ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.304del (p.Leu102fs) (rs786204673)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169476 SCV000220922 likely pathogenic Metachromatic leukodystrophy 2014-11-26 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169476 SCV000918482 pathogenic Metachromatic leukodystrophy 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The ARSA c.304delC (p.Leu102CysfsX6) variant results in a premature termination codon, predicted to cause a truncated or absent ARSA 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.960G>A/Trp320X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 190968 control chromosomes. It has been reported in at least one late-infantile metachromatic leukodystrophy patient as a compound heterozygote, and this patient had a residual arylsulfatase A (ARSA) activity <10% of WT level (Kreysing_1993). In addition, one other clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169476 SCV001592680 pathogenic Metachromatic leukodystrophy 2020-05-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu102Cysfs*6) 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 in individual(s) with metachromatic leukodystrophy (PMID: 8101038). ClinVar contains an entry for this variant (Variation ID: 189073). 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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