ClinVar Miner

Submissions for variant NM_000049.2(ASPA):c.212G>A (p.Arg71His) (rs104894553)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000363108 SCV000485710 likely pathogenic Spongy degeneration of central nervous system 2016-02-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina 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.
OMIM RCV000002734 SCV000022892 pathogenic Canavan disease, mild 2008-03-01 no assertion criteria provided literature only

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