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Bleeding and Platelet Disorders v1.63 PLAT Chirag Patel Marked gene: PLAT as ready
Bleeding and Platelet Disorders v1.63 PLAT Chirag Patel Gene: plat has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.63 PLAT Chirag Patel gene: PLAT was added
gene: PLAT was added to Bleeding and Platelet Disorders. Sources: ClinGen
disputed tags were added to gene: PLAT.
Mode of inheritance for gene: PLAT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PLAT were set to Thrombophilia, familial, due to decreased release of tissue plasminogen activator MONDO:0012872
Review for gene: PLAT was set to RED
Added comment: ClinGen DISPUTED - Jun 2023
Sources: ClinGen
Bleeding and Platelet Disorders v1.59 PTGS1 Zornitza Stark Phenotypes for gene: PTGS1 were changed from Platelet dysfunction; bleeding to Platelet-type bleeding disorder 12 MONDO:0011588
Bleeding and Platelet Disorders v1.58 PTGS1 Zornitza Stark edited their review of gene: PTGS1: Changed phenotypes: Platelet-type bleeding disorder 12 MONDO:0011588
Bleeding and Platelet Disorders v1.57 STAB2 Lucy Spencer gene: STAB2 was added
gene: STAB2 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: STAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STAB2 were set to 40726512
Phenotypes for gene: STAB2 were set to Chronic thromboembolic pulmonary hypertension MONDO:0013024, STAB2-related
Review for gene: STAB2 was set to RED
Added comment: PMID: 40726512 In a cohort of chronic thromboembolic pulmonary hypertension a missense in STAB2 was found in 2 related affected individuals. However, the variant Ala1665Thr is common on gnomad with over 1000 hets and 4 homs. They also observed a significantly higher prevalence of 'qualifying alleles' in STAB2 in their disease cohort compared to the UK biobank- 4.6% in the disease cohort vs 1.2% in UK biobank. Qualifying alleles were rare and predicted deleterious. 78% of these variants were missense and quite a few of them also had thousands of hets and some homs in gnomad v4.
Sources: Literature
Bleeding and Platelet Disorders v1.56 NFE2 Zornitza Stark gene: NFE2 was added
gene: NFE2 was added to Bleeding and Platelet Disorders. Sources: ClinGen
Mode of inheritance for gene: NFE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFE2 were set to 31951293
Phenotypes for gene: NFE2 were set to thrombocytopenia MONDO:0002049, NFE2-related
Review for gene: NFE2 was set to RED
Added comment: Classified as Limited by Hemostasis Thrombosis GCEP on 16/06/2025 Homozygous frameshift variant reported in a single proband (c.952delA, p.T318fsX326 - absent in gnomAD v4.1).
Sources: ClinGen
Bleeding and Platelet Disorders v1.52 EPHB2 Sangavi Sivagnanasundram reviewed gene: EPHB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30213874; Phenotypes: bleeding disorder, platelet-type, 22 MONDO:0032765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v1.47 SERPIND1 Jane Lin gene: SERPIND1 was added
gene: SERPIND1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: SERPIND1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SERPIND1 were set to PMID: 12421148; PMID: 35592395; PMID: 2647747; PMID: 11204559; PMID: 10494755
Phenotypes for gene: SERPIND1 were set to HEPARIN COFACTOR II DEFICIENCY #612356
Review for gene: SERPIND1 was set to AMBER
gene: SERPIND1 was marked as current diagnostic
Added comment: Also known as HCF2. There is evidence of protein to phenotype links but not many recent papers linking specific genetic variants to phenotype. Expect more given the first link to inherited thrombosis was published in 1985 (PMID: 2863444). There are two papers that used PCR to determine mutation in an affected individual (PMID: 2647747) published in 1989 and a paper in 2001 (PMID: 11204559). There is a paper reporting homozygous HCII but could not access paper (abstract only) (PMID: 10494755). This 2002 review (PMID: 12421148) lists 5 publications with 5 different molecular mutations linked to Heparin Cofactor II Deficiency. This review also notes that most of the case reports concluded that "inherited HCII deficiency is not a strong risk factor for thrombosis or that it contributes to thrombotic risk only when combined with other deficiencies." A more recent review (PMID: 35592395) has similar view and literature searches don't reveal recent papers with reports of variants linked to thrombosis.
Sources: Expert list
Bleeding and Platelet Disorders v1.47 SERPINC1 Jane Lin gene: SERPINC1 was added
gene: SERPINC1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: SERPINC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SERPINC1 were set to PMID: 14347873; PMID: 36624481; PMID: 28300866
Phenotypes for gene: SERPINC1 were set to Thrombophilia 7 due to antithrombin III deficiency #613118
Review for gene: SERPINC1 was set to GREEN
gene: SERPINC1 was marked as current diagnostic
Added comment: Well established gene-phenotype relationship. Mostly autosomal dominant inheritance (autosomal recessive inheritance is rare but has been published). Have listed an early publication (1965) establishing this link and two more recent papers.
Sources: Expert list
Bleeding and Platelet Disorders v1.47 PROS1 Jane Lin gene: PROS1 was added
gene: PROS1 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: PROS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: PROS1 were set to PMID: 2521801; PMID: 7545463; PMID: 2231208; PMID: 10063989
Phenotypes for gene: PROS1 were set to Thrombophilia 5 due to protein S deficiency, autosomal dominant #612336; Thrombophilia 5 due to protein S deficiency, autosomal recessive #614514
Review for gene: PROS1 was set to GREEN
gene: PROS1 was marked as current diagnostic
Added comment: Strong gene-phenotype link. Many publications for both both autosomal dominant and autosomal recessive inheritance of PROS1 variants and thrombosis phenotype.
Sources: Expert list
Bleeding and Platelet Disorders v1.43 PROC Jane Lin gene: PROC was added
gene: PROC was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: PROC was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PROC were set to PMID: 2437584; PMID: 7670104; PMID: 10942114; PMID: 28265398
Phenotypes for gene: PROC were set to THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL DOMINANT # 176860; THROMBOPHILIA DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL RECESSIVE, # 612304
Review for gene: PROC was set to GREEN
gene: PROC was marked as current diagnostic
Added comment: Has well established gene-disease association with thrombosis. Biallelic inheritance is rare and there is evidence it is more severe but data is complicated by findings that some patients also have changes in Factor V Leiden so have not selected the option where biallelic inheritance is more severe.
Sources: Expert list
Bleeding and Platelet Disorders v1.43 PIGA Jane Lin gene: PIGA was added
gene: PIGA was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: PIGA was set to Unknown
Publications for gene: PIGA were set to PMID: 9019395; PMID: 28516949
Phenotypes for gene: PIGA were set to PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 1 OMIM# 300818
Review for gene: PIGA was set to RED
gene: PIGA was marked as current diagnostic
Added comment: PIGA variants linked to Paroxysmal nocturnal hemoglobinuria (PNH), clinical features which include thrombosis, but as somatic changes.
Sources: Expert list
Bleeding and Platelet Disorders v1.38 PLG Jane Lin gene: PLG was added
gene: PLG was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: PLG was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PLG were set to Plasminogen deficiency, type I; Dysplasminogenemia; MIM#217090
gene: PLG was marked as current diagnostic
Added comment: Included in Genomics England PanelApp "Thrombophilia with a likely monogenic cause" panel. Adding to this panel as this gene has a gene-disease association with thrombophilia.
Sources: Expert Review
Bleeding and Platelet Disorders v1.37 CFI Zornitza Stark gene: CFI was added
gene: CFI was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: CFI was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFI were set to {Haemolytic uremic syndrome, atypical, susceptibility to, 3}, MIM# 612923
Review for gene: CFI was set to GREEN
Added comment: Thrombotic microangiopathy is part of the phenotype. Note this is a susceptibility locus.
Sources: Expert Review
Bleeding and Platelet Disorders v1.35 CFB Zornitza Stark gene: CFB was added
gene: CFB was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: CFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFB were set to {Hemolytic uremic syndrome, atypical, susceptibility to, 4}, MIM# 612924
Review for gene: CFB was set to GREEN
Added comment: Thrombotic microangiopathy is part of the phenotype. Note this is a susceptibility locus.
Sources: Expert Review
Bleeding and Platelet Disorders v1.33 C3 Zornitza Stark gene: C3 was added
gene: C3 was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: C3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: C3 were set to {Hemolytic uremic syndrome, atypical, susceptibility to, 5}, MIM# 612925
Review for gene: C3 was set to GREEN
Added comment: Thrombotic microangiopathy is part of the clinical presentation. Note this is a susceptibility locus.
Sources: Expert Review
Bleeding and Platelet Disorders v1.30 GALE Zornitza Stark gene: GALE was added
gene: GALE was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: GALE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALE were set to 30247636; 34159722; 36395340
Phenotypes for gene: GALE were set to Thrombocytopenia 12, syndromic, MIM#620776
Review for gene: GALE was set to GREEN
Added comment: 10 individuals from 5 families reported with bi-allelic variants in this gene and congenital thrombocytopenia resulting in increased bleeding. Platelets were enlarged (macrothrombocytopenia) and/or gray and had functional defects. Some individuals have infection-induced leukopenia or anaemia and pancytopenia. Additional more variable features have also been reported, including mitral valve malformations, pyloric stenosis, and impaired intellectual development.
Sources: Expert list
Bleeding and Platelet Disorders v1.27 APOLD1 Lucy Spencer changed review comment from: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.
Sources: Literature; to: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.

SiRNA silencing of APOLD1 in HBDEC cells resulted in altered cell shape and size, and were associated with endothelial cell junction dismantling. These cells were also almost devoid of VWF.
Sources: Literature
Bleeding and Platelet Disorders v1.27 APOLD1 Lucy Spencer gene: APOLD1 was added
gene: APOLD1 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: APOLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOLD1 were set to 35638551
Phenotypes for gene: APOLD1 were set to Bleeding disorder, vascular-type (MIM#620715)
Review for gene: APOLD1 was set to AMBER
Added comment: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.
Sources: Literature
Bleeding and Platelet Disorders v1.26 TPM4 Zornitza Stark Phenotypes for gene: TPM4 were changed from Macrothrombocytopenia to Bleeding disorder, platelet-type, 25, MIM# 620486
Bleeding and Platelet Disorders v1.25 TPM4 Zornitza Stark edited their review of gene: TPM4: Changed phenotypes: Bleeding disorder, platelet-type, 25, MIM# 620486
Bleeding and Platelet Disorders v1.16 TLN1 Achchuthan Shanmugasundram gene: TLN1 was added
gene: TLN1 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: TLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TLN1 were set to 35861643
Phenotypes for gene: TLN1 were set to thrombocytopenia, MONDO:0002049
Review for gene: TLN1 was set to RED
Added comment: PMID:35861643 reported a 20-year old man of Mexican ancestry with a complex phenotype including thrombocytopenia, T lymphopenia, and low IgG levels. The patient generally had a platelet count of <20 000/mcL, but without significant bleeding. He was identified with a de novo heterozygous variant c.685C > T (p.Pro 229 Ser) that was not present in his parents.
Sources: Literature
Bleeding and Platelet Disorders v1.13 KIF15 Krithika Murali gene: KIF15 was added
gene: KIF15 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: KIF15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF15 were set to 28150392
Phenotypes for gene: KIF15 were set to ?Braddock-Carey syndrome 2 - MIM#619981
Review for gene: KIF15 was set to AMBER
Added comment: PMID 28150392 Sleiman et al 2017 report one individual with homozygous R501* variant (NMD-predicted) from a consanguineous family. The child had thrombocytopenia, PRS, microcephaly <3 SD by age 6, dysmorphic facies, bilateral external auditory canal atresia and deafness, microphthalmia, clinodactyly, short stature. Variant absent from gnomAD. Parents confirmed to be carriers and unaffected siblings were carriers/homozygous wild-type.

No other SNVs reported in ClinVar. Variant is absent from gnomAD. Authors note phenotypic similarities with Braddock-Carey syndrome (21q22 contiguous deletion also involving RUNX1).
Sources: Literature
Bleeding and Platelet Disorders v1.12 HRG Zornitza Stark gene: HRG was added
gene: HRG was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: HRG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HRG were set to 8236132; 11057869; 11057869; 29108964
Phenotypes for gene: HRG were set to Thrombophilia 11 due to HRG deficiency, MIM# 613116
Review for gene: HRG was set to GREEN
Added comment: Established gene-disease association.
Sources: Expert Review
Bleeding and Platelet Disorders v1.10 TUBA8 Zornitza Stark gene: TUBA8 was added
gene: TUBA8 was added to Bleeding and Platelet Disorders. Sources: Expert list
Mode of inheritance for gene: TUBA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA8 were set to 34704371
Phenotypes for gene: TUBA8 were set to Macrothrombocytopaenia, isolated, 2, autosomal dominant, MIM# 619840
Review for gene: TUBA8 was set to AMBER
Added comment: 6 unrelated individuals with missense variants found in a large cohort of blood donors, some functional data. Individuals were generally asymptomatic, one had menorrhagia.
Sources: Expert list
Bleeding and Platelet Disorders v1.5 KLKB1 Zornitza Stark gene: KLKB1 was added
gene: KLKB1 was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: KLKB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLKB1 were set to 15461630; 33073460
Phenotypes for gene: KLKB1 were set to Fletcher factor (prekallikrein) deficiency, MIM# 612423
Review for gene: KLKB1 was set to AMBER
Added comment: Prolonged aPTT, but asymptomatic, hence some variants have a high gnomad frequency.
Sources: Expert Review
Bleeding and Platelet Disorders v1.0 SLC37A4 Paul De Fazio gene: SLC37A4 was added
gene: SLC37A4 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: SLC37A4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC37A4 were set to 33964207
Phenotypes for gene: SLC37A4 were set to Congenital disorder of glycosylation; liver dysfunction; coagulation deficiency
Review for gene: SLC37A4 was set to GREEN
gene: SLC37A4 was marked as current diagnostic
Added comment: 7 patients from 4 families, additional to the two reported previously, described with the same recurrent c.1267C>T (p.R423*) variant with liver dysfunction multifactorial coagulation deficiency and cardiac issues. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans. Hepatoma cell-line studies support the pathogenicity of the variant.

Note that although most/all patients had abnormal clotting factors, only one was noted to have a history of bruising/bleeding.
Sources: Literature
Bleeding and Platelet Disorders v0.301 TBXA2R Zornitza Stark Phenotypes for gene: TBXA2R were changed from to {Bleeding disorder, platelet-type, 13, susceptibility to}, MIM# 614009
Bleeding and Platelet Disorders v0.297 TBXA2R Zornitza Stark reviewed gene: TBXA2R: Rating: AMBER; Mode of pathogenicity: None; Publications: 7929844, 19828703, 22517902; Phenotypes: {Bleeding disorder, platelet-type, 13, susceptibility to}, MIM# 614009; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and Platelet Disorders v0.297 P2RY12 Zornitza Stark Phenotypes for gene: P2RY12 were changed from to Bleeding disorder, platelet-type, 8, MIM# 609821; MONDO:0012354
Bleeding and Platelet Disorders v0.294 P2RY12 Zornitza Stark changed review comment from: Platelet-type bleeding disorder-8 is characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation.; to: Platelet-type bleeding disorder-8 is characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation.

Families with bi-allelic and mono-allelic disease reported. Dominant negative mechanism proposed for mono-allelic disease.
Bleeding and Platelet Disorders v0.294 P2RY12 Zornitza Stark edited their review of gene: P2RY12: Changed phenotypes: Bleeding disorder, platelet-type, 8, MIM# 609821, MONDO:0012354
Bleeding and Platelet Disorders v0.294 P2RY12 Zornitza Stark reviewed gene: P2RY12: Rating: GREEN; Mode of pathogenicity: None; Publications: 11196645, 12578987; Phenotypes: Bleeding disorder, platelet-type, 8, MIM# 609821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v0.287 ITGA2B Zornitza Stark changed review comment from: Platelet-type bleeding disorder-16 (BDPLT16) is an autosomal dominant form of congenital macrothrombocytopaenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. Multiple families reported.

Glanzmann thrombasthenia-1 (GT1) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. Multiple families reported.; to: Platelet-type bleeding disorder-16 (BDPLT16) is an autosomal dominant form of congenital macrothrombocytopaenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. Multiple families reported.

Glanzmann thrombasthaenia-1 (GT1) is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. Multiple families reported.
Bleeding and Platelet Disorders v0.287 ITGA2B Zornitza Stark Phenotypes for gene: ITGA2B were changed from to Bleeding disorder, platelet-type, 16, MIM# 187800; MONDO:000855; Glanzmann thrombasthaenia 1, MIM# 273800
Bleeding and Platelet Disorders v0.284 ITGA2B Zornitza Stark reviewed gene: ITGA2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 1638023, 21454453, 8282784, 16463284; Phenotypes: Bleeding disorder, platelet-type, 16, MIM# 187800, MONDO:000855, Glanzmann thrombasthaenia 1, MIM# 273800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v0.275 HPS3 Zornitza Stark edited their review of gene: HPS3: Added comment: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles: melanosomes, platelet-dense granules, and lysosomes.

Well established gene-disease association.; Changed phenotypes: Hermansky-Pudlak syndrome 3, MIM# 614072, MONDO:0013555
Bleeding and Platelet Disorders v0.269 GP9 Zornitza Stark edited their review of gene: GP9: Added comment: Bernard-Soulier syndrome is a bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5.

At least 3 unrelated families reported, animal model.; Changed publications: 8049428, 33553065, 32030720, 31484196
Bleeding and Platelet Disorders v0.269 GP6 Zornitza Stark Phenotypes for gene: GP6 were changed from to Bleeding disorder, platelet-type, 11, MIM# 614201; MONDO:0013623
Bleeding and Platelet Disorders v0.266 GP6 Zornitza Stark reviewed gene: GP6: Rating: GREEN; Mode of pathogenicity: None; Publications: 19549989, 19552682, 23815599; Phenotypes: Bleeding disorder, platelet-type, 11, MIM# 614201, MONDO:0013623; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v0.219 GP1BA Zornitza Stark Phenotypes for gene: GP1BA were changed from to Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS); von Willebrand disease, platelet-type, (MIM#177820), AD (VWD); MONDO:0008332; Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS); MONDO:0007930
Bleeding and Platelet Disorders v0.216 GP1BA Zornitza Stark reviewed gene: GP1BA: Rating: GREEN; Mode of pathogenicity: None; Publications: 24934643; Phenotypes: Bernard-Soulier syndrome, type A1 (recessive), (MIM#231200), AR (AR BSS), von Willebrand disease, platelet-type, (MIM#177820), AD (VWD), MONDO:0008332, Bernard-Soulier syndrome, type A2 (dominant), (MIM#153670) (AD BSS), MONDO:0007930; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Bleeding and Platelet Disorders v0.216 ITGB3 Zornitza Stark Phenotypes for gene: ITGB3 were changed from to Bleeding disorder, platelet-type, 24, MIM#619271; MONDO:0008552
Bleeding and Platelet Disorders v0.213 ITGB3 Zornitza Stark reviewed gene: ITGB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 18065693, 19336737, 20081061, 23253071; Phenotypes: Bleeding disorder, platelet-type, 24, MIM#619271, MONDO:0008552; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bleeding and Platelet Disorders v0.210 MAST2 Elena Savva gene: MAST2 was added
gene: MAST2 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: MAST2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAST2 were set to PMID: 33465109
Phenotypes for gene: MAST2 were set to Thrombophilia; venous thrombosis
Review for gene: MAST2 was set to RED
Added comment: Single missense identified in a family with venous thrombosis and thrombophilia. Missense variant reviewed by in silicos only. Shown to affect regulation of TFP1 and SERPINE1 gene expression.

RNAi of MAST2 followed by RNAseq showed expression changes in many downstream targets
Sources: Literature
Bleeding and Platelet Disorders v0.207 MPI Zornitza Stark gene: MPI was added
gene: MPI was added to Bleeding and Platelet Disorders. Sources: Expert Review
Mode of inheritance for gene: MPI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPI were set to 12414827; 9585601; 10980531; 33098580; 33204592; 32905087; 32266963; 30242110
Phenotypes for gene: MPI were set to Congenital disorder of glycosylation, type Ib, MIM# 602579; MPI-CDG MONDO:0011257
Review for gene: MPI was set to GREEN
Added comment: CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhoea with failure to thrive and protein-losing enteropathy with coagulopathy. Both bleeding and thrombosis reported. Some individuals develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated.

Well established gene-disease association, numerous families reported.
Sources: Expert Review
Bleeding and Platelet Disorders v0.204 Zornitza Stark Panel name changed from Bleeding Disorders to Bleeding and Platelet Disorders
Bleeding and Platelet Disorders v0.201 BLOC1S5 Chirag Patel gene: BLOC1S5 was added
gene: BLOC1S5 was added to Bleeding Disorders. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to PMID: 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome type 11, no OMIM#
Review for gene: BLOC1S5 was set to GREEN
gene: BLOC1S5 was marked as current diagnostic
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2).

Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele.

Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Bleeding and Platelet Disorders v0.201 BLOC1S5 Chirag Patel gene: BLOC1S5 was added
gene: BLOC1S5 was added to Bleeding Disorders. Sources: Literature
Mode of inheritance for gene: BLOC1S5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S5 were set to PMID: 32565547
Phenotypes for gene: BLOC1S5 were set to Hermansky–Pudlak syndrome type 11, no OMIM#
Review for gene: BLOC1S5 was set to GREEN
gene: BLOC1S5 was marked as current diagnostic
Added comment: 2 unrelated patients with mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Identified distinct homozygous variants in the BLOC1S5 gene (patient 1: deletion of exons 3 and 4, patient 2: 1-bp deletion in exon 4). Parental segregation confirmatory in patient 1, quantitative PCR analysis confirmatory in patient 2).

Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5-/- melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele.

Pathogenic variants in the genes encoding three other BLOC-1 subunits (DTNBP1, BLOC1S3, and BLOC1S6) underlie HPS types 7, 8, and 9 respectively.
Sources: Literature
Bleeding and Platelet Disorders v0.189 VIPAS39 Zornitza Stark gene: VIPAS39 was added
gene: VIPAS39 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction, and cholestasis 2, MIM# 613404
Review for gene: VIPAS39 was set to GREEN
Added comment: A defect in platelet alpha-granule biogenesis is a key feature of the syndrome.
Sources: Expert list
Bleeding and Platelet Disorders v0.187 VPS33B Zornitza Stark gene: VPS33B was added
gene: VPS33B was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: VPS33B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33B were set to 26399659; 16896922
Phenotypes for gene: VPS33B were set to Arthrogryposis, renal dysfunction, and cholestasis 1, MIM# 208085
Review for gene: VPS33B was set to GREEN
Added comment: Reports of life-threatening haemorrhage in the context of biopsies in ARC syndrome patients, and experimental data supporting a role of VPS33B in platelet activation.
Sources: Expert list
Bleeding and Platelet Disorders v0.183 TPM4 Zornitza Stark gene: TPM4 was added
gene: TPM4 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: TPM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TPM4 were set to 28134622; 31249973; 21153663
Phenotypes for gene: TPM4 were set to Macrothrombocytopenia
Review for gene: TPM4 was set to GREEN
Added comment: Three families reported in addition to genome-wide association studies in nearly 70,000 individuals which indicate that SNVs in TPM4 exert an effect on the count and volume of platelets.
Sources: Expert list
Bleeding and Platelet Disorders v0.179 THPO Zornitza Stark gene: THPO was added
gene: THPO was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: THPO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THPO were set to 9425899; 10583217
Phenotypes for gene: THPO were set to Thrombocythemia 1, MIM# 187950
Review for gene: THPO was set to GREEN
Added comment: Both thrombotic and bleeding episodes described with this platelet disorder.
Sources: Expert list
Bleeding and Platelet Disorders v0.165 STIM1 Zornitza Stark gene: STIM1 was added
gene: STIM1 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: STIM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: STIM1 were set to Stormorken syndrome, MIM# 185070
Review for gene: STIM1 was set to GREEN
Added comment: Well established gene-disease association, mild bleeding tendency due to platelet dysfunction and thrombocytopaenia.
Sources: Expert list
Bleeding and Platelet Disorders v0.156 SLFN14 Zornitza Stark gene: SLFN14 was added
gene: SLFN14 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: SLFN14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLFN14 were set to 26280575; 26769223
Phenotypes for gene: SLFN14 were set to Bleeding disorder, platelet-type, 20, MIM# 616913
Review for gene: SLFN14 was set to GREEN
Added comment: At least four unrelated families reported.
Sources: Expert list
Bleeding and Platelet Disorders v0.150 RUNX1 Zornitza Stark gene: RUNX1 was added
gene: RUNX1 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: RUNX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RUNX1 were set to 10508512
Phenotypes for gene: RUNX1 were set to Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399
Review for gene: RUNX1 was set to GREEN
Added comment: Well established gene-disease association.
Sources: Expert list
Bleeding and Platelet Disorders v0.145 PTPRJ Zornitza Stark gene: PTPRJ was added
gene: PTPRJ was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: PTPRJ was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPRJ were set to 30591527
Phenotypes for gene: PTPRJ were set to Thrombocytopania
Review for gene: PTPRJ was set to AMBER
Added comment: Two siblings reported with nonsyndromic thrombocytopenia characterised by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Supportive zebrafish model.
Sources: Expert list
Bleeding and Platelet Disorders v0.140 PTGS1 Zornitza Stark gene: PTGS1 was added
gene: PTGS1 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: PTGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTGS1 were set to 32299908; 11442478; 27629384 8562397
Phenotypes for gene: PTGS1 were set to Platelet dysfunction; bleeding
Review for gene: PTGS1 was set to AMBER
Added comment: Single molecularly characterised family reported. However, note at least two previous older reports where deficiency was identified at protein rather than gene level.
Sources: Expert list
Bleeding and Platelet Disorders v0.137 PRKACG Zornitza Stark gene: PRKACG was added
gene: PRKACG was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: PRKACG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKACG were set to 25061177; 30819905
Phenotypes for gene: PRKACG were set to Bleeding disorder, platelet-type, 19, MIM# 616176
Review for gene: PRKACG was set to RED
Added comment: Single family reported only. A heterozygous VOUS reported in another individual in PMID 30819905 together with several other VOUS in same individual.
Sources: Expert list
Bleeding and Platelet Disorders v0.135 PLAU Zornitza Stark gene: PLAU was added
gene: PLAU was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: PLAU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLAU were set to 20007542
Phenotypes for gene: PLAU were set to Quebec platelet disorder, MIM# 601709
Review for gene: PLAU was set to GREEN
Added comment: Note this is a tandem 78kb duplication of the gene.
Sources: Expert list
Bleeding and Platelet Disorders v0.133 PLA2G4A Zornitza Stark gene: PLA2G4A was added
gene: PLA2G4A was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: PLA2G4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLA2G4A were set to 18451993; 25102815; 23268370
Phenotypes for gene: PLA2G4A were set to Gastrointestinal ulceration, recurrent, with dysfunctional platelets, MIM# 618372
Review for gene: PLA2G4A was set to GREEN
Added comment: Sources: Expert list
Bleeding and Platelet Disorders v0.128 NBEAL2 Zornitza Stark edited their review of gene: NBEAL2: Changed publications: 21765412, 21765411, 21765413; Changed phenotypes: Gray platelet syndrome, MIM# 139090
Bleeding and Platelet Disorders v0.127 NBEAL2 Zornitza Stark gene: NBEAL2 was added
gene: NBEAL2 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: NBEAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NBEAL2 were set to Gray platelet syndrome, MIM# 139090
Review for gene: NBEAL2 was set to GREEN
Added comment: Well established gene-disease association.
Sources: Expert list
Bleeding and Platelet Disorders v0.76 FLI1 Zornitza Stark gene: FLI1 was added
gene: FLI1 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: FLI1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FLI1 were set to 24100448; 28255014; 26316623
Phenotypes for gene: FLI1 were set to Bleeding disorder, platelet-type, 21, MIM# 617443
Review for gene: FLI1 was set to GREEN
Added comment: Association with mono-allelic variants better established than bi-allelic variants.
Sources: Expert list
Bleeding and Platelet Disorders v0.74 FLII Zornitza Stark gene: FLII was added
gene: FLII was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: FLII was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FLII were set to 24100448; 28255014; 26316623
Phenotypes for gene: FLII were set to Bleeding disorder, platelet-type, 21, MIM# 617443
Review for gene: FLII was set to GREEN
Added comment: Sources: Expert list
Bleeding and Platelet Disorders v0.72 FERMT3 Zornitza Stark gene: FERMT3 was added
gene: FERMT3 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III, MIM# 612840
Review for gene: FERMT3 was set to GREEN
Added comment: Epistaxis, mucosal bleeding, defective platelet adhesion.
Sources: Expert list
Bleeding and Platelet Disorders v0.66 EPHB2 Zornitza Stark gene: EPHB2 was added
gene: EPHB2 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: EPHB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPHB2 were set to 30213874; 25370417
Phenotypes for gene: EPHB2 were set to Bleeding disorder, platelet-type, 22, MIM# 618462
Review for gene: EPHB2 was set to AMBER
Added comment: Single family and a mouse model.
Sources: Expert list
Bleeding and Platelet Disorders v0.32 ACTN1 Zornitza Stark gene: ACTN1 was added
gene: ACTN1 was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: ACTN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTN1 were set to 23434115
Phenotypes for gene: ACTN1 were set to Bleeding disorder, platelet-type, 15, MIM# 615193
Review for gene: ACTN1 was set to GREEN
Added comment: At least 6 unrelated families reported.
Sources: Expert list
Bleeding and Platelet Disorders v0.31 ACTB Zornitza Stark changed review comment from: Six unrelated individuals reported with heterozygous variants clustered in the 3'-coding region of ACTB and clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy.
Sources: Expert list; to: Six unrelated individuals reported with heterozygous variants clustered in the 3'-coding region of ACTB (exons 5 and 6) and clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy.
Sources: Expert list
Bleeding and Platelet Disorders v0.30 ACTB Zornitza Stark gene: ACTB was added
gene: ACTB was added to Bleeding Disorders. Sources: Expert list
Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTB were set to 30315159
Phenotypes for gene: ACTB were set to Syndromic thrombocytopaenia
Review for gene: ACTB was set to GREEN
Added comment: Six unrelated individuals reported with heterozygous variants clustered in the 3'-coding region of ACTB and clinical features distinct from BWCFF, including mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy.
Sources: Expert list
Bleeding and Platelet Disorders v0.22 RASGRP2 Zornitza Stark gene: RASGRP2 was added
gene: RASGRP2 was added to Bleeding Disorders. Sources: Literature
Mode of inheritance for gene: RASGRP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RASGRP2 were set to 24958846; 32609603; 32041177; 31724816; 30849270
Phenotypes for gene: RASGRP2 were set to Bleeding disorder, platelet-type, 18, MIM# 615888
Review for gene: RASGRP2 was set to GREEN
Added comment: Multiple affected families reported.
Sources: Literature
Bleeding and Platelet Disorders v0.20 GFI1B Bryony Thompson gene: GFI1B was added
gene: GFI1B was added to Bleeding Disorders. Sources: Literature
Mode of inheritance for gene: GFI1B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: GFI1B were set to 24325358; 23927492; 28041820; 11825872
Phenotypes for gene: GFI1B were set to Bleeding disorder, platelet-type, 17 MIM#187900
Review for gene: GFI1B was set to GREEN
Added comment: Three families with a heterozygous variant and one case with a homozygous variant, with supporting in vitro functional assays. A null mouse model contained erythroid and megakaryocytic precursors arrested in their development.
Sources: Literature