ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.237-2A>T (rs780936696)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169526 SCV000221003 likely pathogenic Spongy degeneration of central nervous system 2014-12-31 criteria provided, single submitter literature only
Illumina Clinical Services Laboratory,Illumina RCV000169526 SCV000401981 uncertain significance Spongy degeneration of central nervous system 2017-04-27 criteria provided, single submitter clinical testing The ASPA c.237-2A>T variant occurs in a canonical splice site and is therefore predicted to disrupt or distort the normal gene product. The c.237-2A>T variant has been reported in two studies and in two individuals with Canavan disease, including one in a compound heterozygous state and one in a heterozygous state (Zeng et al. 2002; Zeng et al. 2006). This variant was absent from 50 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Using RT-PCR analysis, Zeng et al. (2002) showed that the c.237-2A>T variant activates a cryptic splice acceptor and causes the retention of 40 nucleotides of intron 1. Due to the potential impact of splice acceptor variants and supporting evidence from the literature, the c.237-2A>T variant is classified as a variant of unknown significance but suspicious for pathogenicity for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000780870 SCV000918495 likely pathogenic Canavan Disease, Familial Form 2018-04-10 criteria provided, single submitter clinical testing Variant summary: ASPA c.237-2A>T 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 a 3 acceptor site. Zeng_2002 indicates that the variant causes the retention of 40 nucleotides that introduces new amino acids to the protein. The variant, c.237-2A>T, has been reported in the literature in individuals affected with Canavan Disease (Leone_2012, Zeng_2002, Zeng_2006). These data indicate that the variant may be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.