Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Clinical Services Laboratory, |
RCV000363108 | SCV000401980 | likely pathogenic | Spongy degeneration of central nervous system | 2017-04-27 | criteria provided, single submitter | clinical testing | The ASPA c.212G>A (p.Arg71His) variant has been reported in three studies and is found in a total of three individuals with a mild form of Canavan disease including one individual in a homozygous state and two sisters in a compound heterozygous state (Janson et al. 2006; Velinov et al. 2007). Control data are unavailable for this variant, which is reported at a frequency of 0.00197 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed only 0% to 5% of ASPA activity compared to wild type (Janson et al. 2006). Bitto et al. (2007) determined the crystal structure of APSA and showed that the Arg71 residue lies in the ASPA active site and proposed a role in substrate binding. Hershfield et al. (2007) used homology-based modeling to analyze the function of the p.Arg71His variant and also concluded that Arg71 was located in the active site and was involved in substrate binding. Expression studies in P. pastoris by Zano et al. (2013) showed that the variant enzyme had 11% of wild type activity and reduced stability. The Arg71 residue is highly conserved. Based on the evidence, the p.Arg71His variant is classified as likely pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV000363108 | SCV000960402 | pathogenic | Spongy degeneration of central nervous system | 2020-06-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 71 of the ASPA protein (p.Arg71His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs104894553, ExAC 0.2%). This variant has been observed to be homozygous or in combination with another ASPA variant in several individuals affected with Canavan disease and has been shown to segregate with disease in a family (PMID: 16437572, 18070137, 25107638). ClinVar contains an entry for this variant (Variation ID: 2616). Experimental studies have shown that this missense change abolishes ASPA enzymatic activity (PMID: 16437572, 22850825). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV000363108 | SCV001163410 | likely pathogenic | Spongy degeneration of central nervous system | criteria provided, single submitter | clinical testing | ||
| Ce |
RCV001093136 | SCV001249971 | pathogenic | not provided | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001093136 | SCV001784518 | pathogenic | not provided | 2020-02-14 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate loss of enzymatic activity (Janson CG, 2006; Zano S, 2013); This variant is associated with the following publications: (PMID: 16437572, 25107638, 18070137, 25668701, 17194761, 22850825) |
| OMIM | RCV000002734 | SCV000022892 | pathogenic | Canavan disease, mild | 2008-03-01 | no assertion criteria provided | literature only | |
| Counsyl | RCV000363108 | SCV000485710 | likely pathogenic | Spongy degeneration of central nervous system | 2018-08-29 | no assertion criteria provided | clinical testing |