ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1210+1G>A (rs80338820)

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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 RCV000723835 SCV000232062 pathogenic not provided 2014-06-13 criteria provided, single submitter clinical testing
Invitae RCV000020312 SCV000627137 pathogenic Metachromatic leukodystrophy 2020-08-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 7) of the ARSA gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs80338820, ExAC 0.002%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 1684088, 19021637, 16110195, Invitae). This variant is also known as c.1204+1G>A and E7S2195 in the literature. ClinVar contains an entry for this variant (Variation ID: 3058). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000723835 SCV001143056 pathogenic not provided 2019-03-14 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient and found in general population data that is consistent with pathogenicity. Predicted to negatively affect a known splice site.
Myriad Women's Health, Inc. RCV000020312 SCV001193871 pathogenic Metachromatic leukodystrophy 2019-11-11 criteria provided, single submitter clinical testing NM_000487.5(ARSA):c.1210+1G>A is classified as pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 23701968 and 1684088. Classification of NM_000487.5(ARSA):c.1210+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020312 SCV001478805 pathogenic Metachromatic leukodystrophy 2021-01-23 criteria provided, single submitter clinical testing Variant summary: ARSA c.1210+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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250804 control chromosomes. c.1210+1G>A has been reported in the literature in individuals affected with Metachromatic Leukodystrophy and has been subsequently cited by others (example, Fluherty_1991, Lugowska_2005, Lugowska_2009, Rauschka_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003204 SCV000023362 pathogenic Metachromatic leukodystrophy, juvenile type 1991-12-01 no assertion criteria provided literature only
GeneReviews RCV000020312 SCV000040687 pathologic Metachromatic leukodystrophy 2011-08-25 no assertion criteria provided curation Converted during submission to Pathogenic.

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