ClinVar Miner

Submissions for variant NM_000049.4(ASPA):c.634+1G>T (rs753871454)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666161 SCV000790407 pathogenic Spongy degeneration of central nervous system 2017-03-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000666161 SCV000914760 likely pathogenic Spongy degeneration of central nervous system 2017-12-05 criteria provided, single submitter clinical testing The ASPA c.634+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.634+1G>T variant has been reported in three studies and is found in a homozygous state in three unrelated probands (Rady et al. 2000; Kaya et al. 2008; Madhavarao et al. 2009). The probands were all clinically diagnosed with Canavan disease and have variable phenotypic expressivity. The variant was also identified in a heterozygous state in the unaffected parents and an unaffected sibling of one of the probands (Rady et al. 2000). Control data are unavailable for this variant, which is reported at a frequency of 0.000011 in the Total population from the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, the c.634+1G>T variant is classified as likely pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780869 SCV000918494 pathogenic Canavan Disease, Familial Form 2017-12-07 criteria provided, single submitter clinical testing Variant summary: The ASPA c.634+1G>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the complete loss of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/277022 control chromosomes at a frequency of 0.0000108, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). This variant has been reported in multiple Canavan disease patients both as homozygotes and compound heterozygotes. Taken together, this variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001093139 SCV001249974 pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Invitae RCV000666161 SCV001591755 pathogenic Spongy degeneration of central nervous system 2020-08-23 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the ASPA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs753871454, ExAC 0.006%). This variant has been observed in individual(s) with Canavan disease (PMID: 10701101, 16854607, 18978679). ClinVar contains an entry for this variant (Variation ID: 551174). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASPA are known to be pathogenic (PMID: 12638939). For these reasons, this variant has been classified as Pathogenic.
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV000666161 SCV001250604 uncertain significance Spongy degeneration of central nervous system no assertion criteria provided clinical testing

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