GP1BA was first reported in relation to autosomal dominant platelet-type von Willebrand disease in 1991 (Miller JL, et al., 1991, PMID: 2052556). At least 7 unique variants have been reported in humans; six missense mutations, located within the VWF binding region and one 27 bp deletion in the macroglycopeptide region. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 23 probands in 18 publications (PMIDs: 26116638, 16704444, 23014764, 17916098, 26988807, 19951970, 9282797, 27683759, 14521605, 25985451, 2052556, 17264965, 15705799, 8384898, 27819553, 7833477, 17233824, 24474090). Variants in this gene segregated with disease in 31 additional family members. Platelet-type von Willebrand disease is an inherited bleeding disorder caused by heterozygous gain-of-function variants of GP1BA conferring enhanced affinity for von Willebrand factor to platelet integrin GPIbα. This disorder is characterized by a mild to moderate bleeding phenotype associated with fluctuating thrombocytopenia. This gene-disease relationship is supported by its function in primary hemostasis, binding vWF, functional alteration in patient cells (PMID: 9226170, 30655369), and a knock-in mouse model (PMID: 18187573). In summary, GP1BA is definitively associated with autosomal dominant platelet-type von Willebrand disease. 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 Bernard-Soulier Syndrome. 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.
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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