ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.960G>A (p.Trp320Ter)

gnomAD frequency: 0.00002  dbSNP: rs1375757476
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588032 SCV000696812 pathogenic Metachromatic leukodystrophy 2017-03-09 criteria provided, single submitter clinical testing Variant summary: The ARSA c.960G>A (p.Trp320X) 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. Multiple publications have cited the variant in affected individuals (varying degrees of onset: late-infantile, juvenile, and adult), who were compound heterozygotes or homozygotes, with significantly lower to nondetectable ARSA enzymatic activity. Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000588032 SCV002237778 pathogenic Metachromatic leukodystrophy 2023-08-04 criteria provided, single submitter clinical testing This variant is also known as W318X. This sequence change creates a premature translational stop signal (p.Trp320*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). This variant is present in population databases (no rsID available, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 11020646, 26553228, 30057904). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495883). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000588032 SCV002810932 pathogenic Metachromatic leukodystrophy 2022-05-13 criteria provided, single submitter clinical testing
Counsyl RCV000588032 SCV001132334 likely pathogenic Metachromatic leukodystrophy 2015-03-25 no assertion criteria provided clinical testing

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