L, alanine aminotransferase, 38 U/L, magnesium 2.2 mg/dL, thyroid-stimulating hormone, 1.96 μIU/mL, hemoglobin A1c, 5.8%.

Genotyping Method: Comprehensive genetic testing identified a pathogenic MYL2 variant.

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.4:c.173G>A

ClinVar: 14067

CAID: CA009915

gnomAD: 12:111352091 C / T, chr12-110914287-C-T

AdditionalInfo: NR

Case#: Female, 57, Korea

DiseaseAssertion:hypertrophic cardiomyopathy

FamilyInfo: Proband and 13 family members with diverse phenotypic expression of cardiomyopathies, elder sister had expired due to severe RCMP. large family, in which the p.Arg145Trp mutation of TNNI3 causes diverse phenotypes ranging from RCMP to HCMP to near-normal heart. Six relatives with RCMP or near-normal phenotypes also carried this mutation. Family pedigree (Figure 1) and Clinical data of affected individuals in a family with the c.433C>T mutation (table 1)

CasePresentingHPOs:HP:0002094, HP:0001640, HP:0001639, HP:6000313, HP:0031295, HP:0001670, HP:0004757, HP:0005135, HP:0004756, HP:0001962

CaseHPOFreeText:restrictive filling pattern, delayed hyper-enhancement, which reflects fibrotic change in the myocardium in the hypertrophied segments (Fig. 2D).

CaseNotHPOs:HP:0032092

CaseNotHPOFreeText:normal LV systolic function and normal cavity size

CasePreviousTesting:Chromatograms, Echocardiogram

Genotyping Method:Sanger Sequencing (Fig. 5)

FunctionalAnalysis:heterozygous nonsynonymous mutation

Variant:NM_000363.5(TNNI3):c.433C>T (p.Arg145Trp)

CAID:CA021667

gnomAD:chr19-55154146-G-A

Case2: A 49 year old woman

DiseaseAssertion: Carried a novel MYBPC3 T494I mutation

FamilyInfo: Both parents were older than 80 years, had no cardiovascular symptoms and declined participation in the study

ParentalTesting:NR

CasePresentingHPOs: HP:0034307, HP:0012666, HP:6000091

CaseHPOFreeText: Had onset of symptoms a few days after giving birth to her first child. She had a short, aggressive disease period, which resulted in HTX within 3 months of onset. Age 35 at onset. Has left ventricular end-diastolic diameter (in mm and indexed by body surface area (cm/m2)) 62 mm and 3.2 cm/m2. A left ventricular ejection fraction of 20%. An ECG at normal. New York Heart Association (NYHA) as 4, Clinical status as heart transplantation (HTX), CAG as normal. HTX, 36 years, postpartum.

CaseNotHPOs:HP:0011675

CaseNotHPOFreeText:No Arrhythmia.

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

Variant:NM_000256.3:c.1481C>T

ClinVar:NR

CAID:CA380325267

gnomAD:NR

AdditionalInfo:This index case carried a novel MYBPC3 T494I mutation, which replaces a conserved hydrophilic side chain with a branched neutral side chain in domain C3 of cardiac myosin-binding protein C (cMyBPC); such an alteration may interfere with the secondary structure of the C3 domain. The missense mutations G490R, R495Q and R502W, all located in the proximity of the 494 residue, have all been described as associated with HCM.

Case1: A 68-year-old female

DiseaseAssertion: dilated cardiomyopathy (DCM), with the MYH7 p.Lys637Glu (K637E) variant identified in the affected patient. The study investigated sarcomeric gene variants associated with DCM

FamilyInfo: The proband's father (M1, II:3) died suddenly at 36 years of age, 2 years after being diagnosed with DCM.

ParentalTesting: Yes from father

CasePresentingHPOs: HP:0011664, HP:0011713, HP:0003677, HP:0001635,

CaseHPOFreeText: was diagnosed as having left ventricular non-compaction (LVNC) based on echocardiography. A left bundle branch block on her ECG. Echocardiography revealed LVNC and she has had a slow progression towards heart failure and an increasing dilatation of her left ventricle. Age 48 at onset, left ventricular end diastolic diameter 59 mm, left ventricular ejection fraction 25%, ventricular extrasystoles for arrhythmia.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting:NR

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

FunctionalAnalysis:NR

Variant: NM_000257.4:c.1909A>G

ClinVar: 1329402

CAID:CA389049558

gnomAD: NR

AdditionalInfo: NR

Case1: 8 year old female

DiseaseAssertion: Heart failure

FamilyInfo: “ no family history of sudden cardiac death or cardiomyopathy” Pedigree in Figure 5.

ParentalTesting: Variant not found in parents

CasePresentingHPOs:HP:0010741, HP:0001723

CaseHPOFreeText: “biatrial enlargement of ST-segment depression in the inferior and lateral precordial leads” “Echocardiography revealed the enlargement of both atria…slight pericardial effusion, and a LV ejection fraction of 55%”

CaseNotHPOFreeText: “LV global longitudinal strain measured by speckle-tracking echocardiography was normal” “Late gadolinium enhancement was negative.” “no evidence of pulmonary embolism, anomalous pulmonary venous drainage, or pulmonary arteriovenous fistulas” “The following laboratory findings were normal: thyroid function, liver chemistry tests, rheumatic disease antibody levels, troponin I, creatinine, and blood urea nitrogen levels, white blood cell count, urine analysis, D-dimer levels, hepatitis panel screening, and serum free light chain concentrations; HIV antibody levels were negative.”

Genotyping Method: Next generation sequencing

Variant: c.574C > T p.R192C)

ClinVar:CA021951

Case1: Female, 53

DiseaseAssertion: Restrictive Cardiomyopathy

FamilyInfo:Pedigree in Fig 1. shows “ The proband (II.11) has five siblings and three nieces with cardiomyopathy,” “the proband’s two oldest siblings were diagnosed with idiopathic DCM”

CasePresentingHPOs: HP:0002094, HP:0001962, HP:0031329, HP:0001688, HP:0001709

CaseHPOFreeText:”Echocardiography revealed massive biatrial enlargement (Fig. 2a) and markedly abnormal diastolic function” “she had mild hypertrophy localized to the mid-septum” “progressive atrial enlargement”

CaseNotHPOs:HP:0012436,

CaseNotHPOFreeText: “with no systolic anterior motion of the anterior mitral valve leaflet or left ventricular outflow tract obstruction” “The sample was negative for eosinophilic infiltrate, myocarditis, sarcoidosis, amyloidosis and hemochromatosis.”

CasePreviousTesting: Sequenced TNNT2, TTN, MYL3, MYBPC, MYL2, MYH7, ACTC1, TPM1, and TNNI3

Genotyping Method: PCR

Variant: c.266T>A (p.Ile89Asn)

ClinVar:CA004157

gnomAD: To be found

AdditionalInfo: Autosomal Dominant trait, heterozygous missense mutation in TNNT2

Case3: 73 year old man

DiseaseAssertion: He carried the MYL2 p.Ala13Thr variant

FamilyInfo: Yes, his wife, son, and daughter

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0002094, HP:0003388, HP:0012828, HP:0001650, HP:0034313, HP:0030882

CaseHPOFreeText: presented with dyspnea on exertion and easy fatigability. He was found to have severe aortic stenosis with an aortic valve area of 1 cm2 and a peak gradient of 68 mmHg. He had mild LVH with a wall thickness of 13 mm on an echocardiogram and a left ventricular ejection fraction (LVEF) of > 70%. A 12-lead ECG was unremarkable without evidence of LVH. He also had an 80% luminal diameter stenosis of left anterior descending coronary artery on coronary angiography. He underwent aortic valve replacement and a single vessel coronary artery bypass surgery. He has been asymptomatic since surgery

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case4: 43 year old woman.

DiseaseAssertion: diagnosed with HCM and carried variants in TTN, ALPK3, and MYL2 (p.Ala13Thr).

FamilyInfo:Other family members, II-1 is a 72-year old woman with history of intermittent atrial flutter with a normal interventricular septal thickness (8 mm) and a normal LVEF (58%). Likewise, individual II-4 is an asymptomatic 70-year old male, who had normal ECG, echocardiogram, and myocardial stress perfusion tomography. Proband’s children (IV-1 and IV-2) were asymptomatic and had normal ECGs and echocardiograms on the last evaluation. Likewise, individual IV-3 was a 7-year old asymptomatic boy who had a normal ECG and echocardiogram.

ParentalTesting: Yes, mother, brother, and father were tested

CasePresentingHPOs:HP:0031664, HP:0012835, HP:0004972, HP:0001670, HP:0034313, HP:0031656, HP:0012825

CaseHPOFreeText: Her physical exam was notable for the presence of a II/VI mid-systolic ejection murmur at left sternal border that radiated toward base of the heart. She also had a mildly elevated arterial blood pressure. A 12-lead ECG showed evidence of LVH, interventricular conduction delay, and repolarization abnormalities. An echocardiogram showed severe asymmetric septal hypertrophy with a hyperdynamic LV systolic function, systolic anterior motion of the mitral leaflet, and a LVOT gradient of 60 to 70 mmHg at rest (Figure 3B). CMR findings were also notable for asymmetric septal hypertrophy and mild patchy hyperenhancement.

CaseNotHPOs:NR

CaseNotHPOFreeText:NR

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis:NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case2: 63 year old woman, diagnosed with HCM

DiseaseAssertion: Individual carried the MYL2 p.Ala13Thr, TTN, and ALPK3 variants.

FamilyInfo: Yes, son and daughter and husband was all diagnosed.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs: HP:0004383, HP:0005144, HP:0001962, HP:0001279, HP:0001278, HP:0031295, HP:0040284, HP:0011703, HP:0025275

CaseHPOFreeText: Echocardiographic findings of a hyperdynamic left ventricle and an interventricular septal thickness of 19 mm. She had a history of brief episodes of palpitations and one episode of syncope a few years earlier, which was thought to be due to orthostatic hypotension. A 12-lead ECG was notable for possible left atrial enlargement. A 30-day rhythm monitoring showed rare ventricular ectopic beats and episodes of sinus tachycardia. CMR showed a normal LV wall thickness and function and minimal patchy mid myocardial hyperenhancement in the basal inferior and infero-lateral wall.

CaseNotHPOs: HP:0000822, HP:0001639, HP:0032092

CaseNotHPOFreeText: No history of systemic arterial hypertension, valvular disease, or other conditions to explain cardiac hypertrophy. No LVOT obstruction.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant:NM_000432.4:c.37G>A

ClinVar:14064

CAID:CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T ,gmonAD v4 chr12-110919160-C-T

AdditionalInfo:NR

Case1: A 44-year old male of European (non-Finnish) ancestry.

DiseaseAssertion: Disease, with the MYL2 p.Ala13Thr variant.

FamilyInfo: Mother, father, and sister was diagnosed at different ages; they all had it.

ParentalTesting: Yes with screening by ECG and Echocardiography; underwent 12-lead electrocardiography (ECG), echocardiography (M-mode, 2D, and Doppler), and cardiac magnetic resonance imaging (CMR).

CasePresentingHPOs:HP:0100749, HP:0002094, HP:0031664, HP:0033678, HP:0011703, HP:0001712, HP:0031296,HP:0020034, HP:0031656

CaseHPOFreeText: Presented 3 years ago with persistent but mild chest pain and dyspnea. presence of II/VI mid-systolic murmur that increased with the Valsalva maneuver. Cardiac enzymes were negative for acute coronary syndromes. A 12-lead ECG was notable for sinus tachycardia at the rate of 104 bpm and evidence of left ventricular hypertrophy (LVH) with repolarization abnormalities. Myocardial stress perfusion tomography showed homogeneous distribution of the radiotracer in the myocardium. An echocardiogram showed a hyperdynamic left ventricle with moderate asymmetric septal hypertrophy, a maximum wall thickness of 1.8 cm. There was a resting left ventricular outflow tract (LVOT) gradient of 20 mmHg that increased to 40 mmHg upon Valsalva maneuver. CMR findings were notable for septal hypertrophy and diffuse patchy hyperenhancement, involving multiple myocardial walls. increasing dyspnea with a mild level of physical activity and chest pain. Evidence of LVH with repolarization abnormalities on a 12-lead ECG and a hyperdynamic left ventricle with a septal thickness of 2 cm, systolic anterior motion of mitral leaflets, mild to moderate mitral regurgitation, and an LVOT gradient of 100 mmHg on echocardiography (Figure 3A). Underwent surgical myectomy, which led to resolution of LVOT gradient and symptoms.

CaseNotHPOs: HP:0011675, HP:0011703

CaseNotHPOFreeText: Not show significant cardiac arrhythmias except for periods of sinus tachycardia at rest.

CasePreviousTesting: Whole exome sequencing (WES)

Genotyping Method: Sanger sequencing

FunctionalAnalysis: May affect cardiac contractile function and actin filament velocity, But NR about the MYL2 p.Ala13Thr variant.

Variant: NM_000432.4:c.37G>A

ClinVar:14064

CAID: CA010242

gnomAD: gnomAD v2 12:111356964 C / T , gnomAD v3 12:110919160 C / T gmonAD v4 chr12-110919160-C-T

AdditionalInfo: NR

Case#:14 year old Female

DiseaseAssertion:nonobstructive hypertrophic cardiomyopathy

FamilyInfo:lacked any family history of cardiomyopathy, including sudden death or cardiac hypertrophy, Family Pedigree (Figure. 1a)

ParentalTesting:none, healthy parents

CasePresentingHPOs:HP:0001663

CaseHPOFreeText: cardiopulmonary arrest

CaseNotHPOs: HP:4000004

CaseNotHPOFreeText: myocardial edema, ventricular arrhythmias, obstructed outflow tract

CasePreviousTesting: echocardiogram, cardiac MRI

Genotyping Method:Whole genome sequencing

FunctionalAnalysis:heterozygous missense variant

Variant: NM_000363.5:c.583A>T (p.Ile195Phe)

CAID:CA407439576

Case: IP #8 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 71

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #62

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 87

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #16 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #9 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 85; VWF:Ac [IU/dL] = 56; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3917G>T p.Arg1306Leu

HGVS:

ClinVarID: 100301

CAID:

gnomAD: 6.196e-7 (1 in 1613956) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019501-C-A?dataset=gnomad_r4

Case: IP #23 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 55

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4022G>A p.Arg1341Gln

HGVS:

ClinVarID: 291

CAID:

gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case: IP #1 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3845T>C p.Leu1282Pro

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #15 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 25.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3923G>A p.Arg1308Pro

HGVS:

ClinVarID: 100303

CAID:

gnomAD: absent

Case: IP #17 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 64; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #19 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 58; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 54

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #43

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 29

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #46

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 64; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 66

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #7 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 35; FVIII:C [IU/dL] = 35

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #21 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 31

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #61

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #15 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 28

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #5 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 44; VWF:Ac [IU/dL] = 25; FVIII:C [IU/dL] = 135

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #22 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 51

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4022G>A p.Arg1341Gln

HGVS:

ClinVarID: 291

CAID:

gnomAD: 0.000001239 (2 in 1613944) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019396-C-T?dataset=gnomad_r4

Case: IP #16 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 93; VWF:Ac [IU/dL] = 48; FVIII:C [IU/dL] = 76

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #18 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 25; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #2 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 37

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #21 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 26; FVIII:C [IU/dL] = 53

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #20 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 10; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 12

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #6 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = 22

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #36

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 40; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 51

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4541T>G p.Phe1514Cys

HGVS:

ClinVarID: 304

CAID:

gnomAD: absent

Case: IP #18

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19.3; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G p.Tyr1146Cys

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #49

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 47

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #14 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 13; FVIII:C [IU/dL] = 39

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #45

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #17 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #19 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 13; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 22

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #20

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 29; VWF:Ac [IU/dL] = 18; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #18 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 151; VWF:Ac [IU/dL] = 121; FVIII:C [IU/dL] = 53

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #14 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>T p.Arg1308Cys

HGVS:

ClinVarID: 289

CAID:

gnomAD: absent

Case: IP #15 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 67; VWF:Ac [IU/dL] = 78; FVIII:C [IU/dL] = 88

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #60

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 38; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 37

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #20 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 49; VWF:Ac [IU/dL] = 41; FVIII:C [IU/dL] = 23

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #17 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 62; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 37

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #3 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 41na44; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4001G>A p.Arg1334Gln

HGVS:

ClinVarID: 2572701

CAID:

gnomAD: 0.000006196 (10 in 1613834) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019417-C-T?dataset=gnomad_r4

Case: IP #25 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD and hemophilia A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 121; VWF:Ac [IU/dL] = 111; FVIII:C [IU/dL] = 1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #13 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #14 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 30; FVIII:C [IU/dL] = 56

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #8 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 33

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #18 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3943C>T p.Arg1315Cys

HGVS:

ClinVarID: 100310

CAID:

gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4

Case: IP #4 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 48; VWF:Ac [IU/dL] = 33; FVIII:C [IU/dL] = 46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #48

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 16; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #44

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 47

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #59

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 28.7; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 32

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4883T>C p.Ile1628Thr

HGVS:

ClinVarID: 284

CAID:

gnomAD: 0.000001859 (3 in 1613848) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018535-A-G?dataset=gnomad_r4

Case: IP #21 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 36; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 36

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #19 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 42; FVIII:C [IU/dL] = 11

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

Case: IP #13 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>T p.Arg1308Cys

HGVS:

ClinVarID: 289

CAID:

gnomAD: absent

Case: IP #16 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 82

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #19

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 12; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 24

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3437A>G

HGVS:

ClinVarID: 31009

CAID:

gnomAD: 0.000001840 (1 in 543518) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022841-T-C?dataset=gnomad_r4

Case: IP #1 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2561G>A p.Arg854Gln

HGVS:

ClinVarID: 296

CAID:

gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

ClinVarID: 288

gnomAD: absent

Case: IP #7 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #20 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 48; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3946G>A p.Val1316Met

HGVS:

ClinVarID: 290

CAID:

gnomAD: absent

Case: IP #12 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 48

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>T p.Arg1308Cys

HGVS:

ClinVarID: 289

CAID:

gnomAD: absent

Case: IP #3 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 37; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #6 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 27

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3916C>T p.Arg1306Trp

HGVS:

ClinVarID: 288

CAID:

gnomAD: absent

Case: IP #47

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 24; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 32

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4789C>T p.Arg1597Trp

HGVS:

ClinVarID: 285

CAID:

gnomAD: 6.196e-7 (1 in 1614028) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018629-G-A?dataset=gnomad_r4

Case: IP #50

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = n/a; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4790G>A p.Arg1597Gln

HGVS:

ClinVarID: 100391

CAID:

gnomAD: absent

Case: IP #38 (also in row 18 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4589T>G p.Val1530Gly

HGVS:

ClinVarID: not found

CAID: CA383501045

gnomAD: absent

Case: IP #11 (also in row 6 table 6)

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3296G>A p.Cys1099Tyr

HGVS:

ClinVarID: not found

CAID: CA383512195

gnomAD: absent

Case: IP #52 (also in row 21 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 24; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4811T>A p.Val1604Asp

HGVS:

ClinVarID: not found

CAID: CA383499144

gnomAD: absent

Case: IP #58 (also in row 22 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 21

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4880C>G p.Pro1627Arg

HGVS:

ClinVarID: not found

CAID: CA383498774

gnomAD: absent

Case: IP #4 in type 2M VWD sub-cohort (also in row 13 table 6)

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 22; VWF:CB (IU/dL) = 20

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4037A>C p.Gln1346Pro

HGVS:

ClinVarID: not found

CAID: CA383505695

gnomAD: absent

Case: IP #22

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 37

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3518G>T p.Cys1173Phe

HGVS:

ClinVarID: not found

CAID: CA383511188

gnomAD: absent

Case: IP #39 in type U VWD sub-cohort (also in row 23 table 6)

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 59; VWF:Ac [IU/dL] = 55; FVIII:C [IU/dL] = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4943C>T p.Pro1648Leu

HGVS:

ClinVarID: not found

CAID: CA6402436

gnomAD: 0.000008056 (13 in 1613708) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018475-G-A?dataset=gnomad_r4

Case: IP #17 (also in row 8 table 6)

DiseaseAssertion: type2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 5; FVIII:C [IU/dL] = 22

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3434G>C p.Arg1145Pro

HGVS:

ClinVarID: not found

CAID: CA383511377

gnomAD: absent

Case: IP #41 (also in row 19 table 6)

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 56; VWF:Ac [IU/dL] = 28; FVIII:C [IU/dL] = 70

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4718G>T p.Gly1573Val

HGVS:

ClinVarID: not found

CAID: CA383499940

gnomAD: absent

Case: IP #11 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 77; VWF:Ac [IU/dL] = 50; FVIII:C [IU/dL] = 82

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3922C>A p.Arg1308Ser

HGVS:

ClinVarID: not found

CAID: CA383506203

gnomAD: absent