Disease: Platelet-type Von-willebrand Disorder (PT-VWD)

Patient: 17 yo, male, adopted

Variant: GP1BA NM_000173.7: c:580C>T p.(P.Leu194Phe), Heterozygous, gain-of-function

Phenotypes: moderate bleeding phenotype, ISTH-BAT bleeding score of 3, recurrent epistaxis, easy bruising, mild thrombocytopenia

Family: Adopted, no other family history mentioned, segregation studies not performed.

Genetic analysis performed: found variant in GP1BA, results obtained by sanger sequencing.

Variant present in gnomAD(rs368111193): low allele frequency, contradictory classifications

Variant is not present in ClinVar, LOVD, or HGMD databases

According to this paper, ACMG guidelines classified this variant as a VUS.

This paper entered it into Clinvar (var ID 1693270)

Disease: mild haemophilia A, influencing VWF levels

Patient: 20 yo, Female

Variant1: F8 NM_000132.3: c.1127T>G: p. Val376Gly (Exon 8, current clinvar interpretation not available)

Variant 2: F8 NM_000132.3: c.3780C>G: p. Asp1260Glu (Exon 14, current ClinVar interpretation is benign)

Variant 3: VWF NM_000552.5: c.1415A>G:p.His484Arg (Exon 13, current ClinVar interpretation is Benign/likely Benign)

Variant 4: VWF NM_000552.5: c.2365A>G:p.Thr789Ala (Exon 18, current ClinVar interpretation is Benign/ likely Benign)

Variant 5: VWF NM_000552.5: c.2771G>A:p.Arg924Gln (Exon 21, current ClinVar interpretation is conflicting interpretations of pathogenicity (VUS-3)(Benign-4)(Likely benign-1))

Variant 6: VWF NM_000552.5: c.4141A>G:p.Thr1381Ala (Exon 28, current ClinVar interpretation is Benign/ Likely Benign)

Variant 7: VWF NM_000552.5: c.6532G>T:p.Ala2178Ser (Exon 37, Conflicting interpretations of pathogenicity: (VUS-1) (Likely Benign-1))

Variant 8: F5 NM_000130.5: c.2773A>G:p.Lys925Glu (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 9: F5 NM_000130.5: c.2594A>G:p.His865Arg (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 10: F5 NM_000130.5: c.2573A>G:p.Lys858Arg (Exon 13, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 11: F5 NM_000130.5: c.5290A>G:p.Met1764Val (Exon 16, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 12: F13A1 NM_000129.4: c.103G>T:p.Val35Leu (Exon 2, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-3))

Variant notes: All are heterozygous

Both variants in F8 are linked to reports associated with haemophilia, though second variant is considered benign.

Phenotypes: History of bleeding (Heavy mentrual bleeding since menarche)(Treated with transdermal oestrogen and Levonorgestel), iron deficiency anaemia. High Janssen score for pictorial blood assessment. Gum bleeding lasting longer than 10 minutes(Treated with local application of tranexamic acid), recurrent nosebleeds, high score for ISTH and BAT assessments. Decrease in VWF:Ag ratio, VWF:CB ratio decreased, VWF: GPIbR ratio decreased

Family: Maternal grandfather possibly haemophiliac, mother asymptomatic

Disease: Von Willebrand Disease (VWD) type 1

Patient(s): 13 yo, female and 14 yo, female, both Italian

Variant: VWF NM_000552.5: c.820A>C p. (Thr274Pro)

Dominant negative effect

Heterozygous carrier

Variant located in the D1 domain on VWF

Phenotypes:

heterozygous carriers have no bleeding history

reduced VWF levels compatible with diagnosis of VWD type 1

increased FVIII:C/VWF:Ag ratio, suggests reduced VWF synthesis/secretion as possible phathophysiological mechanism

Normal VWFpp/VWF:Ag ratio

Modest alteration of multimeric pattern in plasma and platelet multimers

plasma VWF showed slight increase of LMWM and decrease of IMWM and HMWM

Platelet VWF showed quantitative decrease of IMWM, HMWM, and UL multimers

In silico analysis:

SIFT, ALIGN, GVD Polyphen 2.0, SNP&GO, Mutation Taster, Pmut all suggest damaging consequences.

PROVEAN and Effect suggest neutral effect

according to ACMG guidelines this variant was classified as pathogenic

GeneName: DICER1 PMCID: PMC7859642 HGNCID: Unavailable Inheritance Pattern: Autosomal dominant. Disease Entity: Familial pleuropulmonary blastoma (PPB), cervix embryonal rhabdomyosarcoma, multinodular goiter, nasal chondromesenchymal hemartoma, Ciliary body medulloepithelioma, Sertoli-Leydig Cell Tumor (SLCT), differentiated thyroid carcinoma, pituitary blastoma, pineoblastoma, cystic nephroma, Wilm's tumor and sarcomas of different sites including, amongst others, the uterine cervix, kidney and brain. Mutation: Germline Zygosity: Heterozygose Variant: No ClinVarID present. Family Information: No family outline Case: No specified information of patients included. CasePresentingHPO's: n/a CasePrevious Testing: n/a gnomAD: n/a Mutation Type: nonsense, frameshift, or splice affected.

• Gene Name: DICER1 Syndrome (OMIM 606241, 601200)
• PMID: 34599283
• Hugo Gene Nomenclature Committee (HGNCID): N/A
• Inheritance Pattern: Autosomal Dominant
• Disease Entity: pleuropulmonary blastoma (PPB), Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations.
• Mutation: Germline
• Zygosity: Heterozygous
• Variant: has multiple variants associated with it
• Family Information: Germ cell tumors have been reported in family members
• Case: identified affected families w/ pleuropulmonary blastoma (PPB): germline and somatic DICER1 mutations also identified in other familial associated tumors
• CasePreviousTesting: numerous studies confirmed relationship b/t DICER1 variants in carriers and development of range neoplasms and non-neoplastic conditions

Germline mutation Heterozygous Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Autosomal dominant PMID: 34599283 OMIM 606241, 601200)

gene name: DICER 1 PMID (PubMed ID): 33570641 HGNCID: n/a Inheritance Pattern: autosomal dominant Disease Entity: benign and malignant tumor mutation Mutation: somatic Zygosity: heterozygous Variant: n/a Family Information: n/a Case: people of all sexes, ages, ethnicities and races participated CasePresentingHPOs: individuals with DICER1-associated tumors or pathogenic germline DICER1 variants were recruited to participate CasePreviousTesting: n/a gnomAD: n/a

Gene name: DICER1 PMID: 31952842 HGNCID: none found Inheritance pattern: autosomal dominant Disease entity: cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors Mutation: Germline Zygosity: heterozygous Variant: none found Family info: personal or family history of ovarian sex-cord stromal tumor Case: 64 females aged 2 to 72 years; non-Hispanic white families CasePresentingHPOs: benign/malignant tumors CasePreviousTesting: physical examination, hormone testing, pelvic ultrasound gnomAD: N/A mutation type: germline pathogenic variation

Please clarify how you calculated 1:8 ratio. One plant has rr and the other plant has Rr. You create a table and get two Rr and two rr which makes the probability of getting three Rr or RR zero.

Case: young adult, Korean GeneName: MTHFR HGNCgeneID: ArticleID: 23526309 InheritencePattern: No inheritance pattern DiseaseEntity: Hyperhomocysteinemia, strokes Mutation: Germline Zygosity: Homozygous ClinVarID: 187891, www.ncbi.nlm.nih.gov/clinvar/variation/187891/