ClinVar Miner

Submissions for variant NM_000049.3(ASPA):c.693C>A (p.Tyr231Ter) (rs12948217)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000627216 SCV000230836 pathogenic not provided 2014-07-14 criteria provided, single submitter clinical testing
GeneDx RCV000627216 SCV000748203 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing The Y231X nonsense variant in the ASPA gene has been reported previously in association with Canavan disease and is a common pathogenic variant in the Ashkenazi Jewish population (Kaul et al., 1994). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. Functional analysis of Y231X found that it is associated with no detectable residual enzyme activity (Kaul et al., 1994). In summary, we interpret Y231X to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000002727 SCV000402018 pathogenic Spongy degeneration of central nervous system 2017-04-28 criteria provided, single submitter clinical testing The ASPA c.693C>A (p.Tyr231Ter) variant is a stop-gained variant and is predicted to terminate the protein prematurely. It has been reported in two studies and is found in a total of 13 individuals with Canavan disease including one in a homozygous state and 12 in a compound heterozygous state (Kaul et al. 1994; Kaul et al. 1996). All of the individuals except one were of Ashkenazi Jewish descent. Control data are unavailable for this variant, which is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Kaul et al. (1994) demonstrated a complete loss of ASPA activity when the p.Tyr231Ter variant was expressed in COS-1 cells. Based on the collective evidence, the p.Tyr231Ter 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.
Integrated Genetics/Laboratory Corporation of America RCV000588866 SCV000694156 pathogenic Canavan Disease, Familial Form 2016-05-06 criteria provided, single submitter clinical testing Variant summary: The ASPA c.693C>A variant is a nonsense mutation resulting in a premature termination codon. It is predicted to cause a truncated or absent ASPA protein, which is a commonly known mechanism for disease. Mutation taster predicts damaging outcome for this variant. This variant is found in 7/121216 control chromosomes at a frequency of 0.0000577, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). It was reported in several Canavan Disease patients in either homozygosity or in compound heterozygosity with pathogenic ASPA alleles indicating pathogenicity. A functional study demonstrated the variant to result in complete loss of ASPA activity, further supporting a disease causing impact In addition, clinical diagnostic laboratories and reputable databases classify variant as Pathogenic. Moreover, the variant is known to account for 14.8% of the disease alleles in Ashkenazi Jewish patients. Taken together, this variant was classified as Pathogenic.
Invitae RCV000002727 SCV000262467 pathogenic Spongy degeneration of central nervous system 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 231 (p.Tyr231*) of the ASPA gene. It is expected to result in an absent or disrupted protein product. This variant is clearly defined as a Canavan disease causative allele (PMID: 8023850, 8659549, 10909858). It is a common cause of Canavan disease in individuals of Ashkenazi Jewish ancestry. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000002727 SCV000245579 pathogenic Spongy degeneration of central nervous system 2014-10-20 criteria provided, single submitter clinical testing The p.Tyr231X variant in ASPA has been reported in numerous individuals with Canavan disease (Kaul 1994) and is one of the most common disease-causing ASPA variants in the Ashkenazi Jewish population. It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 231 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Canavan disease in an autosomal recessive manner.
OMIM RCV000002727 SCV000022885 pathogenic Spongy degeneration of central nervous system 1998-11-01 no assertion criteria provided literature only

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