ClinVar Miner

Submissions for variant NM_000049.4(ASPA):c.914C>A (p.Ala305Glu) (rs28940574)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000489986 SCV000231464 pathogenic not provided 2014-07-14 criteria provided, single submitter clinical testing
Invitae RCV000002725 SCV000544590 pathogenic Spongy degeneration of central nervous system 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 305 of the ASPA protein (p.Ala305Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs28940574, ExAC 0.04%). This variant is the most common mutation for Canavan disease in non-Jewish population. It has been reported as homozygous or compound heterozygous in multiple affected individuals (PMID: 8023850, 22850825, 10909858, 16217711). ClinVar contains an entry for this variant (Variation ID: 2607). Experimental studies have shown that this variant causes loss of ASPA enzyme activity in vitro (PMID: 22750302, 8023850). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000489986 SCV000577185 pathogenic not provided 2017-04-07 criteria provided, single submitter clinical testing The A305E missense variant has been reported in association with Canavan disease (Kaul et al., 1994;Kaul et al., 1996). The A305E variant accounts for 20-60% of disease-causing ASPA alleles innon-Ashkenazi Jewish individuals (Kaul et al., 1994; Shaag et al., 1995). Functional analysis revealedthat A305E is associated with 10% residual enzyme activity compared to wild type (Zano et al.,2013). The A305E variant is a non-conservative amino acid substitution, which is likely to impactsecondary protein structure as these residues differ in polarity, charge, size and/or other properties.This substitution occurs at a position that is conserved across species. In silico analysis predicts thisvariant is probably damaging to the protein structure/function. In summary, we interpret A305E aspathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588914 SCV000694159 pathogenic Canavan Disease, Familial Form 2017-03-23 criteria provided, single submitter clinical testing Variant summary: The ASPA c.914C>A (p.Ala305Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. These predictions are supported by a functional study, Kaul_1994, that indicates the variant eliminates ASPA enzyme activity in COS1 transfected cells. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 27/117066 (1/4336), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASPA variant of 1/126. The variant of interest has been reported in multiple affected individuals, both homozygotes and compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000002725 SCV000894114 pathogenic Spongy degeneration of central nervous system 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002725 SCV000914762 pathogenic Spongy degeneration of central nervous system 2018-01-26 criteria provided, single submitter clinical testing The ASPA c.914C>A (p.Ala305Glu) variant is frequently reported in non-Jewish individuals with Canavan disease (CD). Across a selection of the available literature, the p.Ala305Glu variant has been identified in a homozygous state in eight patients with severe CD, in a compound heterozygous state in five patients with mild to classic CD, and in a heterozygous state in 13 patients in whom a second variant was not identified (Kaul et al. 1994; Shaag et al. 2005; Yalcinkaya et al. 2005; Janson et al. 2006; Sarret et al. 2015; Merrill et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000372 in the European (non-Finnish) population of the Genome Aggregation Database. Cultured fibroblasts from affected individuals demonstrated negligible (0-5%) ASPA enzymatic activity as compared to fibroblasts from healthy controls (Yalcinkaya et al. 2005; Janson et al. 2006). Significantly reduced ASPA activity was also confirmed in various cell lines (Kaul et al. 1994; Janson et al. 2006; Sommer et al. 2012; Zano et al. 2013). Based on the collective evidence, the p.Ala305Glu variant is classified as pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000002725 SCV000996252 pathogenic Spongy degeneration of central nervous system 2019-02-22 criteria provided, single submitter clinical testing This established pathogenic variant has been previously reported as a homozygous and compound heterozygous change in patients with Canavan Disease (PMID: 20301412, 8023850, 10909858). Experimental studies have shown that this variant causes loss of ASPA enzyme activity (PMID: 22750302, 8023850). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (57/282352) and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.914C>A (p.Ala305Glu) variant is classified as pathogenic.
Baylor Genetics RCV000002725 SCV001163421 pathogenic Spongy degeneration of central nervous system criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002725 SCV001194081 pathogenic Spongy degeneration of central nervous system 2019-11-12 criteria provided, single submitter clinical testing NM_000049.2(ASPA):c.914C>A(A305E) is classified as pathogenic in the context of Canavan disease and can be associated with a severe or mild form of the disease. Sources cited for classification include the following: PMID 22850825, 22750302, 8023850 and 7668285. Classification of NM_000049.2(ASPA):c.914C>A(A305E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000002725 SCV000022883 pathogenic Spongy degeneration of central nervous system 1995-09-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000002725 SCV000536877 pathogenic Spongy degeneration of central nervous system 2015-10-03 no assertion criteria provided research
Myriad Women's Health, Inc. RCV000002725 SCV000678170 pathogenic Spongy degeneration of central nervous system 2015-06-06 no assertion criteria provided clinical testing

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