ClinVar Miner

Submissions for variant NM_001321336.1(SPATA22):c.-74+14393_-74+14396del (rs766720790)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409212 SCV000487300 likely pathogenic Spongy degeneration of central nervous system 2016-11-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000409212 SCV000711750 likely pathogenic Spongy degeneration of central nervous system 2016-07-13 criteria provided, single submitter clinical testing The p.Glu293fs variant in ASPA has been reported in 3 individuals with Canavan d isease, including at least one compound heterozygote (Kaul 1996). This variant h as been identified in 1/66340 of European chromosomes by the Exome Aggregation C onsortium (ExAC, In vitro assays suggest that t his variant abolished ASPA protein activity (Kaul 1996); however, these types of assays may not accurately represent biological function. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 293 and leads to a premature termination codon 8 amino acids dow nstream. This termination codon occurs within the last exon and is more likely t o escape nonsense mediated decay (NMD) and result in a truncated protein. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Glu293fs variant is likely pathogenic.
Invitae RCV000409212 SCV001230214 pathogenic Spongy degeneration of central nervous system 2019-04-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ASPA gene (p.Glu293Leufs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acids of the ASPA protein. This variant is present in population databases (rs766720790, ExAC 0.002%). This variant has been observed in an individual with Canavan disease (PMID: 8659549). 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: 371665). This variant has been reported to substantially reduce the enzymatic activity of the ASPA protein in cell culture (PMID: 8659549). This variant disrupts the p.Ala305 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8023850, 22850825, 10909858, 16217711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Natera Inc RCV000409212 SCV001190706 pathogenic Spongy degeneration of central nervous system 2019-05-20 no assertion criteria provided clinical testing

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