ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.859G>A (p.Ala287Thr) (rs774323189)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169134 SCV000220349 likely pathogenic Spongy degeneration of central nervous system 2014-05-24 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000587229 SCV000694158 pathogenic Canavan Disease, Familial Form 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The ASPA c.859G>A (p.Ala287Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The C-domain of the protein forms a pocket that accommodates the acetyl group of NAA and puts severe restriction on the size of this portion of substrate. The tight pocket is formed by residues Thr-118, Gln-184, Phe-282, Glu-285, Ala-287, and Tyr-288. Thus, p.Ala287Thr is predicted to alter the hydrogen bonding network, which may lead to destabilization of interaction between the N- and C-domain (PMID: 17194761). This variant was found in 3/120632 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). ASPA c.859G>A has been reported in numerous patients with Canavan disease. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV000169134 SCV001163420 likely pathogenic Spongy degeneration of central nervous system criteria provided, single submitter clinical testing
Invitae RCV000169134 SCV001420927 pathogenic Spongy degeneration of central nervous system 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 287 of the ASPA protein (p.Ala287Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs774323189, ExAC 0.01%). This variant has been observed in individual(s) with Canavan disease (PMID: 16854607, 26992473, 12638939). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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