Reported by ClinVar to cause Lewy body dementia (https://www.ncbi.nlm.nih.gov/clinvar/variation/7026/). In ClinVar this variant is reported as “pathogenic” (causing this condition) by a single source, OMIM, which cites Ohtake et al 2004 (https://www.ncbi.nlm.nih.gov/pubmed/15365127).

Ohtake et al found this variant in one of 43 patients screened, and hypothesized it causes a “dominant trait with reduced penetrance or a risk factor polymorphism”. The statistical significance of this observation is unclear; this variant is moderately (but not extremely) rare: according to ExAC it is carried by roughly 1 in 1400 individuals (http://exac.broadinstitute.org/variant/5-176048219-G-T). There don’t appear to be any publications since 2004 that have studied affected patients and confirmed Ohtake et al’s hypothesis regarding this gene (SNCB) as a cause of this disease.

Moderate clinical importance, Uncertain pathogenic

dominant

In a screen of alpha-synuclein and beta-synuclein in 43 individuals with dementia with Lewy bodies, this variant was found in 1 kindred and not seen in 416 control chromosomes nor 45 sporadic Parkinson’s disease chromosomes (OR = 5.48, fisher p-value = 0.1575). This variant is conserved in rat, mouse and bovine. The index case, a Caucasian male, showed dementia onset at 61yo, motor decline at 73yo and death at 79yo. Brain tissue was used for neuropathological study and while diffuse SNCB immunoreactivity was present in a diffuse manner, it was not present in the aggregates or inclusions. A family pedigree

In this review, the authors point out that SNCB mutations are rare and have not been associated with AD Parkinson’s disease. SNCA mutations have more evidence pointing towards their toxicity.

In a functional study, B103 neuroblastoma cells were stably transfected with the P123H mutation showed abundant formation of lysosomal inclusion bodies similar to the histopathology of lysosomal storage diseases. A cell-free system showed increase aggregation properties. The overexpression of SNCA greatly stimulated the formation of these inclusion bodies.