ClinVar Miner

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

dbSNP: rs886041911
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Total submissions: 4
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001192373 SCV001381431 pathogenic Metachromatic leukodystrophy 2023-07-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the ARSA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with metachromatic leukodystrophy (PMID: 7833949). ClinVar contains an entry for this variant (Variation ID: 928475). Studies have shown that disruption of this splice site results in exon 4 skipping and introduces a premature termination codon (PMID: 7833949). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV004590209 SCV005080967 pathogenic not provided 2024-02-17 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25525159, 27535533)
OMIM RCV002221160 SCV000023380 pathogenic Metachromatic leukodystrophy, severe 1994-01-01 no assertion criteria provided literature only

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