Submissions for variant NM_001283.5(AP1S1):c.183-2A>G

gnomAD frequency: 0.00001  dbSNP: rs751430853

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033081	SCV004241940	pathogenic	MEDNIK syndrome	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: AP1S1 c.183-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 3' canonical splicing acceptor site. These predictions were confirmed by experimental studies and the variant was found to result in alternative splicing (e.g., Montpetit_2008). The variant was found at a frequency of 2.2e-05 in 180840 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.183-2A>G has been reported in the literature in several homozygous individuals affected with MEDNIK syndrome (e.g., Montpetit_2008). This report suggests the variant is very likely to be associated with disease. At least one study has reported experimental evidence demonstrating an impact on protein function, and found that the variant was unable to rescue the mutant phenotype in a zebrafish AP1S1 knockdown model (e.g., Montpetit_2008). The following publication was ascertained in the context of this evaluation (PMID: 19057675). No ClinVar submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003574705	SCV004337514	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the AP1S1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AP1S1 are known to be pathogenic (PMID: 19057675). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with MEDNIK syndrome (PMID: 19057675, 23423674). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2-2A>G. ClinVar contains an entry for this variant (Variation ID: 39854). Studies have shown that disruption of this splice site alters AP1S1 gene expression (PMID: 19057675). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000033081	SCV000056861	pathogenic	MEDNIK syndrome	2008-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758617	SCV005354735	pathogenic	AP1S1-related disorder	2024-04-13	no assertion criteria provided	clinical testing	The AP1S1 c.183-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous state in several individuals with MEDNIK syndrome (Reported as IVS2-2A>G in Montpetit et al 2008. PubMed ID: 19057675; Martinelli D et al 2013. PubMed ID: 23423674). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.