ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1492dup (p.Arg498fs) (rs774153480)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411861 SCV000487285 likely pathogenic Metachromatic leukodystrophy 2016-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411861 SCV000916521 likely pathogenic Metachromatic leukodystrophy 2018-12-20 criteria provided, single submitter clinical testing Variant summary: ARSA c.1492dupC (p.Arg498ProfsX75) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.7e-06 in 214108 control chromosomes. c.1492dupC has been reported in the literature in two related individuals affected with Metachromatic Leukodystrophy (Lugowska_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10% of normal activity (Lugowska_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000411861 SCV001421807 pathogenic Metachromatic leukodystrophy 2019-11-09 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the ARSA gene (p.Arg498Profs*75). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acids of the ARSA protein and extend the protein by an additional 63 amino acids. This variant is present in population databases (rs774153480, ExAC 0.004%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 19021637, 26462614). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.2590_2591dupC in the literature. ClinVar contains an entry for this variant (Variation ID: 371650). This variant has been reported to affect ARSA protein function (PMID: 19021637). For these reasons, this variant has been classified as Pathogenic.

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