ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.240dup (p.Gly81fs) (rs786204599)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169355 SCV000220726 likely pathogenic Metachromatic leukodystrophy 2014-09-23 criteria provided, single submitter literature only
Invitae RCV000169355 SCV000752525 pathogenic Metachromatic leukodystrophy 2019-08-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly81Argfs*53) in the ARSA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with metachromatic leukodystrophy (PMID: 17438611). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.234dupC in the literature. ClinVar contains an entry for this variant (Variation ID: 188976). Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169355 SCV001360438 likely pathogenic Metachromatic leukodystrophy 2019-06-04 criteria provided, single submitter clinical testing Variant summary: ARSA c.240dupC (p.Gly81ArgfsX53) 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 (e.g. c.304delC (p.Leu102fsX6), c.960G>A (p.Trp320X)). The variant allele was found at a frequency of 4.3e-06 in 232650 control chromosomes (gnomAD). c.240dupC has been reported in the literature in a compound heterozygous individual affected with Metachromatic Leukodystrophy, with another pathogenic variant in trans (Waye_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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