SNCB P123H

(SNCB Pro123His)

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.

Variant evidence
Computational	2	NBLOSUM=3, conserved residue See Ohtake H et al. 2004 (15365127), unpublished research (below).

Functional	3	Cell free assay, B103 cell lines, co-expression with SNCA See Wei J et al. 2007 (17652097).

Case/Control		OR=5.5, p-value=0.15 See Ohtake H et al. 2004 (15365127).
		OR=5.5, p-value=0.15 See Ohtake H et al. 2004 (15365127).
Familial	1	LOD of 0.6 with low penetrance See Ohtake H et al. 2004 (15365127).


Clinical importance
Severity	4	Early onset dementia and motor-skill impairment See Ohtake H et al. 2004 (15365127), Mukaetova-Ladinska EB et al. 2006 (16297436), Wei J et al. 2007 (17652097).

Treatability	2	Treatments are still in the basic-research stage See Ohtake H et al. 2004 (15365127), Wei J et al. 2007 (17652097).

Penetrance	3

Moderate clinical importance, Uncertain pathogenic

(The "moderate clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

dominant

Allele frequency

T @ chr5:176048219: 0.0% (2/10758) in EVS
Frequency shown in summary reports: 0.0% (2/10758)

Publications

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.

Genomes

Other external references

OMIM

Dementia, lewy body
www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602569

Other in silico analyses

NBLOSUM100 score = 5
GET-Evidence autoscore = 3

Edit history

Feb 23 2017 Madeleine Ball edited variant summary view
Feb 23 2017 Madeleine Ball edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited article 17652097 summary view
Apr 9 2010 Abraham Rosenbaum edited article 15365127 summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum added article 17652097 view
Apr 9 2010 Abraham Rosenbaum edited article 16297436 summary view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum added article 16297436 view
Apr 9 2010 Abraham Rosenbaum edited variant summary view
Apr 9 2010 Abraham Rosenbaum edited article 15365127 summary view
Apr 9 2010 Abraham Rosenbaum added article 15365127 view
Jan 5 2010 OMIM Importing Robot edited variant summary view
Jan 5 2010 OMIM Importing Robot added variant view

SNCB P123H - GET-Evidence