ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.79G>A (p.Gly27Arg) (rs766328537)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169243 SCV000220518 likely pathogenic Spongy degeneration of central nervous system 2014-07-16 criteria provided, single submitter literature only
GeneDx RCV000489399 SCV000577172 pathogenic not provided 2018-01-29 criteria provided, single submitter clinical testing The G27R missense variant has previously been reported in association with Canavan disease (Kaul et al., 1996; Sistermans et al., 2000; Eke et al., 2012). Functional analysis found that G27R is associated with 3% residual enzyme activity compared to wild type (Kaul et al., 1996). The G27R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G27R 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret G27R as pathogenic.
SIB Swiss Institute of Bioinformatics RCV000169243 SCV000803603 likely pathogenic Spongy degeneration of central nervous system 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Canavan disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:8659549).
Integrated Genetics/Laboratory Corporation of America RCV000780871 SCV000918496 pathogenic Canavan Disease, Familial Form 2018-05-11 criteria provided, single submitter clinical testing Variant summary: ASPA c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 277212 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASPA causing Canavan Disease (2.9e-05 vs 0.0079), allowing no conclusion about variant significance. c.79G>A has been reported in the literature in multiple individuals affected with Canavan Disease as both a homozygous and compound heterozygous allele. It was also reported to co-segregate with family history in a recessive manner. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating enzyme activity in cell culture, which shows <10% of normal ASPA enzyme activity (Kaul_1996). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169243 SCV001208728 pathogenic Spongy degeneration of central nervous system 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 27 of the ASPA protein (p.Gly27Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs766328537, ExAC 0.02%). This variant has been observed as homozygous or in combination with another ASPA variant in several individuals affected with Canavan disease (PMID: 8659549, 10909858, 12638939, 18978679, 22611636). 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: 188888). This variant has been reported to affect ASPA protein function (PMID: 8659549). For these reasons, this variant has been classified as Pathogenic.

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