Case#: a 2‐year‐old white girl who was found to have RCM following an evaluation precipitated by the sudden death of her older brother.

DiseaseAssertion: Restrictive cardiomyopathy

FamilyInfo: 4‐year‐old brother presented with a sudden cardiac arrest while running on a soccer field and could not be resuscitated. Her father had restrictive physiology and arrhythmias. The TNNT2 variant was found in the father and two children

ParentalTesting: Father carried the variant. For both paternal grandparents tested negative and the proband inherited the variant from her father.

CasePresentingHPOs: HP:0001723, HP:0001639, HP:0031295, HP:0030718, HP:0001695

CaseHPOFreeText: "Her ECG demonstrated criteria for right and left atrial enlargement with marked repolarization abnormality. Echocardiogram revealed mild right atrial and severe left atrial enlargement (left atrial volume, 61.5 cc/m2; normal, 16–28), with mildly increased left ventricular mass and otherwise normal ventricular dimensions. Right and left ventricular systolic function was preserved. "

CaseNotHPOs: not reported

CaseNotHPOFreeText: Ventricular dimensions and biventricular systolic function were reported as normal.

CasePreviousTesting: Cardiomyopathy‐based panel testing (Familion; Transgenomic, Inc., New Haven, CT) was conducted on the proband, demonstrating a single, heterozygous, variant TNNT2‐R94C (c.280C>T).

Genotyping Method: Clinical genetic testing was performed on family members using the same HCM panel test.

FunctionalAnalysis: Biophysical experiments using recombinant human TNNT2‐R94C demonstrated impaired cardiac regulation at the molecular level attributed to reduced calcium‐dependent blocking of myosin's interaction with the thin filament.

Variant: c.835C>T, p.Gln279Ter

ClinVar: 165549

CAID: CA004288

gnomAD: not reported

AdditionalInfo: not reported

PMID: 32098556

Gene: TNNT2

HGNC ID: 11949

PMID: 37108997

Gene: TNNT2

HGNC ID: 11949

Case#: Male half-brother with mild left ventricular dilation from early childhood and mild left ventricular impairment; latest reported ejection fraction was 51%.

DiseaseAssertion: DCM

FamilyInfo: several of the siblings DCM, two died at age of 12, father had DCM, and heart transplant for an individual who later died

ParentalTesting: father was an obligate carrier

CasePresentingHPOs: HP:0001644

CaseHPOFreeText: Mild left ventricular dilation and mildly increased LV volumes

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: panel-based genetic test was conducted in the index patient.

Genotyping Method: panel-based genetic test was conducted in the index patient. sanger confirmation

FunctionalAnalysis: not reported

Variant: c.659_661del p.(Lys220del)

ClinVar: 43659

CAID: CA006429

gnomAD: not reported

AdditionalInfo: not reported

Case#: A 2-year-old girl with dilated cardiomyopathy (DCM) and left ventricular noncompaction, who received a heart transplant at 26 months.

DiseaseAssertion: DCM with left ventricular noncompaction

FamilyInfo: Family history revealed that three of the father’s (A.II.2) sisters (A.II.4-A.II.6) died in infancy due to cardiac failure.

ParentalTesting: The father and paternal grandmother tested positive for the same TNNT2 variant

CasePresentingHPOs: HP:0001644, HP:0030682, HP:0001635

CaseHPOFreeText: The heart failure signs began at 2 months and got worse. Then got a heart transplant at 26 months.

CaseNotHPOs: not reported

CaseNotHPOFreeText: nothing found

CasePreviousTesting: a genetic panel test, including the genes LDB3, LMNA, MYH7, MYBPC3, and TNNT2, was performed.

Genotyping Method: Variants were confirmed in first-degree family members by Sanger sequencing.

FunctionalAnalysis: not reported

Variant: c.316G>A (p.Glu106Lys)

ClinVar: 224775

CAID: CA088557

gnomAD: not reported

AdditionalInfo: not reported

PMID: 39759977 Gene: ACTC1 HGNC ID: 143

PMID: 34066613

GENE: TNNT2

HGNC ID: 11949

Case#: 19-year-old boy with coarctation of the aorta who complained of mild exertional dyspnea.

DiseaseAssertion: dilated cardiomyopathy (DCMP). LV systolic dysfunction.

FamilyInfo: The family history was positive to sudden death (his cousin died, aged 3 months) and to DCMP and heart transplant (HT): a maternal aunt and her son who then died at 42 and 24 years old. Cascade family screening revealed a TNNT2 variant in the mother (II.1) and his cousin (IV.3).

ParentalTesting: The 19 year old brother's was tested and carried the TNNT2 variant. She was also affected by DCM. The father’s testing status was not reported.

CasePresentingHPOs: HP:0001680, HP:0002875, HP:0025169, HP:4000141

CaseHPOFreeText: surgically repaired coarctation of the aorta who complained of mild exertional dyspnea repaired at birth (NYHA class II–III). Cardiac MRI showed a moderately dilated, hypokinetic LV with an ejection fraction of 45%; echocardiography showed an ejection fraction around 42%.

CaseNotHPOs: not reported

CaseNotHPOFreeText: Nothing was found that was correlated.

CasePreviousTesting: genetic investigations through next generation sequencing (NGS) with a panel of 325 genes, known to be associated with cardiomyopathies

Genotyping Method: targeted next generation sequencing

FunctionalAnalysis: not reported

Variant: c.518G>A (p. Arg173Gln)

ClinVar: 43649

CAID: CA004727

gnomAD: not reported

AdditionalInfo: not reported

PMID: 40421724 Gene: ACTC1 HGNC ID: 143

PMID: 37626566

Gene: TNNT2

HGNC ID: 11949

Case#: a 20-year-old, female, adopted Indian patient with over 662 Mb regions of homozy-gosity who presented with intellectual disability, ataxia, schizophrenia, retinal dystrophy, moder-ate-to-severe progressive sensorineural hearing loss (SNHL), congenital hypothyroidism, cleft mi-tral valve with mild mitral valve regurgitation, and dysmorphic features.

DiseaseAssertion: a cleft mitral valve with mild regurgitation

FamilyInfo: adopted

ParentalTesting: not reported

CasePresentingHPOs: HP:0001249, HP:0001251, HP:0100753, HP:0000556, HP:0000407, HP:0000851, HP:0001633, HP:0001653

CaseHPOFreeText: cleft mitral valve and dysmorphic features

CaseNotHPOs: HP:0001638

CaseNotHPOFreeText: echocardiograms at 18 were normal

CasePreviousTesting: genetic testing, including targeted panel analysis, exome sequencing on a clinical basis, and a research-based review of her raw clinical exome data, led to identifying at least three causal gene disorders to explain distinct aspects of her complex phenotype.

Genotyping Method: Genome-wide single-nucleotide polymorphism (SNP) microarray analysis was clinically performed, with no pathogenic deletions or duplications detected.

FunctionalAnalysis: not reported

Variant: NM_001001430.2:c.68-1592

ClinVar: not reported

CAID: CA032911

gnomAD: total allele frequency: 0.00004522

AdditionalInfo: n/r

Case#: A 50-year-old man diagnosed with HCM at age 41, with asymmetric septal hypertrophy and exertional chest discomfort and pain

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: His third elder sister, niece and daughter were also clinically affected by HCM. The proband's mother and eldest sister had suffered from sudden cardiac death. The proband's father, second elder sister (HCM1 in Fig. 1A), nephew (HCM5 in Fig. 1A) and son (HCM7 in Fig. 1A) were 87, 65, 35, and 14 years old, respectively, and had normal echocardiographic measurements.

ParentalTesting: The mother had died suddenly; the 87-year-old father had normal echocardiographic measurements. There was no testing reported.

CasePresentingHPOs: HP:0001639, HP:0005144, HP:0100749, HP:0011712

CaseHPOFreeText: chest distress and chest pain during exercise for 9 years. He presented with an asymmetric hypertrophic interventricular septum and a maximum interventricular septum thickness of 18.04 mm

CaseNotHPOs: not reported

CaseNotHPOFreeText: no findings found in the proband

CasePreviousTesting: nothing reported in the article

Genotyping Method: hole exome sequencing (WES) Exons were captured using Sure Select Human All Exon V5 kit. Sequenced by Illumina HiSeq 4000 sequencer.

FunctionalAnalysis: not reported

Variant: rs796925245 (g.1:201359630G>A, c.835C>T, p.Gln279Ter) (c.835C>T, p.Gln279Ter)

ClinVar: 1175037

CAID: CA088451

gnomAD: not reported

AdditionalInfo: n/r

PMID: 32846832

Gene: TNNT2

HGNC ID: 11949

PMID: 35717150 Gene: MYBPC3 HGNC ID: 7551

PMID: 21135372

Gene: TNNT2

HGNC ID: 11949

PMID: 42569619

Gene: MYBPC3

HGNC ID: 7551

PMID:30565988

Gene:TNNT2

HGNC ID:11949

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

DiseaseAssertion:Severe hypertrophic cardiomyopathy

FamilyInfo:no information reported

ParentalTesting:no parental testing reported

CasePresentingHPOs:HP:0001639

CaseHPOFreeText: gene panel testing that identified a single variant

CaseNotHPOs: not found

CaseNotHPOFreeText: not found

CasePreviousTesting: gene panel testing that identified a single variant

Genotyping Method:clinical gene panel testing

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

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

ClinVar:not found

CAID:CA090003

gnomAD:not found

AdditionalInfo:not reported

PMID:41969674

Gene:TNNT2

HGNC ID:11949

Case#:male, 41, DCM

DiseaseAssertion:dilated cardiomyopathy

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

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

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

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

CaseNotHPOs:HP:0000822, HP:0003077

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

CasePreviousTesting:No reports of previous testing

Genotyping Method:whole-exome sequencing and Sanger sequencing

FunctionalAnalysis:not reported

Variant:c.547C>T p.Arg183Trp

ClinVar:43628

CAID:CA004294

gnomAD:Overall allele frequency: 0.000001239

AdditionalInfo:not reported

PMID: 42458772 Gene: ACTC1 HGNCID: 143

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

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

DiseaseAssertion:hypokinetic-dilative cardiomyopathy

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

ParentalTesting:n/r

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

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

CaseNotHPOs: HP:0031972, HP:0031972

CaseNotHPOFreeText:Coronary angiography showed no significant stenosis.

CasePreviousTesting:Testing method and scope

GenotypingMethod:n/a

FunctionalAnalysis:not reported

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

Clinvar:not known

CAID:CA391630526

gnomAD:n/r

AdditionalInfo:n/r

PMID:39905734

Gene:TNNT2

HGNC ID:11949

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

DiseaseAssertion:Dilated cardiomyopathy

FamilyInfo: not reported

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

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

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

CaseNotHPOs:HP:0033608,HP:0002716

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

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

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

FunctionalAnalysis:Not reported

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

ClinVar:43637

CAID:CA004540

gnomAD:not reported

AdditionalInfo:not reported

PMID: 42112275

Gene: MYBPC3

HGNC ID: 7551

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

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

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

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

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

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

CaseNotHPOs: HP:0000822; HP:0000819

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

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

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

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

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

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

CAID: N/A

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

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

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

PMID:20973921

Gene:TNNT2

HGNC ID:11949

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

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

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

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

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

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

CaseNotHPOs:not reported

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

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

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

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

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

ClinVar:not found

CAID:CA004513

gnomAD:not found

AdditionalInfo:not reported

PMID: 41647802

Gene: MYBPC3

HGNC ID: 7551

PMID: 36555486

Gene: MYBPC3

HGNC ID: HGNC:7551

PMID: 37122207

Gene: TNNT2

HGNC ID: 11949

Case#: 4 month old boy

DiseaseAssertion: Polymorphic ventricular tachycardia

FamilyInfo: His father carried the RYR2 variant and had ventricular premature beats. His mother carried the SCN10A variant and was asymptomatic.

ParentalTesting: Yes. Familial genetic testing showed the RYR2-A1855D variant was inherited from the father and the SCN10A-Q1362H variant was inherited from the mother.

CasePresentingHPOs: HP:0004756

CaseHPOFreeText: 4-month-old male presenting with polymorphic ventricular tachycardia.

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: Clinical cardiac evaluation followed by genetic testing

Genotyping Method: Genetic testing identified novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants.

FunctionalAnalysis: Functional studies showed abnormal calcium handling, prolonged action potentials, increased susceptibility to early afterdepolarizations, and disrupted Ca2+ homeostasis in cells carrying both variants.

Variant: RYR2 (heterozygous) SCN10A

ClinVar: not found

CAID: not found

gnomAD: not found

AdditionalInfo:

PMID: 28265379

Gene: MYBPC3

HGNC ID: 7551

PMID: 24367055

Gene: MYH7

HGNC ID: HGNC:7471

PMID: : 37929589

Gene: MYBPC3 ,MYH7 ,TNNT2 ,TNNI3,MYL2, MYL3 TPM1, CSRP3 Multiple genes associated with hypertrophic cardiomyopathy (HCM)

HGNC ID: MYBPC3: HGNC:7551, MYH7: HGNC:7577, TNNT2: HGNC:11949, TNNI3: HGNC:11947, MYL2: HGNC:7576 ,MYL3: HGNC:7584, TPM1: HGNC:12010 CSRP3: HGNC:1430

Case#:: no individual case number

DiseaseAssertion:: Hypertrophic cardiomyopathy (HCM)

FamilyInfo::Familial HCM cohorts and at-risk relatives carrying pathogenic or likely pathogenic sarcomeric variants were investigated. Pooled penetrance among non-proband variant-carrying relatives was 57%

ParentalTesting:: No individual parental segregation or parental testing information reported.

CasePresentingHPOs:: Left ventricular hypertrophy

CaseHPOFreeText:: Hypertrophic cardiomyopathy characterized by unexplained left ventricular hypertrophy.

CaseNotHPOs:: N/A

CaseNotHPOFreeText:; N/A

CasePreviousTesting::N/A

Genotyping Method::N/A

FunctionalAnalysis::N/A

Variant:: No specific nucleotide or protein-level variant reported as the subject of an individual case.

ClinVar:: N/A

CAID:: N/A

gnomAD:: N/A

AdditionalInfo:

PMID: : 40115818

Gene: :DSG2 , MYBPC3

HGNC ID: :DSG2: HGNC:3049, MYBPC3: HGNC:7551

Case: Female, 19 y.o., ethnicity unknown.

DiseaseAssertion: VWD2N

FamilyInfo: Proband has one older symptomatic sister who shares an identical compound heterozygous genotype, presenting with a mild bleeding tendency, reduced FVIII activity (20-30%), and severely reduced FVIII binding (<2%). The family features one younger unaffected sister who tested negative for both variants, and an unaffected carrier mother. Both parents had normal factor VIII, and there was no male relative with reduced factor VIII or bleeding symptoms.

ParentalGenotype(s): Mother is heterozygous for the c.2561G>A (p.R854Q) variant, negative for the c.2402G>A (p.S801N) variant, and has normal baseline factor VIII levels, confirming the sisters' variants are in trans. Father unavailable/not tested.

CasePresentingHPOs: HP:0004846 (Prolonged bleeding after surgery), HP:0003645 (Prolonged partial thromboplastin time).

CaseHPOFreeText: Index patient experienced bleeding complications following wisdom tooth surgery. Factor VIII binding activity is reduced at 32%. Reduced coagulation factor VIII activity (30%). Prolonged activated partial thromboplastin time (aPTT) of 37 seconds.

CaseNOTHPOs: HP:0001873 (Thrombocytopenia), HP:0012147 (Reduced quantity of von Willebrand factor), HP:0030130 (Impaired von Willebrand factor collagen binding activity).

CaseNOTHPOFreeText: Normal vWF antigen (vWF:Ag) levels (101%), normal vWF activity (116%), normal vWF-collagen-binding activity (104%), normal vWF multimer distribution structures, normal hemoglobin level (128 g/L), and normal Prothrombin Time (PT/QUICK) of 83%.

CasePreviousTesting: Siblings did not carry any known mutations in the F8 gene or the LMAN1 and MCFD2 genes (which encode for endoplasmic reticulum carrier proteins of coagulation factors V and VIII).

GenotypingMethod: Direct sequence analysis of VWF exons 18-20.

PreviouslyPublished: NA.

Gene: VWF

HGNCID: HGNC:12726

Variant: Heterozygous c.2561G>A (p.R854Q) and heterozygous c.2402G>A (p.S801N).

HGVS: (1) NM_000552.5:c.2561G>A (p.Arg854Gln) (2) NM_000552.5:c.2402G>A (p.Ser801Asn)

ClinVarID: (1) 296 (2) NA

CAID: (1) NA (2) CA383522023

gnomAD: (1) MAF of 0.005974 in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

(2) MAF of 0.00001098 in the South Asian population https://gnomad.broadinstitute.org/variant/12-6044331-C-T?dataset=gnomad_r4

PMID: 42746662 Gene: VWF HGNCID: 12726

PMID: 39160446 Gene: MYBPC3 HGNC: HGNC:7551

PMID: 29652675

Gene: F8

HGNC ID: HGNC:3546

PMID: 24053568

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Gene:VWF

HGNCID:12726

Case:11 yo female

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 4

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Oral cavity and joint bleeding, Bleeding from small wounds and after tooth extraction, VWF:Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB <0.05 U/mL, FVIII 0.01 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:29 yo female

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 1

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0000132, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Skin, GI, muscle, oral cavity, and joint bleeding, VWF: Ag 0.07 U/mL, VWF:Ac 0.08 U/mL, VWF:CB 0.05 U/mL, FVIII 0.02 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:13 yo female

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 2, patient 7

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0004846, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Oral cavity and joint bleeding, VWF:Ag 0.07 U/mL, VWF:Ac 0 U/mL, VWF:CB 0.05 U/mL, FVIII 0.04 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:27 yo male

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 2

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Skin, oral cavity, and joint bleeding, Bleeding after tooth extractions and small wounds, VWF: Ag 0.07 U/mL, VWF:Act 0.05 U/mL, VWF:CB <0.05 U/mL, FVIII:C 0.01 U/mL, Less VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

Gene:VWF

HGNCID:12726

Case:17 yo male

DiseaseAssertion: Type 2N

FamilyInfo:Fig. 1, family 1, patient 3

ParentalGenotype(s):Unknown, obligate carriers

CasePresentingHPOs:HP:0000421, HP:0012147 HP:0030132, HP:0030130

CaseHPOFreeRext:Oral cavity, skin, and muscle bleeding, Bleeding after tooth extractions, VWF: Ag 0.09 U/mL, VWF:Act 0.05 U/mL, VWF:CB 0.04 U/mL, FVIII:C 0.01 U/mL, No VWF Multimers

GenotypingMethod: NGS

Gene:VWF

Variant:c.2311A>G

HGVS:NM_000552.5(VWF):c.2311A>G

ClinVarID:1065273

CAID:CA383522481

PMID: 28691218

Gene: VWF

HGNCID: 12726

PMID: 37168293

Gene: VWF

HGNCID: 12726

PMID: 28306198

Gene: VWF

HGNCID: 12726

PMID: 28026130

Gene: VWF

HGNCID: 12726

PMID: 22479377 Gene: VWF HGNCID: HGNC:12726

PMID: 27380589

Gene: VWF

HGNCID: 12726

PMID: 28750474

Gene: VWF

HGNCID: 12726

PMID: 27819553

Gene: GP1BA

HGNCID: 4439

PMID: 28523822

Gene: VWF

HGNCID: 12726

PMID: 21410641

Gene: VWF

HGNCID: 12726

PMID: 26986123 Gene: von Willebrand factor HGNCID: 12726 Note: reported for group analysis with no associated probands/patient

PMID: 27819553

Gene: VWF

HGNCID: 12726

PMID: 28587726

Gene: VWF

HGNCID: 12726

PMID: 31249928

Gene: VWF

HGNCID: 12726

PMID: 40393667

Gene: VWF

HGNCID: 12726

PMID: 27483487

Gene: VWF

HGNCID: 12726

PMID: 40242192

Gene: VWF

HGNCID: 12726

PMID: 35210927

Gene: VWF

HGNCID: 12726

PMID: 35747851

Gene: VWF

HGNCID: 12726

PMID: 28379876

Gene: VWF

HGNCID: 12726

PMID: 28751564

Gene: VWF

HGNCID: 12726

PMID: 38426552 Gene: ITGA2B Approved name: integrin subunit alpha 2b GNC: HGNC:6138

PMID:22754241

Gene:F8

HGNC ID:3546

Selection A- Gene with same function implicated in disease

ExperimentName: Moye et al. 2018

GOterm: GO:0051179 (localization)

FunctionalEvidence: It was discovered that without ARL2BP, the photoreceptor OS does not develop normally or have correct DMT formation, axoneme extension, and disk alignment.

HGNC: HGNC:10295 (RPGR), HGNC:10263 (RP1), HGNC:6816 (MAK)

GeneEvidence: ARL2BP, RPGR, RP1 and MAK are all localized within the ciliary basal body and rootlet.

SharedGeneImplication: RPGR was classified as having a "definitive" relationship with RP 15 by the Retina GCEP. Refer to the curation for further details. RP1 was classified as having a "definitive" relationship with RP1 by the Retina GCEP. Refer to the curation for further details. MAK was classified as having a "definitive" relationship with MAK-related retinopathy by the Retina GCEP. Refer to the curation for further details.

PMID: 21362127 Gene: von Willebrand factor HGNCID: 12726

PMID: 27344059 Gene: VWF HGNCID: HGNC:12726

PMID: 35596664

Gene: VWF

HGNCID: 12726

PMID: 27543438

Gene: VWF

HGNCID: 12726

PMID: 27203734

Gene: VWF

HGNCID: 12726

PMID: 28572165

Gene: VWF

HGNCID: 12726

PMID: 28577390

Gene: VWF

HGNCID: 12726

PMID: 8839833 Gene: VWF HGNCID: 12726

PMID: 28181360

Gene: VWF

HGNCID: 12726

PMID: 28987708

Gene: VWF

HGNCID: 12726

Gene: VWF

HGNCID: 12726

Case: 4 month old female

DiseaseAssertion: VWD type 3

FamilyInfo: both parents were sequenced ParentalGenotype(s): mother is VWF:c.2435delC carrier, father was negative

CasePresentingHPOs: HP:0011889 CaseHPOFreeRext: bleeding from injection site following vaccination administration CaseNOTHPOs: CaseNOTHPOFreeText: normal PT/PTT at 4 months. prolonged PTT, normal PT and platelet count upon repeat. Factor VIII levels <1%, VWF activity <15%

GenotypingMethod: unknown

Gene: VWF

Variant: c.2435delC in VWF gene, deletion in exon 6 of VWF gene

HGVS: NM_000552.5:c.2435del

ClinVarID: 303

gnomAD: 0.00007187 (116/1613916) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4

Gene:VWF

HGNCID:12726

PMID33550910

Case:38-year-old woman from Saudi Arabia

DiseaseAssertion:VWD type 2B

FamilyInfo:Mother and brother suffered from epistaxis (no genotypes). Two sons and one daughter: both sons carry the same mutation, but only one presents with minimal epistaxis.

ParentalGenotype(s):Not available

CasePresentingHPOs:HP:0001934, HP:0004846, HP:0011871

CaseNOTHPOs:HP:0000421, HP:0000132

CaseNOTHPOFreeText:multiple dental extractions without bleeding complications

CaseHPOFreeRext:RIPA (+) Rist 0.5 mg/mL

CasePreviousTesting:No

GenotypingMethod:NGS

Gene:VWF

Variant:c.4136 G>T (p. R1379 L)

HGVS:NC_000012.12:g.6019282C>A

ClinVarID:

CAID:CA383504438

gnomAD:

PMID: 19687512

Gene: VWF

HGNCID: 12726

PMID: 28789675

Gene: VWF

HGNCID: 12726

Article Information:

PMID: 31320553

Gene: VWF

HGNCID: 12726

PMID: 36324358

Gene: SLC4A1

HGNCID: 12726

PMID: 28756118

Gene: VWF

HGNCID: 12726

PMID: 29115006

Gene: VWF

HGNCID: 12726

PMID: 28236847

Gene: VWF

HGNCID: 12726

PMID: 28696025

Gene: VWF

HGNCID: 12726

PMID: 33556167

Gene: VWF

HGNCID: 12726

PMID: 28660968

Gene: VWF

HGNCID: 12726