Submissions for variant NM_003085.5(SNCB):c.368C>A (p.Pro123His)

gnomAD frequency: 0.00021  dbSNP: rs104893937

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
DASA	RCV000007441	SCV002073741	likely pathogenic	Lewy body dementia	2022-02-05	criteria provided, single submitter	clinical testing	The c.368C>A;p.(Pro123His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7026; OMIM: 602569.0002; PMID: 15365127) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21045828) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Synuclein) - PM1. The variant is present at low allele frequencies population databases (rs104893937 – gnomAD 0.002037%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is likely pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV002223754	SCV002502653	uncertain significance	not provided	2022-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944805	SCV004761672	pathogenic	SNCB-related disorder	2023-12-30	criteria provided, single submitter	clinical testing	The SNCB c.368C>A variant is predicted to result in the amino acid substitution p.Pro123His. This variant was reported in individuals with dementia with Lewy bodies (Ohtake et al. 2004. PubMed ID: 15365127, family study). A functional study showed that transgenic mice expressing this variant developed progressive neurodegeneration (Fujita et al. 2010. Pubmed ID: 21045828). Other studies elaborated on the mechanism of this variant (Janowska et al 2015. PubMed ID: 26332674; Psol et al. 2021. PubMed ID: 33760043). However, family segregation study shows that this variant does not produce a disease phenotype in all individuals suggesting reduced penetrance for this variant (Ohtake et al. 2004. PubMed ID: 15365127).This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-176048219-G-T). This variant is interpreted as pathogenic.
OMIM	RCV000007441	SCV000027641	pathogenic	Lewy body dementia	2004-09-14	no assertion criteria provided	literature only
GenomeConnect - Brain Gene Registry	RCV000007441	SCV004012814	not provided	Lewy body dementia		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.