ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.212G>A (p.Arg71His) (rs104894553)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
CeGaT Praxis fuer Humangenetik Tuebingen RCV001093136 SCV001249971 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
GeneDx 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

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