ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.854A>C (p.Glu285Ala) (rs28940279)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000002723 SCV000218961 pathogenic Spongy degeneration of central nervous system 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 285 of the aspartoacylase protein (p.Glu285Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs28940279, ExAC 0.06%). This variant has been reported as homozygous and as heterozygous in individuals affected with Canavan disease (PMID: 8252036, 8037206). This is a prevalent mutation in the Ashkenazi Jewish population with a carrier rate of 1:59 and reported evidence of disease co-segregation (PMID: 8252036, 8037206). ClinVar contains an entry for this variant (Variation ID: 2605). Experimental studies have shown that this missense change disturbs the active site architecture, leading to altered substrate binding and lower catalytic activity (PMID: 25003821). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000420704 SCV000231463 pathogenic not provided 2016-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000002723 SCV000245578 pathogenic Spongy degeneration of central nervous system 2014-10-02 criteria provided, single submitter clinical testing The p.Glu285Ala variant in ASPA is one of the most frequent pathogenic variants implicated in Canavan disease and has been reported in at least 19 Ashkenazi Jew ish individuals with the disease. Most of these individuals were homozygous (Kau l 1993). This variant has also been identified 0.04% (43/120,682) of chromosomes by the Exome Aggregation Consortium (ExAC,; dbSN P rs28940279). In vitro functional studies also provide evidence that the p.Glu 285Ala variant may impact protein function, leading to <1% of wild type enzymati c activity (Zano 2013). In summary, this variant meets our criteria to be classi fied as pathogenic for Canavan disease in an autosomal recessive manner based up on its biallelic occurrence in affected individuals and functional impact.
GeneDx RCV000420704 SCV000512105 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The E285A variant accounts for approximately 85% of disease-causing ASPA alleles in Ashkenazi Jewish patients with Canavan disease (Kaul et al. 1993). Expression studies found that E285A is associated with 0.3% of wild-type aspartoacylase enzyme activity as well as reduced thermal and conformational stability (Zano et al., 2013). The E285A variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E285A variant is a non-conservative amino acid substitution, which is likely to impact secondary 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. We interpret E285A as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000590467 SCV000694157 pathogenic Canavan Disease, Familial Form 2016-06-25 criteria provided, single submitter clinical testing Variant summary: The ASPA c.854A>C (p.Glu285Ala) variant involves the alteration of a conserved nucleotide. Glu285 is predicted to be part of the catalytic domain of aspartoacylase with the catalytic center of aspartoacylase involves a triad of Ser, His and Glu residues. 4/4 in silico tools predict a damaging outcome for this variant . Functional studies show that patients with this variant have very low enzyme activity. This variant was found in 43/120850 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000633 (42/66354). These frequencies are lower than the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). Furthermore, this variant is a commonly known AJ founder mutation in the literature. The variant has been identified in many compound heterozygous and homozygous patients in the literature. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000002723 SCV000894113 pathogenic Spongy degeneration of central nervous system 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002723 SCV000914761 pathogenic Spongy degeneration of central nervous system 2018-11-24 criteria provided, single submitter clinical testing The ASPA c.854A>C (p.Glu285Ala) missense variant has been reported in two studies in which it was found in a total of 19 individuals with Canavan disease. The p.Glu285Ala variant was identified in a homozygous state in 12 individuals, in a compound heterozygous state in two individuals and in a heterozygous state in five individuals in whom the second variant was not identified (Kaul et al. 1993; Zano et al. 2013). The p.Glu285Ala variant along with a second missense variant (p.Tyr231Ter), accounts for 98% of disease-causing alleles in the Ashkenazi Jewish population and 3% of alleles in non-Ashkenazi Jewish populations (Matalon and Michals-Matalon, 1999). The p.Glu285Ala variant was absent from 84 controls and is reported at a frequency of 0.009257 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies in vitro have shown the enzyme activity to be 0.02% of the wild type (Zano et al. 2013). Based on the collective evidence, the p.Glu285Ala 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.
OMIM RCV000002723 SCV000022881 pathogenic Spongy degeneration of central nervous system 1994-08-01 no assertion criteria provided literature only
Counsyl RCV000002723 SCV000677947 pathogenic Spongy degeneration of central nervous system 2015-06-13 no assertion criteria provided clinical testing

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