BLOC1S3

Inheritance Pattern: AR

Disease ID:MONDO:0013560

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013560

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013560

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013560

Submitter: ClinGen

*BLOC1S3* was first reported in relation to autosomal recessive Hermansky-Pudlak syndrome 8 in 2006 (Morgan et al., PMID: 16385460). Hermansky-Pudlak syndrome 8 is a subtype of HPS, characterized by oculocutaneous albinism, bleeding diathesis and platelet dysfunction. *BLOC1S3* encodes subunit 3 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 *BLOC1S3*, 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 (5.9 points): Variants in this gene have been reported in at least 6 probands in 4 publications (PMID: 16385460, 22709368, 31064749, 32687635). The variant was found to cosegregate with disease in 5 additional individuals in 1 family (PMID: 16385460). The mechanism for disease is expected to be biallelic loss of function. The BLOC1S3 is a two exon gene with essentially 1 coding exon. Truncated transcripts are not expected to undergo NMD; however, the one published report predicts boundary-independent NMD (PMID: 22709368). Summary of Experimental Data (4 points): This gene-disease association is supported by studies of protein interaction with other subunits of BLOC-1(PMID: 15102850), functional alteration of melansome maturation (PMID: 22709368), and by the spontaneously occurring mouse mutation, “reduced pigmentation” or rp that recapitulates the HPS phenotype (PMID: 15265785). 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 pair was originally evaluated by the HT GCEP on 09/23/2020. It was reevaluated on 09/28/2022 and 03/24/2025. As a result of these reevaluations no new evidence was identified and the classification remained at Moderate (SOP Version 11).