Submission Details

GP1BA was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1991 (Ware et al., PMID: 2308962). At least 45 unique variants (e.g. missense, nonsense, and frameshifts) have been reported in humans (PMID: 24934643). The unifying feature of all of the mutations is the ability of the mutation to disrupt the assembly and/or function of a surface-expressed GP Ib-IX-V complex. How individual mutations affect complex assembly or surface expression can be variable. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 10 publications (PMIDs: 9326230, 11054083, 16788318, 7873390, 19448529, 9639514, 7949089, 7579348, 17083647, 21993687). Variants in this gene segregated with disease in 6 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease association is supported by its biochemical function in the GP1b platelet receptor for VWF (PMID: 10669163), its interaction with GP1BB (PMID: 808914), a knock-out animal model (PMID: 10706630), and rescue of the animal model with wildtype GP1BA (PMID: 10706630, 22044935). In summary, GP1BA is definitively associated with autosomal recessive Bernard-Soulier syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Of note, this gene has also been implicated in autosomal dominant Bernard-Soulier syndrome (MONDO:0007930) characterized predominantly by macrothrombocytopenia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found interfamilial phenotypic variability is observed between individuals harboring the same genetic variant between different inheritance patterns and the difference in the inheritance pattern for the disease entities is representative of a continuum of disease, i.e. mild carrier phenotypic features are observed in recessive disease (PMID: 25370924). Thus the disease entities were lumped and the well-established autosomal recessive inheritance pattern has been curated here; additional mono-allelic manifestations have also been reported (PMIDs: 21933849, 18815197, 26849716, 16519708, 7690774).

Additionally, this gene has also been implicated in platelet-type von Willebrand disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (gain of function vs. loss of function), inheritance pattern (autosomal dominant vs. predominantly autosomal recessive), and phenotypic variability. Therefore, we have split curations for the disease entities platelet-type von Willebrand disease and Bernard-Soulier Syndrome; these gene-disease relationships have been assessed separately.