ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.854+1G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192373 SCV001360436 pathogenic Metachromatic leukodystrophy 2019-01-25 criteria provided, single submitter clinical testing Variant summary: ARSA c.854+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. A functional study, Pastor-Soler_1994, supports these predictions and found the variant to cause a deletion of exon 4. The variant was absent in 243414 control chromosomes (gnomAD). c.854+1G>A has been reported in the literature in multiple homozygous individuals affected with Metachromatic Leukodystrophy (Pastor-Soler_1994). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001192373 SCV001381431 likely pathogenic Metachromatic leukodystrophy 2019-06-26 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the ARSA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ARSA-related conditions. 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 ARSA are known to be pathogenic (PMID: 8962139, 10477432). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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