BLOC1S6 was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 9 in 2012 (Badolato et al., PMID: 22461475). Hermansky-Pudlak syndrome 9 is a subtype of HPS, characterized by oculocutaneous albinism and platelet dysfunction. BLOC1S6 encodes the coiled-coil-forming protein, Pallidin, a subunit of the Biogenesis of Lysosome-related Organelles Complex 1, BLOC-1, which is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules (PMID: 15102850). Of the 8 subunits of BLOC-1, mutations in three, including BLOC1S6, are reported in association with HPS subtypes in humans (Huizing et al., Hermansky-Pudlak Syndrome, GeneReviews). Evidence supporting this gene-disease relationship includes case-level and experimental data.
Summary of Case Level Data (9 points): Six variants (nonsense, frameshift, and missense) in this gene have been reported in at least 5 probands in 5 publications (PMID: 22461475, 29054114, 26575419, 32245340, 33543539).
The mechanism for disease is expected to be biallelic loss of function.
Summary of Experimental Data (3 points): This gene-disease association is supported by studies of protein interaction with other subunits of BLOC-1 and by the spontaneously occurring mouse mutation, “pallid” that recapitulates the HPS phenotype.
In summary, BLOC1S6 is definitively associated with autosomal recessive Hermansky-Pudlak syndrome 9. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the HT GCEP on 09/23/2020. It was reevaluated on 05/25/2022. As a result of this reevaluation, the classification changed from Moderate to Definitive due to a new case report (PMID: 33543539).
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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