Submissions for variant NM_000049.4(ASPA):c.237-2A>T

gnomAD frequency: 0.00002  dbSNP: rs780936696

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000169526	SCV000401981	pathogenic	Spongy degeneration of central nervous system	2024-02-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780870	SCV000918495	pathogenic	Canavan Disease, Familial Form	2021-02-21	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: Three predict the variant abolishes a 3' acceptor site. At least one publication reported experimental evidence, confirming that this variant affects mRNA splicing, and results in the retention of 40 intronic nucleotides (Zeng_2002). The variant was absent in 249854 control chromosomes. c.237-2A>T has been reported in the literature in individuals affected with Canavan Disease and subsequently cited by others (example, Zeng_2002, Zeng_2006, Leone_2012), and in one of these reports patient derived fibroblasts were indicated to have very low (<4% wild type) aspartoacylase activities (Leone_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the clinical reports, predicted translational impact bolstered by splicing evidence and reduced enzyme activity levels as evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000169526	SCV002033273	likely pathogenic	Spongy degeneration of central nervous system	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000169526	SCV002060264	likely pathogenic	Spongy degeneration of central nervous system	2021-11-16	criteria provided, single submitter	clinical testing	NM_000049.2(ASPA):c.237-2A>T is a canonical splice variant classified as likely pathogenic in the context of Canavan disease. c.237-2A>T has been observed in cases with relevant disease (PMID: 12638939, 16854607). Functional assessments of this variant are available in the literature (PMID: 12638939). c.237-2A>T has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000049.2(ASPA):c.237-2A>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169526	SCV002309082	likely pathogenic	Spongy degeneration of central nervous system	2023-03-04	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189114). This variant is also known as IVS1-2A>T. Disruption of this splice site has been observed in individual(s) with Canavan disease (PMID: 12638939, 16854607, 23253610). This variant is present in population databases (rs780936696, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 1 of the ASPA 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 ASPA are known to be pathogenic (PMID: 12638939). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000169526	SCV004201738	pathogenic	Spongy degeneration of central nervous system	2023-08-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169526	SCV002093192	pathogenic	Spongy degeneration of central nervous system	2017-03-17	no assertion criteria provided	clinical testing