SLFN14 was first reported in relation to autosomal dominant platelet-type bleeding disorder 20 in 2015 (Fletcher et al, PMID: 26280575). The SLFN14 gene encodes an RNA endoribonuclease protein that regulates ribosomal RNA degradation. Platelet-type bleeding disorder 20 is characterized by moderate thrombocytopenia, enlarged platelets, reduce ATP secretion and aggregation in response to ADP, collagen, and protease activated receptor-1 (PAR-1) and a bleeding diathesis. Evidence supporting this gene-disease curation includes case level data and experimental data.
Summary of Case Level Data (4.25 points): Six unique missense variants have been reported in humans. Variants in this gene have been reported in at least 9 probands in 6 publications (Fletcher et al., 2015, PMID: 26280575; Marconi et al., 2016, PMID: 26769223; Saes et al., 2019, PMID: 30431218; Turro et al., 2020, PMID: 32581362; Ang et al., 2022, PMID: 36237120; Polokhov et al., 2023, PMID: 37041648). Variants in this gene segregated with disease in at least 12 additional family members.
Summary of Experimental Evidence (4 points): The gene-disease relationship is supported by expression studies (Fletcher et al., 2015, PMID: 26280575), biochemical function (Pisareva et al., 2015, PMID: 25996083), functional alteration (patient and non-patient cells) (Ver Donck et al., 2023, PMID: 36790527; Fletcher et al., 2018, PMID: 29678925; Marconi et al., 2016, PMID: 26769223), and a mouse model system (Stapley et al., 2021, PMID: 33496736).
In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This gene-disease relationship was originally curated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel using the Gene Clinical Validity Standard Operating Procedures (SOP), Version 7 and approved on May 25, 2022. This gene-disease pair was re-curated on November 4th, 2024 using Gene Clinical Validity Standard Operating Procedures (SOP), Version 11.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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