ClinVar Miner

Submissions for variant NM_000049.4(ASPA):c.854A>C (p.Glu285Ala) (rs28940279)

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Total submissions: 13
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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 2020-10-31 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 2020-06-29 criteria provided, single submitter clinical testing 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); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23233226, 25003821, 22850825, 25333069, 21228398, 8252036, 30609409, 20301412, 8037206, 31589614)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Baylor Genetics RCV000002723 SCV001163419 pathogenic Spongy degeneration of central nervous system criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002723 SCV001193950 pathogenic Spongy degeneration of central nervous system 2019-11-12 criteria provided, single submitter clinical testing NM_000049.2(ASPA):c.854A>C(E285A) is classified as pathogenic in the context of Canavan disease. Sources cited for classification include the following: PMID 8252036, 8037206 and 22850825. Classification of NM_000049.2(ASPA):c.854A>C(E285A) 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.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000002723 SCV001245018 pathogenic Spongy degeneration of central nervous system 2018-10-12 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000049.2(ASPA):c.854A>C, has been identified in exon 6 of 6 of the ASPA gene. The variant is predicted to result in a major amino acid change from glutamic acid to alanine at position 285 of the protein NP_000040.1(ASPA):p.(Glu285Ala)). The glutamic acid residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the M14 ASPA superfamily domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.8% (104 heterozygotes) and has frequently been reported in the Askenazi Jewish population in association with Canavan disease (ClinVar, Kaul R. et al. (1993), Zano S. et al. (2013), Rivas M. et al. (2018)). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
OMIM RCV000002723 SCV000022881 pathogenic Spongy degeneration of central nervous system 1994-08-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000002723 SCV001142466 likely pathogenic Spongy degeneration of central nervous system 2020-01-06 no assertion criteria provided curation NM_000049.2:c.854A>C in the ASPA gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies demonstrate that c.854A>C has disturbed the active site architecture, leading to altered substrate binding and lower catalytic activity (PMID: 25003821). Elpeleg et al reported that 18 patients with canavan disease, who are homozygous for this variant (PMID: 8037206). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as a Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3; PP3; PP4.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000420704 SCV001554326 pathogenic not provided no assertion criteria provided clinical testing The ASPA p.Glu285Ala variant is a well-known causal variant for autosomal recessive Canavan disease (CD), and is known to be associated with 84% of CD alleles in the Ashkenazi Jewish population (Matalon_1997_PMID: 10464621). This variant was identified in dbSNP (ID: rs28940279), Clinvitae, MutDB, LOVD 3.0 and ClinVar (reported as pathogenic for CD by Invitae, Emory, Partners Laboratory for Molecular Medicine, GeneDx, Counsyl and Integrated Genetics). The variant was identified in control databases in 113 of 282830 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 96 of 10370 chromosomes (freq: 0.009257), Other in 7 of 7228 chromosomes (freq: 0.000969), African in 2 of 24964 chromosomes (freq: 0.00008) and European (non-Finnish) in 8 of 129156 chromosomes (freq: 0.000062); it was not observed in the Latino, East Asian, European (Finnish), and South Asian populations. Multiple functional studies have shown the p.Glu285Ala mutation to cause loss of ASPA enzymatic activity (Hershfield_2007_PMID: 17391648; Mendes_2017_PMID: 28101991). The p.Glu285 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) suggest that the variant impacts the protein. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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