Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
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, |
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. |
Ce |
RCV001093139 | SCV001249974 | pathogenic | not provided | 2018-04-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000666161 | SCV001591755 | pathogenic | Spongy degeneration of central nervous system | 2023-10-07 | 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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASPA are known to be pathogenic (PMID: 12638939). This variant is present in population databases (rs753871454, gnomAD 0.003%). Disruption of this splice site has been observed in individuals 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. For these reasons, this variant has been classified as Pathogenic. |
Genome- |
RCV000666161 | SCV002033129 | pathogenic | Spongy degeneration of central nervous system | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000666161 | SCV002060241 | pathogenic | Spongy degeneration of central nervous system | 2021-11-08 | criteria provided, single submitter | clinical testing | NM_000049.2(ASPA):c.634+1G>T is a canonical splice variant classified as pathogenic in the context of Canavan disease. c.634+1G>T has been observed in cases with relevant disease (PMID: 10701101, 33547378). Functional assessments of this variant are not available in the literature. c.634+1G>T has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000049.2(ASPA):c.634+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000666161 | SCV002072985 | pathogenic | Spongy degeneration of central nervous system | criteria provided, single submitter | clinical testing | The splice donor variant c.634+1G>T in ASPA (NM_000049.4) has been reported previously in affected patients (Rady et al, 2000; Kaya et al, 2008; Madhavarao et al, 2009). It has been submitted to ClinVar as Pathogenic. The c.634+1G>T variant is observed in 1/30,538 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The variant affects an invariant splice nucleotide and is predicted to cause loss of function. Loss of function variants have been reported to be disease causing in ASPA gene. For these reasons, this variant has been classified as Pathogenic. | |
Baylor Genetics | RCV000666161 | SCV004201904 | pathogenic | Spongy degeneration of central nervous system | 2023-01-05 | criteria provided, single submitter | clinical testing | |
Myelin Disorders Clinic- |
RCV000666161 | SCV001250604 | uncertain significance | Spongy degeneration of central nervous system | no assertion criteria provided | clinical testing | ||
Natera, |
RCV000666161 | SCV002093206 | pathogenic | Spongy degeneration of central nervous system | 2017-03-17 | no assertion criteria provided | clinical testing |