ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.109_116del (p.Asp37fs) (rs753415648)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670737 SCV000795630 likely pathogenic Metachromatic leukodystrophy 2017-11-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670737 SCV001360437 pathogenic Metachromatic leukodystrophy 2019-05-13 criteria provided, single submitter clinical testing Variant summary: ARSA c.109_116delGACCTGGG (p.Asp37LeufsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.304delC(p.Leu102fsX6); c.960G>A(p.Trp320X)). The variant allele was found at a frequency of 1.2e-05 in 165594 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (Draghia_1997, Virgens_2015). Three of these patients had infantile metachromatic leukodystrophy. 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. 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 RCV000670737 SCV001419379 pathogenic Metachromatic leukodystrophy 2019-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp37Leufs*36) in the ARSA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753415648, ExAC 0.01%). This variant has been observed in individual(s) with metachromatic leukodystrophy (PMID: 9090526). This variant is also referred to as 103del8bp in the literature. ClinVar contains an entry for this variant (Variation ID: 555003). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.

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