PLAT

Inheritance Pattern: AR

Disease ID:MONDO:0001150

Submitter: LiferaOmics

Genetic evidence – Published PMID: 27417437 – Family 1 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 27417437 total = 1.5 Published genetic evidence total = 1.5 / 12 Genetic evidence – Our case Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied)= (1.5 − 0.5) = 1.0; Segregation = 0; Case-control =0 Family 1 total = 1.0 Our case contribution = 1.0 / 12 Total genetic evidence (published AR + our case) Published genetic evidence: 1.5 Our additional case: 1.0 Total genetic evidence = 2.5 / 12 Experimental evidence – Published PMID: 27417437 – Functional alteration evidence: Western blot in patient-derived lymphoblastoid cells demonstrated complete deficiency of t-PA, supporting loss-of-function pathogenicity. Functional alteration (patient cells) = 1.0 Gene function / biological plausibility (PLAT encodes tissue plasminogen activator; plausible relevance to severe fetal brain disruption via vascular/perfusion/thrombosis pathways) = 0.5 Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 2.5 Experimental evidence = 1.5 Overall score = 4.0 / 18

Inheritance Pattern: AR

Disease ID:MONDO:0012872

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012872

Submitter: ClinGen

*PLAT* encodes tissue-type plasminogen activator (tPA), a secreted serine protease that converts the proenzyme plasminogen to plasmin, a fibrinolytic enzyme. Increased tPA release has been reported with hyperfibrinolysis (PMID: 6401391), which manifests as excessive bleeding, while decreased release leads to hypofibrinolysis (PMID: 665314, PMID: 6890710), which can result in thrombosis or embolism. The reported hypofibrinolysis due to decreased tPA has not been confirmed to be a result of genetic variation in *PLAT* though an assertion has been made for autosomal dominant thrombophilia due to decreased release of tissue plasminogen activator. Diagnostic high-throughput sequencing of bleeding, thrombotic and platelet disorders has identified two heterozygous missense variants in patients with deep vein thrombosis (PMID: 31064749). These are rare variants of uncertain significance, which have not been functionally characterized. The biochemical function of *PLAT* in fibrinolysis (PMID: 6541693) and a homozygous null mouse model (PMID: 8133887) with increased thrombosis are consistent with the possibility of a *PLAT* related thrombophilia. Although there has been an assertion of a gene-disease relationship, the evidence is not compelling with only a few cases with non-specific phenotypes and uncharacterized missense variants. In summary, the evidence supporting the relationship between *PLAT* and autosomal dominant thrombophilia has been disputed. More evidence is needed to either support or entirely refute the role *PLAT* plays in this disease. Of note, several polymorphisms in *PLAT* have been associated with vascular t-PA release, with conflicting results, regarding their possible association with cardiovascular disease (PMIDs: 9193430, 10959683, 12891381, 12643326) however these were not considered in the curation of autosomal dominant thrombophilia. Additionally, an autosomal recessive lethal hydranencephaloly-diaphragmatic hernia syndrome has been reported in one patient with a frameshift variant in *PLAT* (PMID: 27417437), but due to differences in inheritance pattern and phenotypic variability this is considered a separate disease entity from the autosomal dominant thrombophilia and was not considered in this curation.