HPS1 was first reported in relation to Autosomal Recessive Hermasky-Pudlak syndrome 1 in 1996 (Oh et al., PMID: 8896559). At least 36 unique variants including missense, in-frame indel, nonsense, frameshift, and large deletions have been reported in humans. HPS1 is involved in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Hermansky-Pudlak syndrome 1 is characterized by severe oculocutaneous albinism and a bleeding diathesis, but in some cases, also pulmonary fibrosis and granulomatous colitis. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data: 12 Points Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 8896559, 9497254, 9705234, 27593200). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The mechanism for disease is homozygous loss of function (PMID: 9256466)
Summary of Experimental Data: 5.5 Points This gene-disease association is supported by mouse models and in vitro functional assays. The "pale ear" or ep mouse that carries a spontaneously occurring mutation in Hps1 recapitulates the human HPS phenotype (PMID: 9256466, 9158155). HPS1 interacts with HPS4 to form BLOC-3, which is involved in the biogenesis of lysosome-related organelles (PMID: 12847290, 29190429, 25468649).
In summary, HPS1 is definitively associated with Autosomal Recessive Hermasky-Pudlak syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on June 26, 2019 (SOP Version 6).
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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