Submission Details

RAB3GAP2 was first reported in relation to autosomal recessive Martsolf Syndrome in 2006 (Aligianis et al. PMID 16532399) and autosomal recessive Warburg Micro syndrome in 2011 (Borck et al. PMID 20967465). Martsolf syndrome and Warburg Micro syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, microcephaly, hypotonia and neurodevelopmental delay, in which Martsolf syndrome presents with a milder and Warburg Micro syndrome presents with a more severe clinical phenotype. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions. Therefore, the following disease entities: Martsolf syndrome 1 (OMIM: 212720) and Warburg micro syndrome 2 (OMIM: 614225) have been lumped into one disease entity in this curation. Eighteen variants (4 missense, 1 in-frame indel, 10 nonsense, 2 frameshift, 1 splice site) that have been reported in 8 Martsolf and 10 Warburg Micro probands in 5 publications (PMIDs: 16532399, 20967465, 23420520, 32740904, 32376645) are included in this curation; the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by biochemical function assays (PMIDs 24891604). In summary, RAB3GAP2 is definitively associated with autosomal recessive Warburg micro spectrum, a disease entity that includes both Martsolf syndrome (OMIM: 212720) and Warburg micro syndrome (OMIM: 614225). 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 Brain Malformations GCEP on November 28, 2023.